By Kristin Gilmour BHSc (Nat)

TECHNICAL INFORMATION

FEVERFEW ( ) OPTIMALRx P 1300 889 483 W E

FOR PRACTITIONER REFERENCE ONLY Botanical Name: Tanacetum parthenium Common Name: Feverfew Botanical Family: Part Used: Aerial Parts Dosage: 5ml to 15ml per week of a 1:5 liquid extract Synonyms: Chrysanthemum parthenium, Matricaria parthenium, Pyrethrum parthenium1,2,3

Common Names: Altamisa (Spanish), Bachelor’s Buttons, Camomille Grande (French), Grande, Chrysanthemum Atricaire, European Feverfew, Federfoy, Feverfew, Featherfew, Feather Few, Feather-Fully, Featherfoil, Feddygen Fenyw (Welsh), Flirtroot, Flirtwort, Febrifuge , Grande Chamomile, Matrem (Danish), Midsummer Daisy, Mother Herb, Mutterkraut (German), Nosebleed, Parthenolide, Pyrethrum, Santa Maria, Vetter-Voo, Wild Chamomile, Wild Quinine1,3,4

Taste: Bitter, sour5

Thermal Properties: Cooling5

Actions: t Analgesic t Antioxidant t Anthelmintic t Antiparasitic t Antiallergy t Antispasmodic t Antibacterial t Bitter tonic t Anticancer t Emmenagogue (in high doses) t Antifibrotic t Gastroprotective t Antifungal t Hepatoprotective t Anti-inflammatory t Renoprotective t Antinociceptive

Indications: t Allergy (e.g. asthma, hayfever, urticaria) t Arthritis t Bacterial infections o Gram-positive bacteria: Bacillus cereus var. mycoides, Bacillus megaterium, Bacillus subtilis, Micrococcus lysodeikticus, Staphylococcus albus, Staphylococcus aureus, Staphylococcus epidermidis o Gram-negative bacteria: Escherichia coli, Klebsiella pneumoniae, Shigella flexneri, Vibrio fischeri o Mycobacteria: Mycobacterium spp. t Bone destructive disorders t Chemoprevention/adjunct to cancer therapy t Fever t Fungal infections o Aspergillus niger, Candida albicans, Candida krusei t Gastrointestinal disorders (e.g. atonic dyspepsia) t Headache t Inflammatory disorders (e.g. autoimmune disease, rheumatoid arthritis) t Migraine (prophylaxis and treatment) t Kidney injury

2 t Liver disease t Skin conditions involving inflammation and oxidative stress (e.g. acne, dermatitis, eczema, psoriasis, photoageing) t Parasitic infections o Leishmania amazonensis, Trypanosoma cruzi

Traditional Use: The genus Tanacetum contains medicinal herbs belonging to the Asteraceae family, which is commonly referred to as the aster, daisy, or sunflower family6. From this genus, Feverfew (Tanacetum parthenium) is a medicinal plant that has been used for centuries as a febrifuge, hence its common name7. Interestingly, the origin of the Latin species name, parthenium, has been ascribed by the ancient Greek author Plutarch to an incident where Feverfew was administered to save the life of someone who had fallen from the Parthenon during its construction in the 5th century B.C.7. An alternative origin comes from the Greek word ‘parthena’, which means ‘virgin’, presumably because of the reputation of the herb as a medicinal antidote for women’s ailments. This therapeutic use is additionally reflected both in a Germanic name for the plant, ‘mutterkraut’ (meaning mother herb), and in the Welsh ‘feddygen fenyw’ (meaning woman’s plant)7. Feverfew has also been termed ‘Featherfew’, due to its feathery leaves4. Feverfew is a short, bushy, aromatic perennial with yellow-green leaves and flowers that resemble those of Chamomile (Matricaria recutita); comprising a single layer of white outer florets with a yellow centre4.

Medicinally, Feverfew has a long tradition of use in folk medicine, especially among early European herbalists4. Since ancient times Feverfew has been prescribed for the treatment of a wide range of disorders including; rheumatism/arthritis, headache, toothache, earache, tinnitus, vertigo, dizziness, melancholy, nervous debility, the excessive use of opium, coughs and colds, fever, psoriasis, dermatitis, insect bites, worm infestation, asthma, allergies, stomach ache, atonic dyspepsia, wind, colic, constipation, nausea, spasms, swelling, menstrual disorders, threatened miscarriage, for aiding the ejection of afterbirth and stillbirths, for strengthening the womb, and for cleansing the kidneys and bladder4,7,8. Eclectic physicians recommended infusions of Feverfew in water and especially in alcohol. They regarded Feverfew as a tonic that influenced the entire gastrointestinal tract, increased appetite, improved digestion, promoted secretion, and acted upon the renal and cutaneous (skin) functions9. Moreover, infusions of Feverfew have been traditionally prescribed to purge choler (yellow bile), phlegm, and melancholy (black bile); three of the four humors of ancient and medieval physiology. When present in excess, choler was thought to cause anger and irritability, while excess phlegm was believed to cause lethargy and

3 passivity, and excess melancholy was thought to aggravate moodiness and sadness. Sixteenth century herbalist Nicholas Culpeper stated that, “the powder of the herb taken in wine, with some Oxymel, purges both choler and phlegm, and is available for those that are short-winded, and are troubled with melancholy and heaviness, or sadness of spirits”10. Elizabethan herbalist John Gerard echoed this sentiment, writing that “Feverfew dried and made into pouder, and two drams of it taken with hony or sweet wine, purgeth by siege melancholy and flegme; wherefore it is very good for them that are giddie in the head, or which have the turning called vertigo, that is, a swimming and turning in the head. Also it is good for such as be melancholike, sad, pensive, and without speech”11. Gerard also recommends Feverfew for the alleviation of St Anthony’s fire (a very painful burning sensation in the arms and legs caused by excessive exposure to ergotamines), and all inflammations and hot swellings7,11. Likewise, 1st century Greek physician, Dioscorides, prescribed Feverfew for “all hot inflammations” and to prevent or reduce fevers4. Consequently, Feverfew has been referred to as ‘medieval aspirin’4,7.

Clinical Tip: For the management of fevers, a tincture combination of Feverfew, Echinacea (Echinacea angustifolia), and Cayenne (Capsicum annuum) has been recommended in North American texts3.

Traditional Applications of Feverfew in and America4,5,7,8 Body System Traditional Use Cardiovascular System Cardiotonic activity Female Reproductive Emmenagogue activity, menstrual cramps, menstrual disorders, menstrual tonic System for strengthening the womb, morning sickness, threatened miscarriage Gastrointestinal System Atonic dyspepsia, bitter tonic activity, colic, constipation, intestinal parasites, nausea, poor appetite, stomach ache, wind Immune System Allergies, inflammations, insect bites, fever, worm infestation Integumentary System Dermatitis, psoriasis Musculoskeletal System Joint pain, rheumatism/arthritis, spasms, swelling Nervous System Dizziness, earache, headache, irritability, melancholy, nervous debility, the excessive use of opium, tinnitus, toothache, vertigo Renourinary System Cleansing the kidneys and bladder, kidney pain Respiratory System Asthma, coughs and colds

The more recent surge of interest in Feverfew’s medicinal properties can be traced back to newspaper reports in the late 1970s, mainly emanating from Wales, that patients were successfully using the herb in the prophylaxis of both migraines and arthritis7. These observations were in line with previous historical texts. Eighteenth century herbalist John Hill reported of Feverfew that, “in the worst headache this herb exceeds whatever else is known”7. Furthermore, Culpeper advocated Feverfew’s topical benefit in head pain, stating that Feverfew “is very effectual for all pains in the head coming from a cold cause, the herb being bruised and applied to the crown of the head”10. Subsequently, Feverfew has become renowned for its ability to alleviate migraine headaches.

Clinical Note: The first modern, public account of Feverfew’s use in migraine prevention appeared in 1978 in the British Health Magazine, Prevention. The story concerned a Welsh female patient who had suffered from severe migraines since 16 years of age. At 68 years of age, this woman took the advice of a friend, which was supposedly based on the recommendation of a traditional Welsh healer, and began ingesting three fresh leaves of Feverfew daily. After ten months her migraines ceased completely and did not return as long as she continued the Feverfew4.

4 Phytochemistry: The phytochemistry of Feverfew is well defined4. Feverfew contains many sesquiterpene lactones, with a high concentration of parthenolide (comprising up to 85% total sequiterpene content). There appears to be more parthenolide in the flower heads of Feverfew than in the leaves, and there is none present in the stems4,12. Parthenolide has displayed significant anti-inflammatory and anticancer activity in vitro and in vivo. Due to results from clinical trials, a minimum 0.2% parthenolide content is generally recommended for herbal medicines used in the prevention of migraine headaches. Although parthenolide is known as a key bioactive constituent of Feverfew, preclinical studies show that parthenolide is not solely responsible for Feverfew’s pharmacological activity and that other constituents play a significant role13,14,15,16,17. Both lipophilic compounds and hydrophilic compounds are thought to contribute to the bioactivity of Feverfew16,17. Further to these constituents, it has been ascertained that the flowering aerial parts of Feverfew contain approximately 0.02%-0.07% volatile oils such as l-camphor, l-borneol, terpenes, and miscellaneous esters18,19,20,21. In addition to sesquiterpene lactones and volatile oils, Feverfew contains a broad variety of flavonoids, including kaempferol, quercetin, apigenin, luteolin, chrysoeriol, tanetin, santin, jaceidin, and centaureidin. These phytochemicals are thought to be significant contributors to the documented antioxidant and anti-inflammatory activity of Feverfew13,15,17. Trace amounts of the hormone melatonin have also been detected in leaf samples of Feverfew (1.37mcg/g- 2.45mcg/g) and in a commercially available product (0.57mcg/g)2.

Clinical Note: Parthenolide, although a key bioactive constituent, is not solely responsible for the therapeutic effects of Feverfew. Feverfew extracts containing no parthenolide have been shown to exhibit anti-inflammatory and antioxidant activity, andadditionally many other isolated constituents have shown bioactivity in preclinical trials. Therefore, it is misleading to focus exclusively on one constituent, as the whole plant part extract is synergistic and elicits therapeutic activity.

Research: Migraine headache: Traditionally, Feverfew has been valued for the treatment and prevention of headaches. A 1983 survey found that 70% of 270 migraine sufferers who had eaten Feverfew leaves daily for prolonged periods of time claimed that the herb decreased the frequency and/or intensity of their attacks22. Consequently, Feverfew’s growing popularity in the 1980s in the United Kingdom led researchers to examine its effectiveness in controlled clinical trials. In 1985, the first double-blind clinical trial investigating Feverfew in migraine prophylaxis was published22. This randomised, double-blind, placebo-controlled trial involved 17 participants who had suffered from classical or common migraines for at least two years and who, for at least three months prior to the study, ate fresh leaves of Feverfew daily as prophylaxis against migraine. Eight of the study participants received capsules containing freeze-dried Feverfew leaf powder (50mg daily dose) and the other nine participants received placebo capsules. Participants were instructed to take their capsules every morning with food for six periods of four weeks. They were instructed to treat acute attacks of migraine with soluble aspirin or their usual drug. Those who received placebo experienced a significant increase in the frequency and severity of headache, nausea, and vomiting during the early months of withdrawal (p<0.05). The group given Feverfew capsules showed no change in the frequency or severity of symptoms of migraine, demonstrating prophylaxis efficacy22. Since this early study, numerous clinical trials have been conducted to further elucidate the role of Feverfew in migraine prevention and treatment, the results of which have been assessed in three meta-analyses23,24,25. The first two of these reviews determined that the majority of studies show Feverfew extracts to be superior to placebo for decreasing the frequency and severity of migraine headaches, although some of the studies were of low methodological quality and efficacy was not proven beyond a reasonable doubt24,25.

5 Both the 1998 systematic review of five randomised, double-blind, placebo-controlled trials, and the 2000 systematic review of six randomised, double-blind, placebo-controlled trials concluded that the evidence favours Feverfew as an effective and well-tolerated preventative treatment against migraine headache24,25. Following this, a 2004 Cochrane review of evidence from randomised, double-blind, placebo-controlled clinical trials was inconclusive in establishing the efficacy of Feverfew for preventing migraine headaches23. A total of five trials published up to 2002 and involving a total of 343 patients met the inclusion criteria of this review22,26,27,28,29. Results from the meta-analysis reported insufficient evidence to conclude whether Feverfew was superior to placebo in reducing the frequency and severity of migraine attacks. Dosage extracts, administration, and methodological quality varied in the trials, and thus may have been a reason for the mixed results23. After this review was published, further studies of Feverfew in migraine prophylaxis have been conducted and have reported positive results30.

Clinical trials investigating Feverfew for migraine prophylaxis Year Study Extract, Dose & Study Design Results Notes Population Duration 198522 17 patients Patients either Randomised, Prior to this trial, the Small sample size. suffering received capsules double-blind, reduction in frequency from classical containing freeze- placebo-controlled and severity of migraines The Feverfew users or common dried Feverfew leaf clinical study. during self-medication included in this migraines for at powder 50mg daily with Feverfew was study exhibited least two years (n=8) or placebo significant for both normal biochemical and who, for at capsules daily (n=9) groups. During the trial, and haematological least three months for six periods of four those who received parameters, prior to the study, weeks. placebo experienced a demonstrating the ate fresh leaves significant increase in the safety of longer-term of Feverfew daily frequency and severity administration of the as prophylaxis of headache, nausea, and plant. against migraine. vomiting during the early months of withdrawal Furthermore, in this trial (p<0.05). The group fewer adverse events were given continued Feverfew reported in the Feverfew treatment in the form of group than in the placebo freeze-dried Feverfew group. leaf capsules showed no change in the frequency Due to severe migraine or severity of symptoms of attacks, two patients migraine, demonstrating in the placebo group prophylaxis efficacy. withdrew from the study to resume treatment with raw Feverfew leaves, which they found prevented any further attacks.

6 Year Study Extract, Dose & Study Design Results Notes Population Duration 198829 59 patients After one month Randomised, Feverfew was associated There were no adverse with classical or single-blind placebo double-blind, with a 24% reduction effects reported. common migraine, run-in, patients placebo-controlled, in the mean number of 17 of whom had received either crossover clinical migraine attacks and a Although there was previously tried freeze-dried study. significant reduction in no washout period Feverfew. powdered Feverfew the degree of nausea between Feverfew and capsules (averaging and vomiting (p<0.02) placebo treatments, 82mg, 2.2mmol for each two month patients receiving parthenolide) or assessment period. placebo after Feverfew placebo for four There was also a non- did not experience less months. Patients significant trend (p=0.06) deterioration compared were then crossed towards a reduction in to the placebo levels over to the other the severity of attacks, from the first phase of treatment for four although there was no the trial. This indicated months. change in the duration of that there were no severe individual attacks. Visual withdrawal symptoms analogue scores were also from the Feverfew. significantly improved in the Feverfew group (p<0.0001).

199431 20 patients Patients either Randomised, No effect of Feverfew Small sample size. between the ages received 100mg placebo-controlled, on serotonin uptake or of 18 years old and Feverfew extract per double-blind, platelet activity. Reported only as 60 years old. day for two months crossover clinical abstract thus pertinent or placebo. study. details are missing. There is no mention of Feverfew preparation details, further outcome measures, or withdrawals.

199628 50 patients (42 All patients received Randomised, A prophylactic effect could Lack of positive findings female and eight one placebo capsule placebo-controlled, not be demonstrated for may be associated with male; ages ranging daily for one month, double-blind, the Feverfew preparation, extract type, patient from 18 years old which was considered crossover clinical as both treatment groups population, or length of to 64 years old) a wash-out period. study. suffered the same number trial – original advocates who experienced of migraine attacks. of Feverfew found that at least one After this, patients it took six months or migraine attack either received one However, when patients longer of continual use to per month, with or capsule of 142mg were using Feverfew establish a reduction in without an aura, dried alcoholic they seemed to have migraine frequency. and who had not extract of granulated a tendency to use previously used Feverfew (equivalent fewer symptomatic There were six Feverfew. to approximately pharmaceutical drugs. withdrawals and thus 44 170mg of original patients completed the dried herb), which study. contained 0.5mg parthenolide, daily A 31 year old woman for four months, withdrew due to then a capsule of diarrhoea, which she the placebo for ascribed to the use of the the following four Feverfew preparation. months, or the She was the only patient opposite sequence. who clearly indicated a possible side effect using There was no wash- Feverfew or the placebo. out period between the four month treatment periods.

7 Year Study Extract, Dose & Study Design Results Notes Population Duration 199727 57 patients (47 Capsules of Phase 1 was In phase 1, the difference In this trial, Feverfew female and ten powdered dried designed as an in pain intensity of appeared to reduce the male) with a leaves of Feverfew open-labelled, migraines before and after severity of migraines and median age of 38 containing 0.2% randomised clinical treatment with Feverfew the prevalence of typical years old (ranging parthenolide were study. was significant (p<0.01). related symptoms, rather from nine years used as an active than the frequency of old to 65 years treatment and Phases 2 & 3 were In phase 2, patients attacks. old), who suffered capsules of powdered designed as a receiving Feverfew chronic migraines dried leaves of double-blind, continued to experience A longer treatment time (43% suffered Parsley (Petroselinum placebo-controlled, a decrease in pain and higher dosing may more than ten crispum) were used as randomised, cross- intensity, while pain have also seen a reduction attacks per placebo. over clinical study. intensity increased in in migraine frequency. month). those taking placebo. The The study was difference between the divided into three two groups was significant phases. (p<0.01). Typical migraine symptoms of vomiting, Phase 1: In this phase nausea, and sensitivity both groups (Group to light and noise were A and B) received a profoundly reduced in the daily dose of 100mg Feverfew group (p<0.001). Feverfew (two capsules) for 60 days. In phase 3, when patients who were taking Phases 2 & 3: Feverfew transferred to Group A (n=30) the placebo group, their continued to receive symptoms worsened Feverfew for an and they experienced an additional 30 days increase in pain intensity. and was then shifted Furthermore, when to the placebo patients in the placebo treatment for 30 group were transferred days (100mg daily of to the Feverfew group, Parsley). they experienced an Group B (n=27) first improvement in pain and received placebo other symptoms. treatment for 30 days, and then was transferred to Feverfew treatment for the last 30 days.

No washout periods between the experimental phases were conducted.

8 Year Study Extract, Dose & Study Design Results Notes Population Duration 200226 147 (120 female After a four week A randomised, No statistically significant A dose-response and 27 male) baseline period multicentre, double- differences between the relationship was observed patients between without migraine blind, placebo- study groups were found in this study. 18 years old and prophylaxis, a controlled clinical (assessed on the third 28 65 years old, 12 week active comparison of four day period of Feverfew Researchers asserted suffering from treatment phase parallel groups: therapy versus baseline) that 6.25mg of Feverfew

migraine with compared three three different in regards to number of CO2 extract containing and without different doses dosages of Feverfew migraine attacks, total 0.5mg parthenolide aura according (2.08mg, 6.25mg, extract versus and average duration was equivalent to to International 18.75mg) of a placebo. and intensity of migraine 1.05g of Feverfew leaf Headache Society supercritical carbon attacks, mean duration of (presumably dried). This

(IHS) criteria. dioxide (CO2) extract a single attack, number of would equate to dosing of Feverfew to days with accompanying 3.15g Feverfew leaf as placebo. migraine symptoms, the highest prescription

number of days with (18.75mg CO2 extract) During the inability to work due to in this study, which is active treatment migraine, as well as type quite a large daily dose. period, patients and amount of additional However, as bioactive either received medication needed for constituent levels vary 2.08mg Feverfew migraine attacks. in different extracts, the capsules (0.17mg dried herb equivalent of parthenolide) daily, However, clinically the CO2 extract doses may 6.25mg Feverfew positive results were be overstated in relation capsules (0.5mg observed in a subset to good quality raw parthenolide) daily, of patients (n=49) that material32. 18.75mg Feverfew experienced at least four capsules (1.5mg migraine attacks during 112 patients completed parthenolide) daily, the baseline period. The the study. Overall, 35% or placebo capsules frequency of migraine of patients reported at daily. attacks in this patient least one adverse event, population decreased in a however the incidence dose-dependent manner of adverse events in the with the highest dose treatment groups was (18.75mg/day Feverfew) similar to that in the achieving the best result. placebo group. The only serious adverse event occurred in the placebo group and concerned an ovarian cyst leading to hospitalisation. Furthermore, no dose- related effect was observed for any safety parameter.

9 Year Study Extract, Dose & Study Design Results Notes Population Duration 200530 170 patients After a four week A randomised, The daily oral dose of Adverse events were mild, between 18 years baseline period multicentre, double- 6.25mg three times generalised, and similarly old and 65 years without migraine blind, placebo- daily (total of 18.75mg) distributed in both the

old, suffering prophylaxis, a controlled, phase III Feverfew CO2 extract was Feverfew and placebo from migraine 16 week active clinical study. significantly superior to groups. with and without treatment phase placebo in regards to aura according compared 18.75mg migraine prophylaxis. Researchers concluded to International total daily dose of In the Feverfew group, that this Feverfew extract

Headache Society a supercritical CO2 migraine attack frequency showed a favourable (IHS) criteria. extract of Feverfew to was reduced by 1.9 attacks benefit-risk ratio for Approximately placebo. per month compared with reducing attack frequency 82.8% of the baseline. in patients suffering with patients in this The Feverfew capsule chronic migraines. study were female group had 89 patients The efficacy of Feverfew and 17.2% were and the placebo began after one month male. capsule group had 81 of treatment, reached patients. maximum levels after two months of treatment and then seemed to stabilise (did not decline) for the remaining two months of treatment. The most pronounced effect was observed with regard to migraine attack frequency, total number of migraine days, and migraine duration.

10 Clinical trials using a combination of Feverfew with another migraine prophylactic Year Study Extract, Dose & Study Design Results Notes Population Duration 200433 49 patients (aged After a one month A randomised, Both the treatment and Three patients withdrew between 18 years run-in period, double-blind, placebo intervention from the study. old and 65 years patients were divided placebo-controlled showed comparable old) experiencing into two groups clinical study. clinical effects. Placebo contained migraine with or and received either an active ingredient without aura, as a combination of Although there was (riboflavin). defined by the Feverfew (100mg no difference between International containing 0.7mg groups, there were In this study, there Headache Society parthenolide), statistically significant appeared to be little (IHS) criteria. magnesium (300mg reductions for both active additional benefit in containing 1:1 ratio and placebo groups, adding Feverfew and Patients who of magnesium citrate compared to baseline, magnesium to riboflavin successfully and magnesium for number of migraines, intervention, perhaps completed the oxide), and riboflavin migraine days, and indicating that Feverfew at run-in month and (400mg) daily for migraine index. this low dose is ineffective had at least two three months, or at preventing migraines. migraine days placebo for three were included in months. Feverfew extraction type the study. not reported. Placebo capsules contained 25mg riboflavin (due to the fact that it causes bright yellow urine, which may have alerted to patients that they were receiving active treatment).

11 Year Study Extract, Dose & Study Design Results Notes Population Duration 200634 12 patients (five Feverfew 600mg in A prospective, Attack frequency was Small sample size. male and seven combination with open-label clinical significantly reduced female aged Willow Bark (Salix study. by 57.2% at six weeks No placebo group. between 18 alba) 600mg was (p<0.029) and by 61.7% years old and 55 administered in at 12 weeks (p<0.025) in Two of the 12 patients years old with capsule form daily nine out of ten patients, were excluded from the a mean age of for 12 weeks. Both with 70% of patients study due to reasons 35.8 years old) herbal extracts experiencing a reduction unrelated to treatment. diagnosed with were hydroalcoholic of at least 50%. migraine without freeze-dried extracts The herbal treatment was aura according and the herbal Attack intensity was well-tolerated and no to International combination was significantly reduced adverse events occurred. Headache Society standardised for by 38.7% at six weeks (IHS) criteria, parthenolide (0.2%) (p<0.005) and by 62.6% Results indicate that and who had and salicilin (1.5%). at 12 weeks (p<0.004) combining a higher not employed in all of the ten patients, dose of Feverfew with any migraine with 70% of patients Willow Bark may result prophylactic experiencing a reduction in a significant clinical treatment for at of at least 50%. improvement in migraine least one month frequency within six prior to the study. Attack duration decreased weeks of treatment. by 67.2% at six weeks Placebo-controlled trials (p<0.001) and by 76.2% at are needed. 12 weeks (p<0.001) in all of the ten patients. This herbal combination was selected due to Self-assessed general previous in vitro studies health, physical by the same researchers performance, memory showing that Feverfew and anxiety also improved and Willow Bark inhibit by the end of the study. binding to certain serotonin receptors

(5-HT2A/2C) and the combination of Willow Bark with Feverfew further

inhibited 5-HT1D receptors, whereas Feverfew on its own did not.

12 Year Study Extract, Dose & Study Design Results Notes Population Duration 201235 69 female patients Patients were divided Randomised, single- Compared with baseline No placebo group. between 18 into three groups blind clinical trial. values, significant years old and 56 and either received improvements in the Of the 69 patients, one years old, with acupuncture (twice visual analogue scale (VAS patient in the acupuncture a diagnosis of weekly), Feverfew - rating from 0 [pain free] group dropped out owing migraine without (fine-powdered to 10 [unbearable pain]) to an inability to take time aura according leaf capsule, were observed for all three off work. to International 150mg daily), or treatment groups. Headache Society the combination of This trial indicates that (IHS) criteria, acupuncture and However, the combination both Feverfew and and who had Feverfew for ten of acupuncture acupuncture may be not employed consecutive weeks. and Feverfew was effective for preventing any migraine statistically significantly migraine and shows prophylactic The acupuncture more effective than that their combination treatment for at protocol consisted acupuncture or Feverfew is more effective (in least four weeks of 20 sessions of 30 alone in both reducing regards to quality of life prior to the study. minutes acupuncture the mean score of pain on and analgesic effect) than treatment. Fixed and the VAS (p<0.05) as well either therapy alone. classic acupuncture as reducing the Migraine points were used Disability Assessment in each patient’s (MIDAS) score (p<0.05). sessions without modification for the specific symptoms of the patient.

The Feverfew protocol consisted of taking Feverfew capsules (150mg daily) at bedtime.

Patients assigned to the Feverfew plus acupuncture group received both treatments.

Clinical Note: There have also been clinical trials conducted using Feverfew in combination with (Zingiber officinalis), which demonstrated beneficial results36,37. However, these trials used a homoeopathic sublingual preparation and therefore the results are not relevant to the practical use of a Western .

13 Presently, the available scientific data investigating the clinicaluse of Feverfew in the prevention and treatment of migraine headaches is promising, however more vigorous research into the most effective formulation and dosage regimen is needed to deliver more consistent results38.

Clinical Tip: Results obtained from clinical studies indicate that four to six months of continued treatment, beginning initially with the higher end of the dosage range, may be required to achieve adequate migraine prophylaxis (even though many patients report benefits sooner, for instance within four weeks). Furthermore, combining Feverfew with other relevant herbs (such as Willow Bark) may increase the speed and efficacy of treatment due to a synergistic effect.

It is not yet clear exactly how Feverfew works in the prevention of migraines, however current mechanistic data suggests that Feverfew is able to exert its prophylactic effects partially via decreasing vascular smooth muscle spasm, inhibiting prostaglandin synthesis, and inhibiting the secretion of platelet granules as well as potentially inhibiting serotonin release and binding4,5,39,40,41,42.

Acts as an anti-inflammatoranti-inflammatoryy iinhibitingnhibiting prostaglandin ssynthesisynthesis

FFeverfeweverfew

DDecreasesecreases IInhibitsnhibits tthehe vvascularascular ssecretionecretion ooff ssmoothmooth plplateletatelet mmuscleuscle s spasspasmpasm granules

Figure 1: Proposed Feverfew mechanisms in migraine headache prophylaxis.

Clinical Note: Feverfew is a unique herbal medicine useful in the prevention and treatment of migraines and headaches. Feverfew has been shown to reduce inflammation and prevent blood vessel constriction, subsequently benefitting migraine patients.

Cardiovascular System Platelet aggregation inhibition: The evidence is contradictory as to whether Feverfew extracts inhibit platelet aggregation. Several preclinical studies have determined that Feverfew does indeed inhibit platelet aggregation, however a human clinical trial involving ten patients who had been taking Feverfew for between three and eight years showed no significant inhibition of platelet aggregation when compared with control patients who had not used Feverfew within the previous six months5,43,44,45.

14 Gastrointestinal System Gastroprotective: Feverfew is a bitter tonic herb used traditionally by Eclectic physicians for a plethora of digestive disorders9. In preclinical research, the oral administration of a chloroform Feverfew extract or isolated parthenolide significantly reduced the gastric ulcer index in a rat model of gastric ulcer46.

Hepatobiliary System Hepatoprotective: Parthenolide, a principle sequiterpene lactone in Feverfew, has demonstrated a protective role against acute hepatitis in mice47. Mechanistic studies found that parthenolide is able to act as an anti-inflammatory agent to the liver, inactivating macrophages by downregulating signals such as signal transducer and activator of transcription 3 (STAT3) and p38 mitogen-activated protein kinases (MAPKs), and upregulating signals such as tumour suppressing protein p53. Therefore, parthenolide is able to significantly inhibit the transcription of inflammatory cytokines such as tumour necrosis factor-alpha (TNF-α) and interleukin (IL)-1β in vitro and in vivo, providing an anti-inflammatory and hepatoprotective effect47.

Figure 2: Parthenolide activity in an animal model of hepatitis47.

Furthermore, parthenolide has demonstrated potent hepatoprotective and antifibrotic activity both in vitro and in vivo48. A key cellular process of hepatic fibrosis is the activation and phenotypic change of hepatic stellate cells into proliferative, contractile, and chemotactic myofibroblasts producing extracellular matrix. In an in vitro study, parthenolide was shown to inhibit cell growth and induce apoptotic cell death in hepatic stellate cells in a dose- dependent manner. Moreover, an additional in vivo study found that parthenolide ameliorated hepatic fibrosis significantly in a thioacetamide-treated rat model48.

15 Immune System Antiallergy: Feverfew has been traditionally used for allergic conditions. In laboratory research using rat peritoneal mast cells, Feverfew extract demonstrated a dose-dependent inhibition of histamine release63. Additionally, preclinical studies using isolated parthenolide have also reported antiallergenic activity. Administration of parthenolide significantly inhibited immunoglobulin E (IgE) antigen-induced mastcell degranulation in a dose-dependent manner in vivo and strongly inhibited passive cutaneous anaphylaxis reaction49. Parthenolide is thought to exert its mast cell stabilisation effects by exhibiting tubulin/microtubule-interfering activity (the formation of microtubules is known to be crucial for IgE antigen-induced degranulation of mast cells)49.

Antibacterial: The essential oil of Feverfew has displayed antibacterial activity preclinically19,50. Gram-positive bacteria Staphylococcus aureus and Staphylococcus epidermidis were shown to be significantly sensitive to the essential oil of Feverfew (p=0.001) in vitro. The essential oil of Feverfew also had a significant in vitro antimicrobial effect (p=0.016) on Gram-negative bacteria Shigella flexneri, Klebsiella pneumoniae, and Escherichia coli50. Based on the results of growth diameter of inhibition zone and minimum concentrations of growth, the Gram-negative bacteria studied were less sensitive to the essential oil of Feverfew than the Gram-positive bacteria were (p=0.003)50. Isolated essential oils from Feverfew demonstrated strong antibacterial activity against Gram-negative Vibrio fischeri in vitro, as well as some antibacterial activity against Gram-positive bacteria Bacillus subtilis, Staphylococcus aureus and methicillin-resistant Staphylococcus aureus19. In an older in vitro trial, isolated parthenolide inhibited the growth of certain Gram-positive bacteria, including Bacillus cereus var. mycoides, Bacillus megaterium, Bacillus subtilis, Micrococcus lysodeikticus, Staphylococcus albus, and Staphylococcus aureus, as well as Mycobacterium species. Corynebacterium farciens, Streptococcus spp., and Gram-negative bacteria were unaffected in this study51.

Anticancer: Isolated parthenolide has displayed potent anticancer activity in a variety of preclinical studies due to multiple mechanisms, however as yet no clinical studies have been published to determine its efficacy in humans52. Parthenolide has demonstrated in vitro anticancer activity against a number of cancer cell lines, including bone cancer, breast cancer, cervical cancer, cholangiocarcinoma (chemoresistant intrahepatic bile duct cancer), colorectal cancer, gastric cancer, glioblastoma, leukaemia, lymphoblastic leukaemia, melanoma, mesenchyme, multiple myeloma, and prostate cancer52,53,54,55,56,57,58. Feverfew ethanolic extracts have also shown in vitro anticancer activity against breast cancer cell lines and a cervical cancer cell line59. Furthermore, parthenolide has displayed benefit in many animal models of cancer, including models of bladder cancer, bone cancer, brain cancer, breast cancer, colon cancer, kidney cancer, leukaemia, liver cancer, lung cancer, mesenchyme, pancreatic cancer, pituitary cancer, prostate cancer, skin cancer, and stomach cancer52,53. The potent anticancer activity of parthenolide is significantly due to its ability to inhibit transcription factor nuclear factor-kappa B (NF-κB), thereby reducing survival potential in a number of cancer cells60. Studies show that on the transcriptional level, parthenolide affects both NF-κB (either via interaction with inhibitor of kappa B (IκB) kinase (IKK) enzyme complex or more directly with its p65 subunit) and STAT activity61. The upregulation or downregulation of specific genes results in the elimination of antiapoptotic proteins such as survivin, cellular inhibitor of apoptosis protein (cIAP), Bcl-xL and/or additional reactive oxygen species (ROS) generation and intrinsic apoptotic pathway induction. Parthenolide also amplifies the apoptotic signal through the sensitisation of cancer cells to extrinsic apoptosis induced by TNF-α. All these intrinsic and extrinsic changes help to restore the natural processes of cancer cell deletion58,60.

16 PARTHENOLIDE  TNF- TNF-R1

DD Cytokine DD D DD TRADD APOPTOSIS P cIAP TRADD TRADD Jak RIP CIKS P FADD P TRAI 2 cytochrome c P ROS

FLICE

BAK Jak STAT

IKK BAX tBID

XX P APOPTOSIS p50 STAT p65 MITOCHONDRION P NF-B IB STAT P XX X APOPTOSIS SURVIVAL

NUCLEUS SURVIVAL STAT

P p50 STAT P p65 XX XX ANTIAPOPTOTIC GENE TRANSCRIPTION

Figure 3: Potential model for the mechanisms of parthenolide-mediated apoptosis induction60. Parthenolide-dependent inhibition of NF-κB and STATs transcriptional activity results in the downregulation of antiapoptotic gene transcription. As a consequence the cancer cells become sensitive to induction of extrinsic apoptosis. Additionally, the parthenolide- induced oxidative stress to the cancer cell mediates mitochondrial dysfunction and initiates intrinsic apoptosis. This facilitates apoptosis of cancer cells. Key: BAK = proapoptotic protein; BAX = proapoptotic protein also known as bcl-2-like protein 4; cIAP = cellular inhibitor of apoptosis protein; CIKS = connection to IKK and SAPK/JNK; DD = intracellular death domain; FADD = Fas-associated death domain; FLICE = part of the CD95 death-inducing signalling complex; IB = inhibitor of kappa B; Jak = Janus kinase; NF-B = nuclear factor-kappa B; P = phosphorylate; p50 = NF-B p50 subunit; p65 = NF-B p65 subunit; ROS = reactive oxygen species; STAT = signal transducer and activator of transcription; tBID = truncated p15 BID; TNF-α = tumour necrosis factor-alpha; TNF-R1 = tumour necrosis factor-receptor 1; TRADD = TNFR1-associated death domain protein; TRAF2 = TNF-α receptor associated factor 2

Additionally, parthenolide appears to modulate signalling pathways that endow it with selective toxicity toward several tumour cell types while sparing and even protecting normal cells from ultraviolet (UV) B and oxidative stress60,61,62. For instance, in vitro studies found that parthenolide induced robust apoptosis in primary human acute myelogenous leukaemia cells and blast crisis chronic myelogenous leukaemia cells while sparing normal hematopoietic cells58. When compared with the standard chemotherapy drug cytosine arabinoside, parthenolide’s apoptotic activity was much more specific to leukaemia cells. Cytosine arabinoside was shown to kill both normal hematopoietic cells and leukaemia cells to an equivalent extent, whereas parthenolide was shown to be a selectively acting apoptotic agent58. Additionally, parthenolide has demonstrated further selective apoptotic activity, targeting breast and prostate cancer stem cells in vitro while sparing healthy cells61. Furthermore, parthenolide’s inhibition of STAT, as well as MAPKs, and the induction of sustained c-Jun N-terminal kinase (JNK) activity, may lead to an increased susceptibility of cancer cells to chemotherapy and radiotherapy61.

17 Moreover, in vivo parthenolide increased radiosensitivity of mouse xenograft tumours, yet it protected normal prostate and bladder tissues against radiation-induced injury62. Mechanistically, parthenolide increased the level of cellular ROS and caused oxidation of thioredoxin (TrX) in prostate cancer cells, leading to a TrX- dependent increase in a reduced state of kelch like ECH associated protein 1 (KEAP1), which in turn led to KEAP1- mediated mitochondrial phosphatase PGAM5 and Bcl-xL degradation. In contrast, parthenolide increased oxidation of KEAP1 in normal prostate epithelial cells, leading to increased Nrf2 protein levels and subsequent Nrf2-dependent expression of antioxidant enzymes. These preclinical results reveal a novel redox-mediated modification of KEAP1 in controlling the differential effect of parthenolide on tumour cell and normal cell radiosensitivity. Further to this, the results indicate that parthenolide has the potential to act as a tumour-specific radiosensitising agent with radioprotective properties in normal cells62.

Clinical Tip: Higher doses of Feverfew may act as a useful adjunct in cancer therapy, as preclinical studies have shown that parthenolide is able to induce apoptosis in a variety of cancer cell lines, has chemosensitising properties, and is non-toxic to normal cells60,61.

Antifungal: The essential oil of Feverfew was found to exhibit strong antifungal activity in vitro50. This effect was noted to be more potent than the essential oil’s antibacterial effect. Candida albicans was found to be the most sensitive to the essential oil, followed by Aspergillus niger and Candida krusei50. Isolated parthenolide has also demonstrated antifungal activity against yeasts and filamentous fungi in vitro51.

Anti-inflammatory:

Clinical Note: Feverfew and its constituents have demonstrated anti-inflammatory activity in preclinical research, inhibiting NF-κB and prostaglandin synthesis.

The oral administration of a Feverfew ethanolic extract has exhibited strong anti-inflammatory activity in animal studies, which was comparable to nonsteriodal anti-inflammatory drugs (NSAIDs)64.

Inhibition of eicosanoid generation by tanetin may contribute to the anti-inflammatory properties of Feverfew. In vitro studies demonstrate that the isolated constituent tanetin inhibited both the cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) pathways of arachidonic acid metabolism15,17.

Parthenolide has also displayed anti-inflammatory activity, and a recent review of the preclinical research reported that parthenolide has been shown to effect the following molecules that influence inflammation47,65: t NF-κB t ICAM-1 t IKK-β t Prostaglandins t iNOS t Leukotrienes t STAT1/STAT3 t Histamine t COX t Glutathione (increases activity) t IL-1/6 t Nrf2-antioxidant responsive element (ARE) t TNF-α t TrX reductase 1 & 2

To expand further, parthenolide has been shown to inhibit cytokine release (such as TNF-α and IL-1β) from activated macrophages47. Moreover, parthenolide has been shown to inhibit the activation of transcription factor NFκB, both at the transcriptional level and by direct inhibition of associated kinases (IKK-β)66. Furthermore, the effect of parthenolide on inducible nitric oxide synthase (iNOS) synthesis and nitric oxide (NO) release has been investigated using primary rat microglia67. Parthenolide was shown to be an effective inhibitor of iNOS/NO

18 synthesis, leading the researchers to purport its potential significance as an effective treatment of certain central nervous system inflammatory and autoimmune diseases (including migraine and multiple sclerosis) where NO plays an important role in the pathophysiology of the disease67.

Antioxidant: Interestingly, parthenolide appears to modulate oxidative stress in vivo and in vitro: parthenolide appears to increase intracellular glutathione in non-cancerous cells, thereby decreasing ROS and acting as an antioxidant, while contrastingly it has been shown to increase ROS in cancerous cells, causing mitochondrial dysfunction and cancer cell death53,60,62.

Clinical Note: Parthenolide appears to display selective activity in oxidation; causing oxidative stress and death to cancer cells while acting as an antioxidant and protective molecule to normal cells.

Moreover, extracts of Feverfew that contain no parthenolide have been found to possess potent and wide ranging free radical scavenging activity in vitro and in vivo as well as in clinical studies, demonstrating the value of using a whole plant part extract14,68.

Antiparasitic: In particular, two sesquiterpene lactones, parthenolide and guauanolide, isolated from the dried aerial parts of Feverfew have demonstrated antileishmania activity in preliminary research69,70,71. In a recent study, a sesquiterpene lactone-rich extract of Feverfew exhibited in vitro antileishmania activity against the promastigote form and the amastigote form of Leishmania amazonensis. Furthermore, in vivo intramuscular administration of the Feverfew extract (30mg/kg once every three days for four weeks) decreased the growth and size of footpad lesions in the infected mice and significantly decreased the parasite population compared with mice treated with the reference drug Glucantime (100mg/kg/day intramuscularly)69. There were no toxic effects for the Feverfew extract observed in this study, demonstrating treatment safety as well as efficacy. Furthermore, in vitro activity against the epimastigote form of the protozoal parasite Trypanosoma cruzi was observed for both crude extracts of Feverfew and isolated parthenolide72. In a later in vitro study, parthenolide exhibited strong synergistic activity against epimastigote forms of Trypanosoma cruzi when combined with antiparasitic medication benznidazole73.

Leishmania amazonensis

19 Integumentary System Protection against skin damage: Studies have shown that Feverfew may protect the skin from external assaults as well as reduce damage to the skin caused by oxidative stress14,68,74. This activity supports Feverfew’s traditional application in dermatological disorders such as dermatitis and psoriasis. In particular, parthenolide-depleted Feverfew extracts (PD-Feverfew) have been investigated in various skin conditions and experimental models14,68,74. In vitro, PD-Feverfew restored cigarette smoke-mediated depletion of cellular thiols, attenuated the formation of UV-induced hydrogen peroxide, reduced pro-inflammatory cytokine release, increased endogenous defence mechanisms, and aided in DNA repair of damaged skin cells via activation of a phosphoinositide 3-kinase (PI3K)-dependent Nrf2-ARE pathway14,68. In vivo, the topical application of PD-Feverfew reduced UV-induced epidermal hyperplasia and DNA damage. PD- Feverfew was also found to possess free radical scavenging activity against a wide range of ROS, with its activity shown to be greater than that of vitamin C14. Furthermore, in a randomised, double-blind, placebo-controlled human clinical trial involving 12 participants, PD-Feverfew treatment significantly reduced erythema compared to placebo after 24hours post-UV exposure (p<0.05)14. Following this, another randomised, controlled trial involving eight participants found that prior topical application of a PD-Feverfew emulsion dose-dependently reduced forearm erythema induced by methyl nicotinate, demonstrating the anti-inflammatory activity of the extract75.

Musculoskeletal System Antispasmodic: The results from several in vitro studies generally indicate that Feverfew may decrease smooth muscle spasm40,41,42.

Bone destructive disorders: Abnormal activation of NF-κB signalling in osteoclasts has been associated with excessive osteoclastic activity, and thus Feverfew and its constituent parthenolide have been implicated as potential therapeutic interventions in osteolytic conditions due to their ability to inhibit NF-κB76. In preclinical trials, parthenolide dose-dependently inhibited receptor activator of NF-κB ligand (RANKL)-mediated osteoclast differentiation in bone marrow macrophages and inhibited the bone resorbing activity of mature osteoclasts77. These results suggest Feverfew may possess potential therapeutic value for bone destructive disorders associated with osteoclast-mediated bone resorption, such as arthritis, osteoporosis, Paget’s disease of bone, periodontitis, periprosthetic osteolysis, and the bone changes secondary to cancer, such as those that occur in myeloma and metastases from breast cancer76,77,78.

Rheumatoid arthritis: Consistent with the herb’s traditional use, in vitro studies have implicated Feverfew in the treatment of rheumatoid arthritis due to the herb’s anti-inflammatory activity. Human synovial fibroblasts express an intracellular adhesion molecule-1 (ICAM-1) that has been implicated in the pathogenesis of rheumatoid arthritis4. Feverfew extracts and isolated parthenolide have been shown to inhibit the increased expression of ICAM-1 in human synovial fibroblasts probably via inhibition of IL-1 and TNF-α79. Despite these positive findings and although Feverfew has been traditionally prized as a therapeutic herb for inflammatory joint conditions, a human clinical trial did not show any benefit80. This randomised, double-blind, placebo-controlled trial involved 40 female patients with symptomatic rheumatoid arthritis who received either dried, chopped Feverfew capsules (70mg/day-80mg/day) or placebo (dried, chopped cabbage) capsules for six weeks. Patients continued with their NSAID or drug treatment throughout the trial, which has been suggested to lessen the efficacy of Feverfew80. Further clinical trials utilising a higher dosage of Feverfew are needed to determine therapeutic benefit in rheumatoid arthritis.

20 Nervous System Analgesic & Antinociceptive: In vivo, the oral administration of a Feverfew ethanolic extract (10mg/kg, 20mg/kg, 40mg/kg) led to significant dose-dependent antinociceptive and anti-inflammatory effects against acetic acid-induced writhing in mice and carrageenan-induced paw oedema in rats, respectively64. These effects were comparable to intraperitoneally administered nimesulide (2mg/kg), an NSAID. Additionally, intraperitoneally administered parthenolide (1mg/ kg, 2mg/kg), an active constituent of Feverfew, also produced antinociceptive and anti-inflammatory effects in these animal models64. Moreover, in these animal trials, naloxone, an opiate antagonist, failed to block the antinociception activity of Feverfew and parthenolide indicating that there was no involvement of the opiate system in their mechanism of action64. Furthermore, the oral administration of Feverfew in higher doses (40mg/kg, 60mg/kg) neither altered the locomotor activity nor potentiated the pentobarbitone-induced sleep time in mice. It also did not change the rectal temperature in rats. These results led researchers to conclude that Feverfew exerted its antinociceptive and anti-inflammatory effects without altering the normal behaviour of the animals64. The antinociceptive activity of Feverfew was not associated with sedation and did not seem to be mediated by the opiate pathway in this study. However, a later study conversely showed that Feverfew’s antinociceptive activity may in fact be due to the opiate system as naloxone was seen to reduce the analgesic activity of Feverfew in mice81. In this experimental animal trial, oral administration of Feverfew ethanolic extract (40mg/kg) elicited a significantly stronger analgesic effect in mice compared to (p<0.001) and a non-statistically significant stronger analgesic effect compared to morphine81. Additionally, recent animal models of acute, inflammatory, articular, and neuropathic pain have all determined that Feverfew flower extracts possess potent analgesic activity82.

Renourinary System Renoprotective: In a rat model, renal damage induced by the chemotherapy drug cisplatin was reduced by intraperitoneal administration of parthenolide (3mg/kg/day), potentially due to parthenolide’s anti-inflammatory activity83.

21 Safety: Feverfew demonstrates a good safety profile24. Data from systematic reviews suggest that Feverfew is associated with only mild and transient adverse effects and few other safety concerns23,24,25. Feverfew is contraindicated in patients with allergy/hypersensitivity to in the Asteraceae family5,84. Ingestion of Feverfew leaves has been associated with mouth ulcers, lip swelling, and contact dermatitis in certain individuals, although whether these adverse effects were caused by Feverfew has been disputed5. Nonetheless, tincture or solid-dose preparations of Feverfew may be better tolerated than chewing the fresh leaves5.

Safety in Pregnancy and Lactation: In regards to safety in pregnancy, Feverfew has been classified as Category B3 – indicating that there has been no increase in frequency of malformation or other harmful effects on the foetus from limited use in women, however animal studies have shown evidence of an increased occurrence of foetal damage, the significance of which is unclear in humans85. Preclinical animal models have suggested that Feverfew may have detrimental effects in pregnancy: Feverfew treated animals had reduced litter sizes, a greater proportion of smaller sized foetuses than the control group, and increased pre-implantation loss86. These outcomes indicate both maternal and embryonic effects however it should be noted that the dosage of Feverfew employed was equivalent to 58.7 times the accepted human dose, and therefore the clinical relevance of these findings is uncertain86. Nevertheless, as Feverfew is classified as an emmenogogue when given in high doses, it is not usually recommended during pregnancy. Some herbal texts advise lower doses during pregnancy (no more than 500mg/day or equivalent)85. It is interesting to note that in traditional Western herbal medicine, a decoction of Feverfew flowers in wine was administered to bring on menstruation and to expel the afterbirth and stillborn children4,7,10. Conversely, Feverfew was also historically prescribed during pregnancy for threatened miscarriage5. Feverfew is not typically recommended for lactating women or for children under two years old due to a lack of safety data4,5.

Caution: Bleeding disorders – Although inhibition of platelet aggregation has not been demonstrated in human studies, parthenolide has been shown to affect platelet aggregation in some in vitro studies and therefore high doses of Feverfew may potentially theoretically increase the risk of bleeding in certain individuals with particular bleeding disorders5,84. Surgery – Although inhibition of platelet aggregation has not been demonstrated in human studies, parthenolide has been shown to affect platelet aggregation in some in vitro studies and therefore high doses of Feverfew may potentially theoretically increase the risk of bleeding in some people if used before or during surgery. It is recommended that the use of Feverfew is discontinued two weeks prior to scheduled surgery5,84.

Interactions: / Antiplatelet medication – Although inhibition of platelet aggregation has not been demonstrated in human studies, parthenolide has been shown to affect platelet aggregation in some in vitro studies and therefore combining high doses of Feverfew with pharmaceuticals that have anticoagulant or antiplatelet activity may theoretically increase the risk of bleeding5,84. Drugs metabolised by cytochrome P450 enzymes – Due to preliminary evidence showing that Feverfew potentially inhibits CYP450 enzymes, Feverfew may theoretically increase the level of drugs metabolised by these enzymes84.

22 migraine prophylaxis--a double-blind, multicentre, randomized placebo- References controlled dose-response study. Cephalalgia, 22(7), 523-532. 1. Grieve, M. (1998). A Modern Herbal. Twickenham, United Kingdom: Tiger 27. Palevitch, D., Earon, G., & Carasso, R. (1997). Feverfew (Tanacetum Books International. parthenium) as a prophylactic treatment for migraine: a double-blind placebo- 2. Murch, S. J., Simmons, C. B., & Saxena, P. K. (1997). Melatonin in feverfew and controlled study. Phytotherapy Research, 11(7), 508-511. other . Lancet, 350(9091), 1598-1599. 28. De Weerdt, C. J., Bootsma, H. P., & Hendriks, H. (1996). Herbal medicines in 3. Hutchens, A. R. (1991). Indian Herbology of . Massachusetts, migraine prevention. Randomized double-blind placebo-controlled crossover United States of America: Shambala Publications, Incorporated. trial of a Feverfew preparation. Phytomedicine, 3(3), 225-230. 4. Pareek, A., Suthar, M., Rathore, G. S., & Bansal, V. (2011). Feverfew 29. Murphy, J. J., Heptinstall, S., & Mitchell, J. R. (1988). Randomized double- (Tanacetum parthenium L.): A systematic review. Pharmacognosy Review, 5(9), blind placebo-controlled trial of Feverfew in migraine prevention. Lancet, 103-110. 332(8604), 189-192. 5. Kemper, K. J. (1999). Feverfew (Tanacetum parthenium). The Longwood 30. Diener, H. C., Pfaffenrath, V., Schnitker, J., Friede, M., Zepelin, H. H. H-V. Herbal Task Force and The Center for Holistic Pediatric Education and Research, (2005). Efficacy and safety of 6.25 mg t.i.d. Feverfew CO2-extract (MIG-99) Retrieved Online From: http://www.longwoodherbal.org/feverfew/feverfew. in migraine prevention--a randomized, double-blind, multicentre, placebo- pdf controlled study. Cephalalgia, 25(11), 1031-1041. 6. Kumar, V., & Tyagi, D. (2013). Chemical Composition and Biological Activities 31. Kuritzky, A., Elhacham, Y., Yerushalmi, Z., & Hering, R. (1994). Feverfew in of Essential Oils of Genus Tanacetum - a review. Journal of Pharmacognosy and the treatment of migraine: its effect on serotonin uptake and platelet activity. Phytochemistry, 2(3), 159-163. Neurology, 44(suppl. 2), 293P. [Abstract Only] 7. Knight, D. W. (1995). Feverfew: chemistry and biological activity. Natural 32. Cutlan, A. R., Bonilla, L. E., Simon, J. E., & Erwin, J. E. (2000). Intra-specific Product Reports, 12(3), 271-276. variability of Feverfew: correlations between parthenolide, morphological 8. Chavez, M. L., & Chavez, P. I. (1999). Monographs on alternative therapies: traits and seed origin. Planta Medica, 66(7), 612-617. Feverfew. Hospital Pharmacy, 34(4), 436-461. 33. Maizels, M., Blumenfeld, A., & Burchette, R. (2004). A combination of 9. Felter, H. W., & Lloyd, J. U. (1898). King’s American Dispensatory. Retrieved riboflavin, magnesium, and feverfew for migraine prophylaxis: a randomized Online From: http://www.henriettes-herb.com/eclectic/kings/tanacetum-part. trial. Headache, 44(9), 885-890. html 34. Shrivastava, R., Pechadre, J. C., & John, G. W. (2006). Tanacetum parthenium 10. Culpeper, N. (2007). Culpeper’s Color Herbal. New York, United States of and (Mig-RL) combination in migraine prophylaxis: a prospective, America: Sterling Publishing Company, Inc. open-label study. Clinical Drug Investigation, 26(5), 287-296. 11. Gerard, J. (1998). Gerard’s Herbal. Twickenham, United Kingdom: Senate, 35. Ferro, E. C., Biagini, A. P., da Silva, I. E. F., & Silva, J. R. T. (2012). The combined Tiger Books International. effect of acupuncture andTanacetum parthenium on quality of life in women 12. Heptinstall, S., Awang, D. V., Dawson, B. A., Kindack, D., Knight, D. W., & with headache: randomised study. Acupuncture in Medicine, 30(4), 252-257. May, J. (1992). Parthenolide content and bioactivity of feverfew (Tanacetum 36. Cady, R. K., Goldstein, J., Nett, R., Mitchell, R., Beach, M. E., & Browning, R. parthenium (L.) Schultz-Bip.). Estimation of commercial and authenticated (2011). A double-blind placebo-controlled pilot study of sublingual feverfew feverfew products. Journal of Pharmacy and Pharmacology, 44(5), 391-395. and ginger (LipiGesic™ M) in the treatment of migraine. Headache, 51(7), 1078- 13. Bowe, W. P., & Logan, A. C. (2012). Antioxidants in acne vulgaris and aging: 1086. focus on Green Tea and Feverfew. Journal of Drugs in Dermatology, 11(9), 37. Cady, R. K., Schreiber, C. P., Beach, M. E., & Hart, C. C. (2005). Gelstat S11-S15. Migraine (sublingually administered feverfew and ginger compound) for 14. Martin, K., Sur, R., Liebel, F., Tierney, N., Lyte, P., Garay, M., Oddos, T., acute treatment of migraine when administered during the mild pain phase. Anthonavage, M., Shapiro, S., & Southall, M. (2008). Parthenolide-depleted Medical Science Monitor, 11(9), PI65-PI69. Feverfew (Tanacetum parthenium) protects skin from UV irradiation and 38. Rajapakse, T., & Pringsheim, T. (2016). Nutraceuticals in Migraine: A external aggression. Archives of Dermatological Research, 300(2), 69-80. Summary of Existing Guidelines for Use. Headache, 56(4), 808-816. 15. Williams, C. A., Harborne, J. B., Geiger, H., & Hoult, J. R. S. (1999). 39. Mittra, S., Datta, A., Singh, S. K., & Singh, A. (2000). 5-Hydroxytryptamine- The flavonoids ofTanacetum parthenium and T. vulgare and their anti- inhibiting property of Feverfew: role of parthenolide content. Acta inflammatory properties.Phytochemistry , 51(3), 417-423. Pharmacologica Sinica, 21(12), 1106-1114. 16. Brown, A. M., Edwards, C. M., Davey, M. R., Power, J. B., & Lowe, K. C. (1997). 40. Barsby, R. W., Salan, U., Knight, D. W., & Hoult, J. R. (1993). Feverfew and Pharmacological activity of feverfew (Tanacetum parthenium (L.) Schultz- vascular smooth muscle: extracts from fresh and dried plants show opposing Bip.): assessment by inhibition of human polymorphonuclear leukocyte pharmacological profiles, dependent upon sesquiterpene lactone content. chemiluminescence in-vitro. The Journal of Pharmacy and Pharmacology, 49(5), Planta Medica, 59(1), 20-25. 558-561. 41. Barsby, R. W., Salan, U., Knight, D. W., & Hoult, J. R. (1992). Feverfew extracts 17. Williams, C. A., Hoult, J. R., Harborne, J. B., Greenham, J., & Eagles, J. and parthenolide irreversibly inhibit vascular responses of the rabbit aorta. (1995). A biologically active lipophilic flavonol fromTanacetum parthenium. The Journal of Pharmacy and Pharmacology, 44(9), 737-740. Phytochemistry, 38(1), 267-270. 42. Collier, H. O., Butt, N. M., McDonald-Gibson, W. J., & Saeed, S. A. (1980). 18. Pourianezhad, F., Tahmasebi, S., Abdusi, V., Nikfar, S., & Mirhoseini, M. Extract of Feverfew inhibits prostaglandin biosynthesis. Lancet, 2(8200), 922- (2016). Review on Feverfew, a valuable medicinal plant. Journal of HerbMed 923. Pharmacology, 5(2), 45-49. 43. Heptinstall, S., Groenewegen, W. A., Spangenberg, P., & Lösche, W. (1988). 19. Polatoglu, K., Demirci, F., Demirci, B., Goren, N., & Baser, K. H. C. (2010). Inhibition of platelet behaviour by Feverfew: a mechanism of action involving Antibacterial Activity and the Variation of Tanacetum parthenium (L.) Schultz sulphydryl groups. Folia Haematologica, 115(4), 447-449. Bip. Essential Oils from Turkey. Journal of Oleo Science, 59(4), 177-184. 44. Makheja, A. N., & Bailey, J. M. (1982). A platelet phospholipase inhibitor 20. Heinrich, M., Barnes, J., Gibbons, S., & Williamson, E. M. (2004). from the medicinal herb feverfew (Tanacetum parthenium). Prostaglandins, Fundamentals of Pharmacognosy and Phytotherapy. London, United Kingdom: Leukotrienes, and Medicine, 8(6), 653-660. Churchill Livingstone. 45. Biggs, M. J., Johnson, E. S., Persaud, N. P., & Ratcliffe, D. M. (1982). Platelet 21. Bohlmann, F., & Zdero, C. (1982). Sesquiterpene lactones and other aggregation in patients using Feverfew for migraine. Lancet, 2(8301), 776. constituents from Tanacetum parthenium. Phytochemistry, 21(10), 2543-2549. 46. Tournier, H., Schinella, G., de Balsa, E. M., Buschiazzo, H., Mañez, S., & 22. Johnson, E. S., Kadam, N. P., Hylands, D. M., & Hylands, P. J. (1985). Efficacy Mordujovich de Buschiazzo, P. (1999). Effect of the chloroform extract of feverfew as prophylactic treatment of migraine. British Medical Journal, of Tanacetum vulgare and one of its active principles, parthenolide, on 291(6495), 569-573. experimental gastric ulcer in rats. The Journal of Pharmacy and Pharmacology, 23. Pittler, M. H., & Ernst, E. (2004). Feverfew for preventing migraine. The 51(2), 215-219. Cochrane Database of Systematic Reviews, 1, CD002286. 47. Wang, D., Wang, H., Fu, S., Cheng, X., Yang, F., Zhang, Q., Li, Y., Xue, Z., 24. Ernst, E., & Pittler, M. H. (2000). The efficacy and safety of feverfew Zhang, L., Huang, W., Yang, L., Na, D., Da, Y., Kong, Y., & Zhang, R. (2016). (Tanacetum parthenium L.): an update of a systematic review. Public Health Parthenolide ameliorates Concanavalin A-induced acute hepatitis in mice Nutrition, 3(4A), 509-514. and modulates the macrophages to an anti-inflammatory state. International Immunopharmacology, 38, 132-138. 25. Vogler, B. K., Pittler, M. H., & Ernst, E. (1998). Feverfew as a preventative treatment for migraine: a systematic review. Cephalalgia, 18(10), 704-708. 48. Kim, I. H., Kim, S. W., Kim, S. H., Lee, S. O., Lee, S. T., Kim, D-G., Lee, M-J., & Park, W. H. (2012). Parthenolide-induced apoptosis of hepatic stellate cells 26. Pfaffenrath, V., Diener, H. C., Fischer, M., Friede, M., & Zepelin, H. H. H-V. and anti-fibrotic effects in an in vivo rat model.Experimental and Molecular (2002). The efficacy and safety of Tanacetum parthenium (Feverfew) in

23 Medicine, 44(7), 448-456. LPS-induced p42/44 MAP kinase activation and iNOS/NO synthesis by 49. Miyata, N., Gon, Y., Nunomura, S., Endo, D., Yamashita, K., Matsumoto, K., parthenolide in rat primary microglial cells. Journal of Neuroimmunology, Hashimoto, S., & Ra, C. (2008). Inhibitory effects of parthenolide on antigen- 132(1-2), 18-24. induced microtubule formation and degranulation in mast cells. International 68. Rodriguez, K. J., Wong, H. K., Oddos, T., Southall, M., Frei, B., & Kaur, S. (2013). Immunopharmacology, 8(6), 874-880. A purified feverfew extract protects from oxidative damage by inducing DNA 50. Izadi, Z., Aghaalikhani, M., Esna-Ashari, M., & Davoodi, P. (2013). repair in skin cells via a PI3-kinase-dependent Nrf2/ARE pathway. Journal of Determining Chemical Composition and Antimicrobial Activity of Feverfew Dermatological Science, 72(3), 304-310. (Tanacetum parthenium L.) Essential Oil on Some Microbial Strains. Zahedan 69. Rabito, M. F., Britta, E. A., Pelegrini, B. L., Scariot, D. B., Almeida, M. B., Journal of Research in Medical Sciences, 15(6), 8-13. Nixdorf, S. L., Nakamura, C. V., & Ferreira, I. C. P. (2014). In vitro and in vivo 51. Blakeman, J. P., & Atkinson, P. (1979). Antimicrobial properties and possible antileishmania activity of sesquiterpene lactone-rich dichloromethane role in host-pathogen interactions of parthenolide, a sesquiterpene lactone fraction obtained from Tanacetum parthenium (L.) Schultz-Bip. Experimental isolated from glands of Chrysanthemum parthenium. Physiological Plant Parasitology, 143, 18-23. Pathology, 15(2), 183-192. 70. da Silva, B. P., Cortez, D. A., Violin, T. Y., Dias Filho, B. P., Nakamura, C. 52. Ghantous, A., Sinjab, A., Herceg, Z., & Darwiche, N. (2013). Parthenolide: V., Ueda-Nakamura, T., & Ferreira, I. C. (2010). Antileishmanial activity of from plant shoots to cancer roots. Drug Discovery Today, 18(17-18), 894-905. a guaianolide from Tanacetum parthenium (L.) Schultz Bip. Parasitology 53. Kim, S-L., Trang, K. T., Kim, S. H., Kim, I. H., Lee, S. O., Lee, S. T., Kim, D. G., International, 59(4), 643-646. & Kim, S-W. (2012). Parthenolide suppresses tumor growth in a xenograft 71. Tiuman, T. S., Ueda-Nakamura, T., Garcia Cortez, D. A., Dias Filho, B. P., model of colorectal cancer cells by inducing mitochondrial dysfunction and Morgado-Díaz, J. A., de Souza, W., & Nakamura, C. V. (2005). Antileishmanial apoptosis. International Journal of Oncology, 41(4), 1547-1553. activity of parthenolide, a sesquiterpene lactone isolated from Tanacetum 54. Carlisi, D., D’Anneo, A., Angileri, L., Lauricella, M., Emanuele, S., Santulli, parthenium. Antimicrobial Agents and Chemotherapy, 49(1), 176-182. A., Vento, R., & Tesoriere, G. (2011). Parthenolide sensitizes hepatocellular 72. Izumi, E., Morello, L. G., Ueda-Nakamura, T., Yamada-Ogatta, S. F., Filho, B. carcinoma cells to TRAIL by inducing the expression of death receptors P., Cortez, D. A., Ferreira, I. C., Morgado-Díaz, J. A., & Nakamura, C. V. (2008). through inhibition of STAT3 activation. Journal of Cellular Physiology, 226(6), Trypanosoma cruzi: antiprotozoal activity of parthenolide obtained from 1632-1641. Tanacetum parthenium (L.) Schultz Bip. (Asteraceae, Compositae) against 55. Yun, B-R., Lee, M-J., Kim, J-H., Kim, I-H., Yu, G-R., & Kim, D-G. (2010). epimastigote and amastigote forms. Experimental Parasitology, 118(3), 324- Enhancement of parthenolide-induced apoptosis by a PKC-alpha inhibition 330. through heme oxygenase-1 blockage in cholangiocarcinoma cells. 73. Pelizzaro-Rocha KJ, Tiuman TS, Izumi E, Ueda-Nakamura T, Dias Filho BP, Experimental and Molecular Medicine, 42(11), 787-797. Nakamura CV. (2010). Synergistic effects of parthenolide and benznidazole on 56. Zhao, L. J., Xu, Y. H., & Li, Y. (2009). Effect of parthenolide on proliferation Trypanosoma cruzi. Phytomedicine, 18(1), 36-39. and apoptosis in gastric cancer cell line SGC7901. Journal of Digestive Diseases, 74. Finkey, M. B., Southall, M., Lyte, P., & Pinto, J. (2005). Parthenolide- 10(3), 172-180. free feverfew extract protects the skin against ultraviolet damage and 57. Anderson, K. N., & Bejcek, B. E. (2008). Parthenolide induces apoptosis inflammation.Journal of American Academy of Dermatology, 52(3), 93. in glioblastomas without affecting NF-kappaB.Journal of Pharmacological 75. Sur, R., Martin, K., Liebel, F., Lyte, P., Shapiro, S., & Southall, M. (2009). Sciences, 106(2), 318-320. Anti-inflammatory activity of parthenolide-depleted Feverfew Tanacetum( 58. Guzman, M. L., Rossi, R. M., Karnischky, L., Li, X., Peterson, D. R., Howard, parthenium). Inflammopharmacology, 17(1), 42-49. D. S., & Jordan, C. T. (2005) The sesquiterpene lactone parthenolide induces 76. Xu, J., Wu, H. F., Ang, E. S. M., Yip, K., Woloszyn, M., Zheng, M. H., & Tan, R. apoptosis of human acute myelogenous leukemia stem and progenitor cells. X. (2009). NF-κB modulators in osteolytic bone diseases. Cytokine and Growth Blood, 105, 4163-4169. Factor Reviews, 20(1), 7-17. 59. Wu, C., Chen, F., Rushing, J. W., Wang, X., Kim, H. J., Huang, G., Haley-Zitlin, 77. Kim, J-Y., Cheon, Y-H., Yoon, K-H., Lee, M. S., & Oh, J. (2014). Parthenolide V., & He, G. (2006). Antiproliferative activities of parthenolide and golden inhibits osteoclast differentiation and bone resorbing activity by down- feverfew extract against three human cancer cell lines. Journal of Medicinal regulation of NFATc1 induction and c-Fos stability, during RANKL-mediated Food, 9(1), 55-61. osteoclastogenesis. BMB Reports Online, 47(8), 451-456. 60. Pajak, B., Gajkowska, B., & Orzechowski, A. (2008). Molecular basis 78. Russell, G., Mueller, G., Shipman, C., & Croucher, P. (2001). Clinical disorders of parthenolide-dependent proapoptotic activity in cancer cells. Folia of bone resorption. Novartis Foundation Symposium, 232, 251-267, discussion Histochemica et Cytobiologica, 46(2), 129-135. 267-271. 61. Koprowska, K., & Czyz, M. (2010). [Molecular mechanisms of parthenolide’s 79. Piela-Smith, T. H., & Liu, X. (2001). Feverfew extracts and the sesquiterpene action: Old drug with a new face]. Postępy Higieny i Medycyny Doświadczalnej, lactone parthenolide inhibit intercellular adhesion molecule-1 expression in 64, 100-114. [Abstract Only – Article in Polish] human synovial fibroblasts.Cellular Immunology, 209(2), 89-96. 62. Xu, Y., Fang, F., Miriyala, S., Crooks, P. A., Oberley, T. D., Chaiswing, L., Noel, 80. Pattrick, M., Heptinstall, S., & Doherty, M. (1989). Feverfew in rheumatoid T., Holley, A. K., Zhao, Y., Kiningham, K. K., St. Clair, D. K., & St. Clair, W. H. (2013). arthritis: a double blind, placebo controlled study. Annals of the Rheumatic KEAP1 Is a Redox Sensitive Target That Arbitrates the Opposing Radiosensitive Diseases, 48(7), 547-549. Effects of Parthenolide in Normal and Cancer Cells. Cancer Research, 73(14), 81. Asgari, A., Parvin, N. (2013). The analgesic effect of ethanolic extract of 4406-4417. Tanacetum parthenium in acetic acid model. Zahedan Journal of Research in 63. Hayes, N. A., & Foreman, J. C. (1987). The activity of compounds extracted Medical Sciences, 15(8), 22-25. from Feverfew on histamine release from rat mast cells. The Journal of 82. Mannelli, L. D. C., Tenci, B., Zanardelli, M., Maidecchi, A., Lugli, A., Mattoli, L., Pharmacy and Pharmacology, 39(6), 466-470. & Ghelardini, C. (2015). Widespread pain reliever profile of a flower extract of 64. Jain, N. K., & Kulkarni, S. K. (1999). Antinociceptive and anti-inflammatory Tanacetum parthenium. Phytomedicine, 22(7-8). 752-758. effects of Tanacetum parthenium L. extract in mice and rats. Journal of 83. Francescato, H. D., Costa, R. S., Scavone, C., & Coimbra, T. M. (2007). Ethnopharmacology, 68(1-3), 251-259. Parthenolide reduces cisplatin-induced renal damage. Toxicology, 230(1), 64- 65. Dey, S., Sarkar, M., & Giri, B. (2016). Anti-inflammatory and Anti-tumor 75. Activities of Parthenolide: An Update. Journal of Chemical Biology and 84. Natural Medicines. (2016). Feverfew [Monograph]. Retrieved Online From: Therapeutics, 2(1), doi:10.4172/ jcbt.1000107. https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs- 66. Hehner, S. P., Heinrich, M., Bork, P. M., Vogt, M., Ratter, F., Lehmann, V., supplements/professional.aspx?productid=933. Schulze-Osthoff, K., Dröge, W., & Schmitz, M. L. (1998) Sesquiterpene lactones 85. Bone, K., & Mills, S. (2013). Principles and Practice of Phytotherapy, 2nd specifically inhibit activation of NF-kappa B by preventing the degradation of Edition. Great Britain: Churchill Livingstone Elsevier. I kappa B-alpha and I kappa B-beta. The Journal of Biological Chemistry, 273(3), 86. Yao, M., Ritchie, H. E., & Brown-Woodman, P. D. (2006). A reproductive 1288-1297. screening test of Feverfew: is a full reproductive study warranted?. 67. Fiebich, B. L., Lieb, K., Engels, S., & Heinrich, M. (2002). Inhibition of Reproductive Toxicology, 22(4), 688-693. OPTIMALRx P 1300 889 483 W E

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