Fenugreek

Summary and Pharmaceutical Comment

Fenugreek seeds contain a high proportion of mucilaginous fibre, together with various other pharmacologically active compounds including steroidal and amine components. The majority of the traditional uses of fenugreek are probably attributable to the mucilage content. In addition,

F hypocholesterolaemic and hypoglycaemic actions have been documented for fenugreek in both laboratory animals and humans. The mechanism by which fenugreek exerts these actions is unclear. Proposed theories include a reduction in carbohydrate absorption by the mucilaginous fibre, and an effect on cholesterol metabolism, cholesterol absorption and bile acid excretion by the saponin components. Toxicity studies indicate fenugreek seeds to be relatively non-toxic, although the presence of pharmacologically active constituents would suggest that excessive ingestion is inadvisable.

Species (Family)

Trigonella foenum-graecum L. (Leguminosae)

Synonym(s)

Bockshornsame

Figure 1 Selected constituents of fenugreek.

Part(s) Used

Seed

Pharmacopoeial and Other Monographs

BHP 1996(G9)

BP 2007(G84)

Complete German Commission E(G3)

Martindale 35th edition(G85)

Ph Eur 2007(G81)

Legal Category (Licensed Products)

GSL(G37)

Constituents

The following is compiled from several sources, including General Reference G2.

Alkaloids Pyridine-type. Gentianine, trigonelline (up to 0.13%), choline (0.05%).

Proteins and amino acids Protein (23–25%) containing high quantities of lysine and tryptophan. Free amino acids include 4- hydroxyisoleucine (0.09%), histidine, lysine and arginine.

Flavonoids Flavone (apigenin, luteolin) glycosides including orientin and vitexin, quercetin (flavonol).

Saponins 0.6–1.7%. Glycosides yielding steroidal sapogenins diosgenin and yamogenin (major), with tigogenin, neotigogenin, gitogenin, neogitogenin, smilagenin, sarsasapogenin, yuccagenin;(1) fenugreekine, a sapogenin-peptide ester involving dios-

genin and yamogenin;(2) trigofoenosides A–G (furostanol glycosides).(3–6)

Other constituents Coumarin,(7) lipids (5–8%),(8) mucilaginous fibre (50%),(8) vitamins (including nicotinic acid) and minerals.

Food Use

Fenugreek is listed by the Council of Europe as a natural source of food flavouring (category N2). This category indicates that fenugreek can be added to foodstuffs in small quantities, with a possible limitation of an active principle (as yet unspecified) in the final product.(G16) Previously fenugreek extracts have been permitted in foods at concentrations usually below 0.05%. In addition, fenugreek has been listed as GRAS (Generally Recognised As Safe).

Herbal Use

Fenugreek is stated to possess mucilaginous demulcent, laxative, nutritive, expectorant and orexigenic properties, and has been used topically as an emollient and vulnerary. Traditionally, it has been used in the treatment of anorexia, dyspepsia, gastritis and

convalescence, and topically for furunculosis, myalgia, lymphadenitis, gout, wounds and leg ulcers.(G2, G7, G22, G64)

Dosage

Dosages for oral administration (adults) for traditional uses recommended in older standard herbal reference texts are given below.

Seed 1–6 g or equivalent three times daily.(G49)

Figure 2 Fenugreek (Trigonella foenum-graecum).

Fenugreek 261

F

Figure 3 Fenugreek – dried drug substance (seed).

Pharmacological Actions

In vitro and animal studies

Hypocholesterolaemic activity has been reported for fenugreek in rats(9, G41) and alloxan-diabetic dogs.(10) Activity has been

attributed to the fibre and saponin fractions, and not to lipid or amino acid fractions.(9, 10) Studies have reported a reduction in cholesterol but not triglyceride concentrations,(9) or in both cholesterol and triglyceride concentrations, but without significant alterations in high-density lipoprotein (HDL) and lowdensity lipoprotein (LDL) concentrations.(10)

Hypoglycaemic activity has been observed in rabbits, rats and dogs, and attributed to the defatted seed fraction (DSF),(8) trigonelline, nicotinic acid and coumarin.(7, 11) Oral administration of DSF reduced hyperglycaemia in four alloxan-diabetic dogs, and reduced the response to an oral glucose tolerance test in eight normal dogs, whereas the lipid fraction had no effect on serum glucose and insulin concentrations.(8) The high fibre content (50%) of DSF was thought to contribute to its antidiabetic effect although the initial rate of glucose absorption was not affected.(8) Nicotinic acid and coumarin were reported to be the major hypoglycaemic components of fenugreek seeds, following administration to normal and alloxan-diabetic rats.(7) The hypoglycaemic action exhibited by coumarin was still significant 24 hours post administration.(7) In addition, a slight antidiuretic action was noted for coumarin.(7) Trigonelline inhibited cortisone-induced hyperglycaemia in rabbits if administered (250 mg/kg) concomitantly or two hours before, but not two hours after, cortisone.(11) In addition, trigonelline exhibited significant hypoglycaemic activity in alloxan-diabetic rats (50 mg/kg), lasting 24 hours.(11)

A stimulant action on the isolated uterus (guinea-pig), especially during late pregnancy, has been noted for both aqueous and alcoholic extracts.(G41) An aqueous extract is stated to

increase the number of heart beats in the isolated mammalian heart.(G41)

In vitro antiviral activity against vaccinia virus has been reported for fenugreekine, which also possesses cardiotonic, hypoglycaemic, diuretic, antiphlogistic and antihypertensive properties.(2)

Clinical studies

There is a lack of clinical research assessing the effects of fenugreek and rigorous randomised controlled clinical trials are required.

262 Fenugreek

A transient hypoglycaemic effect was observed in 5 of 10

diabetic patients who received 500 mg oral trigonelline whilst fasting.(11) Increasing the dose did not increase this effect, and

500 mg ingested three times a day for five days did not alter the diurnal blood glucose concentration.(11) Hypoglycaemic activity in healthy individuals has been reported for whole seed extracts, with slightly lesser activity exhibited by gum isolate, extracted seeds and cooked seeds.(12) The addition of fenugreek to an oral glucose tolerance test reduced serum glucose and insulin concentrations. Chronic ingestion (21 days) of extracted seeds (25 g seeds daily incorporated into two meals) by non-insulin- dependent diabetics improved plasma glucose and insulin

Fglucose concentrations.(12) Furthermore, in two diabetic insulindependent subjects, daily administration of 25 g fenugreek seed powder reduced fasting plasma-glucose profile, glycosuria and daily insulin requirements (56–20 units) after eight weeks. A

significant reduction in serum cholesterol concentrations in diabetic patients was also noted.(12)

Side-effects, Toxicity

None documented. However, there is a lack of clinical safety and toxicity data for fenugreek and further investigation of these

aspects is required. Acute toxicity values (LD50) documented for fenugreek alcoholic seed extract are 5 g/kg (rat, oral) and 2 g/kg (rabbit, dermal).(13) The alcoholic seed extract is reported to be

non-irritating and non-sensitising to human skin and nonphototoxic (mice, pigs).(13) Coumarin is a toxic seed component.(7) Acute LD50 (rat, oral) values per kilogram documented for various seed constituents are 5 g (trigonelline), 8.8 g (nicotinic acid), 7.4 g (nicotinamide) and 0.72 g (coumarin).(7)

Contra-indications, Warnings

Drug interactions None documented. However, the potential for preparations of fenugreek to interact with other medicines administered concurrently, particularly those with similar or opposing effects, should be considered. There is limited evidence from preclinical and preliminary clinical studies that fenugreek has hypoglycaemic activity. Caution may be advisable in patients receiving monoamine oxidase inhibitor (MAOI), hormonal or anticoagulant therapies in view of amine, steroidal saponin and coumarin constituents, respectively, although their clinical significance is unclear. Cardioactivity has been documented in vitro.

The absorption of drugs taken concomitantly with fenugreek may be affected (high mucilaginous fibre content).responses (no control group), and reduced 24-hour urinary

Pregnancy and lactation Fenugreek is reputed to be oxytocic(G22) and in vitro uterine stimulant activity has been

documented. In view of this, and the documented pharmacologically active components, the use of fenugreek during pregnancy and lactation in doses greatly exceeding those normally encountered in foods is not advisable.

Preparations

Proprietary single-ingredient preparations

France: Fenugrene; Sthenorex.

Proprietary multi-ingredient preparations

Australia: Garlic and Horseradish þ C Complex; Panax Complex. India: Happy'tizer. Malaysia: Horseradish Plus.

References

1Gupta RK et al. Minor steroidal sapogenins from fenugreek seeds,

Trigonella foenum-graecum. J Nat Prod 1986; 49: 1153.

2Ghosal S et al. Fenugreekine, a new steroidal sapogenin-peptide ester of Trigonella foenum-graecum. Phytochemistry 1974; 13: 2247–2251.

3 Gupta RK et al. Two furostanol saponins from Trigonella feonumgraecum. Phytochemistry 1986; 25: 2205–2207.

4Varshney IP et al. Saponins from Trigonella foenum-graecum leaves. J Nat Prod 1984; 47: 44–46.

5Gupta RK et al. Furostanol glycosides from Trigonella foenumgraecum seeds. Phytochemistry 1984; 23: 2605–2607.

6 Gupta RK et al. Furostanol glycosides from Trigonella foenumgraecum seeds. Phytochemistry 1985; 24: 2399–2401.

7Shani J et al. Hypoglycaemic effect of Trigonella foenum graecum and Lupinus termis (Leguminosae) seeds and their major alkaloids in alloxan-diabetic and normal rats. Arch Int Pharmacodyn Ther 1974;

210: 27–37.

8Ribes G et al. Hypocholesterolaemic and hypotriglyceridaemic effects of subfractions from fenugreek seeds in alloxan diabetic dogs.

Phytother Res 1987; 1: 38–42.

9Ribes G et al. Effects of fenugreek seeds on endocrine pancreatic secretions in dogs. Ann Nutr Metab 1984; 28: 37–43.

10Sharma RD. An evaluation of hypocholesterolemic factor of fenugreek seeds (T. foenum graecum) in rats. Nutr Rep Int 1986; 33: 669–677.

11Mishkinsky J et al. Hypoglycaemic effect of trigonelline. Lancet 1967; 2: 1311–1312.

12Sharma RD. Effect of fenugreek seeds and leaves on blood glucose and serum insulin responses in human subjects. Nutr Res 1986; 6: 1353– 1364.

13Opdyke DLJ. Fenugreek absolute. Food Cosmet Toxicol 1978; 16 (Suppl. Suppl.): 755–756.

Summary and Pharmaceutical Comment

Feverfew is characterised by the sesquiterpene lactone constituents, in particular by parthenolide which is thought to be the main active component. In vitro studies provide some evidence to support the reputation of feverfew as a herb used to treat migraine and arthritis. Some clinical studies have suggested that feverfew leaf preparations may be a useful prophylactic remedy against migraine, although further research is deemed necessary to establish the benefits. It has been recommended that feverfew should only be used by sufferers who have proved unresponsive to conventional forms of migraine treatment. Those using feverfew as a remedy for migraine should preferably do so under medical supervision.

Results of a study that investigated the usefulness of feverfew in treating rheumatoid arthritis were less encouraging: feverfew provided no additional benefit when added to existing non-steroidal anti-inflammatory treatment. Feverfew products currently available are unlicensed and vary in their recommended daily doses. Furthermore, variation between the stated and actual amount of feverfew in commercial products (based on their ability to inhibit platelet secretion) has been reported.

Species (Family)

Tanacetum parthenium (L.) Schultz Bip. (Asteraceae/Compositae)

Synonym(s)

Altamisa, Chrysanthemum parthenium (L.) Bernh., non (Lam.) Gaterau, Leucanthemum parthenium (L.) Gren & Godron,

Pyrethrum parthenium (L.) Sm.

Part(s) Used

Leaf, aerial parts

Pharmacopoeial and Other Monographs

BHC 1992(G6)

BHP 1996(G9)

BP 2007(G84)

ESCOP 2003(G76)

Martindale 35th edition(G85)

Ph Eur 2007(G81)

USP29/NF24(G86)

Legal Category (Licensed Products)

Feverfew is not included in the GSL.(G37)

Constituents

The following is compiled from several sources, including General Reference G6.

Terpenoids Sesquiterpene lactones: germacranolides (GE), guaianolides (GU) and eudesmanolides (EU). The structural

feature common to all three types is an a-unsaturated g-lactone moiety, and examples of each type include parthenolide, 3-b- hydroxy-parthenolide, costunolide, 3-b-hydroxycostunolide, artemorin, 8-a-hydroxyestafiatin and chrysanthemonin (novel dimeric nucleus) (GE); artecanin, chrysanthemin A (canin) and B (stereoisomers), chrysanthemolide, partholide, two chlorine-con-

taining sesquiterpene lactones (GU); magnolialide, reynosin, F

santamarine, 1-b-hydroxyarbusculin and 5-b-hydroxyreynosin (EU).(1–5)

Volatile oils (0.02–0.07%). Various monoterpene and sesquiterpene components (e.g. camphor, borneol, a-pinene derivatives, germacrene, farnesene and their esters).

Other constituents Pyrethrin, flavonoids, tannins (type unspecified) and melatonin.(6)

Food Use

Feverfew is not generally used in foods.

Herbal Use

Feverfew has traditionally been used in the treatment of migraine, tinnitus, vertigo, arthritis, fever, menstrual disorders, difficulty during labour, stomach ache, toothache and insect bites. Modern use of feverfew is focused on its effects in the prevention and treatment of migraine.(7, 8)

Feverfew products currently available are unlicensed adn vary in their recommended daily doses.(9)

Dosage

Limited information is available regarding the traditional dose of feverfew. The doses (oral administration, adults) that have been recommended for migraine prophylaxis are as follows.

Leaf (fresh) 2.5 leaves daily with or after food.

Figure 1 Selected constituents of feverfew.

264 Feverfew

Leaf (freeze-dried) 50 mg daily with or after food.

Aerial parts (dried) 50–200 mg daily; equivalent to 0.2–0.6 mg parthenolide daily.(G6, G52)

Clinical trials of feverfew for the prevention of migraine have assessed the effects of, for example, 143 mg of a dried alcoholic extract of feverfew daily (equivalent to 0.5 mg parthenolide),(10) and capsules containing powdered feverfew leaf 50 mg daily,(11, 12) for one to six months.

Pharmacological Actions

In vitro and animal studies

FFeverfew extracts have been documented to inhibit platelet aggregation and prostaglandin, thromboxane and leukotriene production, although feverfew has also been reported to have no

effect on cyclooxygenase (the mechanism by which non-steroidal anti-inflammatory drugs inhibit prostaglandin production).(13–15) Instead, feverfew is thought to act by inhibiting the enzyme

phospholipase A2, which facilitates the release of arachidonic acid from the phospholipid cellular membrane.(14–16) The clinical significance of this action has been questioned.(17) In addition, in

vitro experiments have shown that feverfew extracts inhibit the interaction of human platelets with collagen substrates.(18, 19) Feverfew has been shown to inhibit granule secretion in blood

platelets and neutrophils, which has been associated with the aetiology of migraine and rheumatoid arthritis, respectively.(20)

Feverfew was also found to inhibit the release of vitamin B12- binding protein from polymorphonuclear leukocytes, but to be

ineffective against platelet and polymorphonucleocyte secretion induced by calcium ionophore A2318.(20) Sesquiterpene lactone

constituents of feverfew containing an a-methylene butyrolactone unit are thought to be responsible for the antisecretory activity.(21) Their inhibitory effect on platelet aggregation is thought to involve neutralisation of sulfhydryl groups on specific enzymes of

proteins that are necessary for platelet aggregation and secretion.(22) A similar mode of action has been proposed for the

inhibitory action of feverfew on polymorphonuclocyte secretion.(23) In addition, feverfew extracts have been reported to

produce a concentration-dependent inhibition of anti-IgE-induced histamine release from mast cells.(24) The authors concluded that the mechanism of action of the feverfew extract was different to that of both cromoglycate and quercetin.

Parthenolide markedly interfered with contractile and relaxant mechanisms in blood vessels.(G52) An aqueous extract of feverfew

administered intravenously significantly inhibited collageninduced bronchoconstriction in guinea-pigs.(G52)

The presence of large numbers of lymphocytes and monocytes in the synovium is considered to be of significance in rheumatoid arthritis.(25) Feverfew extract and parthenolide have been documented to inhibit mitogen-induced proliferation of human peripheral blood mononuclear cells and mitogen-induced prostaglandin E2 (PGE2) production by synovial cells.(25) The feverfew extract and parthenolide also proved to be cytotoxic to mitogentreated peripheral blood mononuclear cells and the authors considered that this cytotoxicity was responsible for the actions observed.(25) In vitro studies using crude feverfew extracts and parthenolide have documented other activities that may contribute to the reported anti-inflammatory effects of feverfew. Pretreatment of human synovial fibroblasts with feverfew extract and with purified parthenolide inhibited cytokine-induced expression of intercellular adhesion molecule 1 (ICAM-1) expression.(26) A reduction in T cell adhesion to the treated fibroblasts also occurred. In other in vitro studies, parthenolide inhibited lipopolysaccharide-induced interleukin-12 (IL-12) production by mouse macrophages in a concentration-dependent manner.(27) Parthenolide has also been shown to inhibit promoter activity of the inducible nitric oxide synthase gene in a human monocyte cell line, THP-1, in a concentration-dependent manner.(28) (Excessive nitric oxide production in inflammatory cells is thought to be a causative factor in cellular injury in inflammatory disease.) Antiinflammatory activity of feverfew has also been attributed to the presence of flavonoids, e.g. santonin.(29)

Anti-inflammatory properties have also been documented for feverfew extract and parthenolide in vivo. Oral administration of

feverfew extract (10, 20 and 40 mg/kg) reduced carrageenaninduced oedema in rat paw in a dose-dependent manner.(30)

Intraperitoneal parthenolide (1 and 2 mg/kg) also demonstrated anti-inflammatory effects in this model.

Parthenolide has been documented to have cytotoxic activity in Eagle's 9KB carcinoma of the nasopharynx cell culture system, the activity being associated with the presence of an a-methylene-g- lactone moiety in the molecule.(31) In vitro, parthenolide has been shown to inhibit growth of mouse fibrosarcoma (MN-11) and human lymphoma (TK6) cell lines.(32) The effect appeared to be reversible.

Antinociceptive properties have been reported for feverfew and parthenolide in vivo. Oral administration of feverfew extract (10, 20 and 40 mg/kg) and intraperitoneal administration of parthe-

nolide (1 and 2 mg/kg) led to reductions in acetic acid-induced writhing in mice.(30)

Antimicrobial properties against Gram-positive bacteria, yeasts and filamentous fungi in vitro have been documented for parthenolide.(33) Gram-negative bacteria were not affected.

Clinical studies

Migraine Several placebo-controlled clinical trials have assessed

the effects of preparations of feverfew in the prevention of migraine.(10–12, 34)

A randomised, double-blind, placebo-controlled trial involved 17 patients who had been successfully controlling their migraine by eating raw feverfew leaves for at least three months.(11) Patients either continued to receive feverfew (50 mg daily) or were given placebo for six periods of four weeks. The authors reported that the placebo group experienced a significant increase in the frequency and severity of headache. Those given feverfew showed no change. It was suggested that the placebo group was in fact suffering withdrawal symptoms from feverfew and a 'postfeverfew syndrome' was described (see Side-effects, Toxicity).

Another study, a randomised double-blind, placebo-controlled, crossover trial involved 72 adults who had experienced migraine for more than two years and who had at least one attack per month.(34) The only concurrent medication allowed was the oral contraceptive pill. Patients completed a one-month, single-blind, placebo run-in phase, followed by four months' administration of placebo/active and four months' crossover. It was reported that patients experienced a 24% reduction in the number of attacks during feverfew treatment (one capsule daily; 70–114 mg feverfew equivalent to 2.19 mg parthenolide) although the duration of each individual attack was not significantly affected. Patients allocated to the active and then placebo group did not experience the withdrawal symptoms documented in another study,(11) although patients involved in the previous study had used feverfew over a longer period of time.

In a randomised, double-blind, placebo-controlled trial, 57 patients received capsules of dried, powdered feverfew leaves (parthenolide 0.2%) 100 mg daily for 60 days (open-label phase), followed by randomisation to feverfew or placebo (ground

parsley) for 30 days then crossover to the other arm for 30 days.(12) There was no wash-out between crossover. At the end of

the open-label phase (i.e. during which all participants received feverfew), there was a significant reduction in pain intensity and symptoms, such as vomiting and sensitivity to light, compared with baseline values (p < 0.001). At the end of the double-blind, crossover phase, it was reported that pain intensity was significantly lower during feverfew administration, compared with placebo administration (p < 0.01).

Thus, these three studies reported beneficial effects for feverfew, as demonstrated by fewer and/or less severe migraine episodes and/or reductions in pain intensity, compared with placebo.(11, 12, 34) However, one double-blind, placebo-controlled trial involving 50 feverfew-naïve patients who experienced migraine attacks at least once a month reported no difference in the number of migraine attacks between placebo recipients and participants who received capsules containing a dried alcoholic extract of feverfew equivalent to 0.5 mg parthenolide daily for nine months.(10) Another randomised, double-blind, placebo-controlled, crossover trial involving 20 patients with migraine assessed the effects of feverfew 100 mg daily for two months on serotonin uptake and platelet activity.(35) This trial found no effect for feverfew in the prevention of migraine attacks and also reported that feverfew

all in controlled clinical trials.

Rheumatoid arthritis A double-blind, placebo-controlled, noncrossover trial studying the use of feverfew in rheumatoid arthritis has also been documented.(37) Forty-one female patients with inflammatory joint symptoms inadequately controlled by nonsteroidal anti-inflammatory drugs were given either one feverfew capsule (70–86 mg equivalent to 2–3 mmol parthenolide) daily, or one placebo capsule, for six weeks. Current non-steroidal therapy was maintained. It was concluded that patients in the trial had experienced no additional benefit from feverfew.(37) The authors commented that while concomitant non-steroidal anti-inflamma- tory drug therapy has been stated to reduce the effectiveness of feverfew, the majority of rheumatoid arthritis sufferers will use feverfew to supplement existing therapy.

Side-effects, Toxicity

Clinical safety and toxicity data for feverfew is limited, and further investigation of these aspects is required.

Randomised, double-blind, placebo-controlled trials have documented the following adverse effects during feverfew administration, although most effects were also reported (sometimes more frequently) during placebo administration: mouth ulcers (reported more frequently during placebo administration in one study(34)), sore mouth, abdominal pain and indigestion, diarrhoea, flatulence, nausea, dizziness and skin rash.(10, 11, 34) On balance, adverse effects reported for feverfew are mild and transient, are similar to those reported during placebo administration and occur with a similar frequency.

A 'post-feverfew syndrome' has been described on stopping feverfew administration(11) (see Pharmacological Action, Clinical studies) with symptoms such as nervousness, tension headaches, insomnia, stiffness/pain in joints and tiredness.

The onset of side-effects with feverfew is reported to vary, with symptoms becoming apparent within the first week of treatment, or appearing gradually over the first two months.

Sesquiterpene lactones that contain an a-methylene butyrolactone ring are known to cause allergic reactions.(38, G51) Com-

pounds with this structure are present in feverfew and reports of contact dermatitis have been documented.(39–42) No documented allergic reactions following oral ingestion were located.

No chronic toxicity studies have been reported. However, detailed haematological analysis of 60 feverfew users, some of whom had used feverfew for more than one year, did not show any significant differences when compared with analysis of controls.(43) A human toxicity study has investigated whether the sesquiterpene lactones in feverfew induce chromosomal or other changes in normal human cells of individuals who have taken the

266 Feverfew

herb.(44) The study compared 30 chronic female feverfew users (leaves, tablets or capsules taken daily for more than 11 consecutive months) with matched non-users. The results of lymphocyte cultures established from blood samples taken over a period of several months were stated to indicate that feverfew affects neither the frequency of chromosomal aberrations nor the frequency of sister chromatid exchanges in the circulating peripheral lymphocytes.

Preclinical data

An LD50 value for feverfew has not been estimated. No adverse effects were reported for rats and guinea-pigs receiving feverfew at

Fdoses 100 and 150 times the human daily dose, respectively.(43)

Contra-indications, Warnings

Feverfew is contra-indicated in individuals with a known hypersensitivity to other members of the family Compositae (Asteraceae), such as chamomile, ragweed and yarrow. Feverfew should not be ingested by individuals who develop a rash on contact with the plant.

Feverfew should only be considered as a treatment for migraine that has proved unresponsive to conventional forms of medication. Although traditionally recommended as a remedy for rheumatic conditions, self-medication with feverfew should not be undertaken without first consulting a doctor.

Drug interactions None documented. However, in view of the documented pharmacological actions of feverfew, the potential for preparations of feverfew to interact with other medicines administered concurrently, particularly those with similar or opposing effects, should be considered.

Pregnancy and lactation Feverfew is contra-indicated during pregnancy. It is reputed to be an abortifacient and to affect the menstrual cycle. It is documented to modify menstrual flow, cause

abortion in cattle and induce uterine contraction in full-term women.(G30)

Preparations

Proprietary single-ingredient preparations

Australia: Herbal Headache Relief. Brazil: Tanaceto; Tenliv. Canada: Tanacet. UK: Tanacet.

Proprietary multi-ingredient preparations

Australia: Albizia Complex; Extralife Arthri-Care; Extralife

Migrai-Care; Guaiacum Complex.

References

1Stefanovic M et al. Sesquiterpene lactones from the domestic plant species Tanacetum parthenium L. (Compositae). J Serb Chem Soc

1985; 50: 435–441.

2Bohlmann F, Zdero C. Sesquiterpene lactones and other constituents from Tanacetum parthenium. Phytochemistry 1982: 21: 2543–2549.

3Osawa T, Taylor D. Revised structure and stereochemistry of chrysartemin B. Tetrahedron Lett 1977; 13: 1169–1172.

4Hylands DM, Hylands PJ. New sesquiterpene lactones from feverfew.

Phytochem Soc Eur Symp 1986: 17.

5 Wagner H et al. New chlorine-containing sesquiterpene lactones from

Chrysanthemum parthenium. Planta Med 1988; 54: 171–172.

6Murch SJ et al. Melatonin in feverfew and other medicinal plants. Lancet 1997; 350: 1598–1599.

7Awang DVC. Feverfew fever – a headache for the consumer. Herbalgram 1993; 29: 34–36.

8 Berry M. Feverfew. Pharm J 1994; 253: 806–808.

9 Baldwin CA et al. What pharmacists should know about feverfew. Pharm J 1987; 239: 237–238.

10De Weerdt CJ, Bootsma HPR, Hendriks H. Herbal medicines in migraine prevention. Randomized double-blind placebo-controlled crossover trial of a feverfew preparation. Phytomedicine 1996; 3: 225– 230.

11Johnson ES et al. Efficacy of feverfew as prophylactic treatment of migraine. BMJ 1985; 291: 569–573.

12Palevitch D et al. Feverfew (Tanacetum parthenium) as a prophylactic treatment for migraine: a double-blind placebo-controlled study. Phytother Res 1997; 11: 508–511.

13Collier HOJ et al. Extract of feverfew inhibits prostaglandin biosynthesis. Lancet 1980; ii: 922–973.

14Makheja AM, Bailey JM. The active principle in feverfew. Lancet 1981; ii, 1054.

15Capasso F. The effect of an aqueous extract of Tanacetum parthenium L. on arachidonic acid metabolism by rat peritoneal leucocytes. J Pharm Pharmacol 1986; 38: 71–72.

16Makheja AM, Bailey JM. A platelet phospholipase inhibitor from the medicinal herb feverfew (Tanacetum parthenium). Prostaglandins Leukot Med 1982: 8: 653–660.

17Biggs MJ et al. Platelet aggregation in patients using feverfew for migraine. Lancet 1982; ii: 776.

18Loesche W et al. Feverfew – an antithrombotic drug? Folia Haematol 1988; 115: 181–184.

19Groenewegen WA, Heptinstall S. Amounts of feverfew in commercial preparations of the herb. Lancet 1986; i: 44–45.

20Heptinstall S et al. Extracts of feverfew inhibit granule secretion in blood platelets and polymorphonuclear leucocytes. Lancet 1985; i: 1071–1073.

21Groenewegen WA et al. Compounds extracted from feverfew that have anti-secretory activity contain an a-methylene butyrolactone unit. J Pharm Pharmacol 1986; 38: 709–712.

22Heptinstall S et al. Extracts of feverfew may inhibit platelet behaviour via neutralization of sulphydryl groups. J Pharm Pharmacol 1987; 39: 459–465.

23Lösche W et al. Inhibition of the behaviour of human polynuclear leukocytes by an extract of Chrysanthemum parthenium. Planta Med

1988; 54: 381–384.

24Hayes NA, Foreman JC. The activity of compounds extracted from feverfew on histamine release from rat mast cells. J Pharm Pharmacol 1987; 39: 466–470.

25O'Neill LAJ et al. Extracts of feverfew inhibit mitogen-induced human peripheral blood mononuclear cell proliferation and cytokine mediated responses: a cytotoxic effect. Br J Clin Pharmac 1987; 23: 81–83.

26Piela-Smith TH, Liu X. Feverfew extracts and the sesquiterpene lactone partenolide inhibit intercellular adhesion molecule-1 expression in human synovial fibroblasts. Cell Immunol 2001; 209: 89–96.

27Kang BY et al. Inhibition of interleukin-12 production in lipopolysaccharide-activated mouse macrophages by parthenolide, a predominant sesquiterpene lactone in Tanacetum parthenium: involvement of nuclear factor-kappa-B. Immunol Lett 2001; 77: 159– 163.

28Fukuda K et al. Inhibition by parthenolide of phorbol ester-induced transcriptional activation of inducible nitric oxide synthase gene in a human monocyte cell line THP-1. Biochem Pharmacol 2000; 60: 595– 600.

29Williams CA et al. A biologically active lipophilic flavonol from

Tanacetum parthenium. Phytochemistry 1995; 38: 267–270.

30Jain NK, Kulkarni SK. Antinociceptive and anti-inflammatory effects of Tanacetum parthenium L. extract in mice and rats. J Ethnopharmacol 1999; 68: 251–259.

31Berry MI. Feverfew faces the future. Pharm J 1984; 232: 611–614.

32Ross JJ et al. Low concentrations of the feverfew component parthenolide inhibit in vitro growth of tumor lines in a cytostatic fashion. Planta Med 1999; 65: 126–129.

33Blakeman JP, Atkinson P. Antimicrobial properties and possible role in host–pathogen interactions of parthenolide, a sesquiterpene lactone

isolated from glands of Chrysanthemum parthenium. Physiol Plant Pathol 1979; 15: 183–192.

34Murphy JJ et al. Randomised double-blind, placebo-controlled trial of feverfew in migraine prevention. Lancet 1988; ii: 189–192.

35Kuritzky A et al. Feverfew in the treatment of migraine: its effects on serotonin uptake and platelet activity. Neurology 1994; 44(Suppl 2): A201.

36Pittler MH, Ernst E. Feverfew for preventing migraine (Review). Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No. CD002286

37Pattrick M et al. Feverfew in rheumatoid arthritis: a double blind, placebo controlled study. Ann Rheum Dis 1989; 48: 547–549.

38Rodríguez E et al. The role of sesquiterpene lactones in contact hypersensitivity to some North and South American species of

Feverfew 267

feverfew (Parthenium – Compositae). Contact Dermatitis 1977; 3: 155–162.

39 Burry J. Compositae dermatitis in South Australia: Contact dermatitis from Chrysanthemum parthenium. Contact Dermatitis 1980; 6: 445.

40 Mitchell JC et al. Allergic contact dermatitis caused by Artemisia and Chrysanthemum species. The role of sesquiterpene lactones. J Invest Dermatol 1971; 56: 98–101.

41 Schmidt RJ, Kingston T. Chrysanethemum dermatitis in South Wales; diagnosis by patch testing with feverfew (Tanacetum parthenium) extract. Contact Dermatitis 1985; 13: 120–127.

42 Mensing H et al. Airborne contact dermatitis. Der Hautarzt 1985; 36: 398–402.

43 Johnson S. Feverfew. London: Sheldon Press, 1984.

44 Johnson ES et al. Investigation of possible genetoxic effects of feverfew

in migraine patients. Hum Toxicol 1987; 6: 533–534.

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