(2004; 358 pages)
Herba Tanaceti Parthenii
Herba Tanaceti Parthenii consists of the dried leaves (1), or dried aerial parts of Tanacetum parthenium (L.) Schultz Bip. (Asteraceae) (2, 3).
Chrysanthemum parthenium (L.) Bernh., Leucanthemum parthenium (L.) Gren & Gordon, Matricaria eximia Hort., M. parthenium L., Pyrethrum parthenium (L.) Sm. (4-6). Asteraceae are also known as Compositae.
Selected vernacular names
Acetilla, âghovân, alfinetes de senhora, altamisa, altamisa mexicana, altamza, amargosa, artemijio, artemijo, artmija, bachelor’s buttons, boulet, bouton d’argent, camamieri, camomilla, camoumida, camsumilha, canamelha, featherfew, featherfoil, feather-fully, febrifuge plant, feverfew, feverfew tansy, flirtwort, grande camomille, hierba Santa Maria, manzanilla, matricaria, matricaria comum, midsummer daisy, Moederkruid, Mutterkraut, natsushirogiku, Santa Maria, varadika, vettervoo (3-5, 7).
Indigenous to south-east Europe, as far east as the Caucasus, but commonly found throughout Europe and the United States of America (8, 9).
A perennial plant up to 30-90 cm high. Stem up to 5mm in diameter, more or less branched. Leaves greenish-yellow, 2-5 cm, sometimes up to 10cm, long; pinnatisect to bipinnate, petiolate, alternate, more or less pubescent on both sides. Capitula grouped in wide corymbs of 5-30 florets, each floret with long pedicels, and 1.2-2.2 cm in diameter. Involucre in the shape of a hemisphere, 6-8mm wide and composed of numerous partly overlapping sheathing bracts; interior bracts narrow, obtuse, scarious and fragmented at apex; exterior bracts oval and membranous on edges. Central hermaphrodite flowers yellow, tubiform, 5-toothed, and have 5 stamens inserted on the corolla; filaments entirely free, but the anthers welded together in a tube, through which passes the style with its 2 stigmatic branches. Peripheral female flowers have a white 3-toothed ligule 2-7 mm long. Fruit an achene, 1.2-1.5mm long, brown when mature, with 5-10 white longitudinal ribs; glandular with a short membranous, crenulate crown (3, 5, 7, 10).
Plant material of interest: dried leaves or aerial parts
Stem bright green, longitudinally furrowed, almost quadrangular, slightly pubescent. Leaves pinnatisect or bipinnate, divided into 5-9 segments of which the lamina is coarsely crenate at edge, apex obtuse, a prominent central vein to the underside, both surfaces pubescent (1-3).
Odour: camphorous; taste: bitter (3).
Epidermal cells have sinuate walls, striated cuticle and anomocytic stomata, more frequent on the lower epidermis. Trichomes, more abundant on the lower epidermis, of 2 types: covering trichomes uniseriate, consisting of a trapezoidal basal cell with a striated cuticle composed of 3-5 small, rectangular, thickwalled cells, and elongated, tapering apical cells, often curved at 90° to the axis of the basal cell; glandular trichomes slightly sunken, composed of a short, biseriate, 2- or 4-celled stalk and a biseriate head of 4 cells, around which the cuticle forms a bladder-like covering; spherical, echinulate pollen grains about 25 µm in diameter with 3 germinal pores (1, 3).
Powdered plant material
Epidermal cells have sinuate walls and a striated cuticle. Numerous large multicellular, uniseriate trichomes, consisting of a trapezoidal basal cell with a striated cuticle composed of 3-5 small, rectangular, thick-walled cells, and terminated by elongated, tapering apical cells, often curved at 90° to the axis of the basal cell. Secretory hairs sparse, but typical of Asteraceae family. Numerous punctate spiral vessels; stratified parenchyma or collenchyma cells; isolated calcium oxalate crystals in the interior of the mesophyll (3).
General identity tests
Macroscopic and microscopic examinations, thin-layer chromatography, and high-performance liquid chromatography for the presence of parthenolide (1, 3).
Tests for specific microorganisms and microbial contamination limits are as described in the WHO guidelines on quality control methods for medicinal plants (11).
Foreign organic matter
Not more than 10%, including stems greater than 5mm in diameter (1, 3).
Not more than 12% (1, 3).
Not more than 3% (1, 2).
Not less than 15% (2).
Loss on drying
Not more than 10% (1, 3).
The recommended maximum limit of aldrin and dieldrin is not more than 0.05 mg/kg (12). For other pesticides, see the European pharmacopoeia (12), and the WHO guidelines on quality control methods for medicinal plants (11) and pesticide residues (13).
For maximum limits and analysis of heavy metals, consult the WHO guidelines on quality control methods for medicinal plants (11).
Where applicable, consult the WHO guidelines on quality control methods for medicinal plants (11) for the analysis of radioactive isotopes.
Other purity tests
Chemical, sulfated ash and alcohol-soluble extractive tests to be established in accordance with national requirements.
Contains not less than 0.2% parthenolide (dry weight), as determined by highperformance liquid chromatography (3).
Major chemical constituents
The major constituent is parthenolide (up to 0.9%), a germacranolide sesquiterpene lactone (14-16). Parthenolide and other characteristic sesquiterpene lactones, including members of the guaianolides (e.g. canin and artecanin), contain an α-methylenebutyrolactone structure. To date, more than 45 sesquiterpenes have been identified in Herba Tanaceti Parthenii. Monoterpenes, flavonoids and polyacetylenes have also been detected (1, 4, 10, 12, 17-19). The structures of the representative sesquiterpene lactones, parthenolide, 3β-hydroxyparthenolide, canin and artecanin, are presented below.
R = H
R = OH
Uses supported by clinical data
Prevention of migraine (20-24). Although Herba Tanaceti Parthenii has been used for treatment of rheumatoid arthritis, a clinical study failed to prove any beneficial effects (25).
Uses described in pharmacopoeias and traditional systems of medicine
Uses described in folk medicine, not supported by experimental or clinical data
Treatment of anaemia, arthritis, asthma, common cold, constipation, diarrhoea, dysmenorrhoea, dyspepsia, oedema, fever, indigestion, insect bites, rheumatism, sciatica, tinnitus, toothache and vertigo (4, 26-30).
Prevention and treatment of migraine
The mechanism of action of Herba Tanaceti Parthenii in the prevention of migraine is currently a matter of debate (27, 31, 32). However, based on pharmacological studies of the herb and parthenolide, the mechanism appears to be threefold: antiinflammatory activity, an effect on platelets and inhibition of serotonin binding.
Extracts of the herb and parthenolide both inhibit the biosynthesis of prostaglandins, leukotrienes and thromboxanes, collectively known as eicosanoids, which are potent mediators of inflammation. An aqueous extract of the herb (50 µg/ml) inhibited the activity of lipoxygenase in rat leukocytes in vitro, thereby reducing the biosynthesis of prostaglandins and thromboxane B2 (33). A chloroform extract of the leaves (IC50 < 50 µg/ml) inhibited the biosynthesis in vitro of leukotriene B4 and thromboxane B2 in human and rat leukocytes which had been stimulated by N-formyl-methionyl-leucyl-phenylalanine or the calcium ionophore A23187 (34). The powdered leaf inhibited arachidonic acid metabolism in Pseudomonas fluorescens in vitro (35). A buffered aqueous extract of the leaves (pH 7.4) inhibited the activity of phospholipase A2 in human platelets in vitro (30 µl). Phospholipase A2 facilitates the release of arachidonic acid (the precursor of the eicosanoids) from the cell membrane (36). The extract was also shown to prevent both arachidonic acid release and metabolism in human platelets in vitro (36, 37). A chloroform-methanol extract of the leaves (100 µl) inhibited the release of vitamin B12-binding protein in vitro from human polymorphonuclear leukocytes induced by N-formyl-methionylleucyl- phenylalanine or sodium arachidonate (38). An acetone, chloroform or saline extract of the leaves (IC50 0.79 mg/ml) inhibited oxidative burst in vitro in human polymorphonuclear leukocytes induced by phorbol 12-myristate 13- acetate (39, 40). A chloroform extract of the leaves inhibited histamine release in vitro in rat peritoneal mast cells stimulated by anti-IgE antibodies or the calcium ionophore A23187 (41). Parthenolide inhibited gene expression in vitro of cyclooxygenase and the proinflammatory cytokines, tumour necrosis factor-α and interleukin-1, in murine macrophages stimulated by lipopolysaccharide. Parthenolide also suppressed protein tyrosine phosphorylation in these cells, which correlated with its inhibitory effect on the expression of cyclooxygenase and the cytokines (42).
Effect on platelets
Another possible mechanism of action of the herb and its constituent sesquiterpene lactones involves the inhibition of platelet aggregation and serotonin release from platelets in response to various chemical stimuli (27, 43-45). Aqueous, chloroform or chloroform-methanol extracts of the leaves (up to 100 µl) inhibited human platelet aggregation in vitro induced by arachidonic acid, collagen or adrenalin (35, 36, 38, 44, 46, 47). A chloroform extract of the fresh leaves of Tanaceti parthenium completely inhibited human platelet aggregation in vitro. After fractionation of the extract, only fractions containing constituents with an α-methylenebutyrolactone functional group were active.
Parthenolide was the most active; canin, tanaparthin-α-peroxide and cis-cycloheptane lactone ester were partially active (48). Although the exact mechanism by which these compounds affect platelet function is unknown, it has been suggested that their ability to undergo Michael addition with thiol groups may influence their biological activity (48). The following evidence supports this hypothesis: addition of cysteine or 2-mercaptoethanol to the crude extract or parthenolide completely suppressed their ability to inhibit platelet aggregation. Furthermore, the inhibitory effects of the extract and parthenolide were both dose- and time-dependent, and treatment of platelets with the extract or parthenolide caused a dramatic reduction in the number of thiol groups (44, 45, 48). Acetone, chloroform or chloroform-methanol extracts of the leaves (100 µl) inhibited serotonin release in vitro from human platelets and polymorphonuclear leukocytes stimulated by arachidonic acid, adenosine diphosphate, collagen and adrenalin (38, 46, 47). A chloroform-methanol extract did not, however, inhibit serotonin release from human platelets or polymorphonuclear leukocytes stimulated by the calcium ionophore A23187 (38). A 95% ethanol extract of the leaves inhibited serotonin release from bovine platelets in vitro (IC50 1.3-2.9 mg/ml) (49). The ability of freeze-dried or air-dried aqueous leaf extracts to inhibit serotonin release from human platelets correlated with the concentration of parthenolide in the extracts (16, 32).
Inhibition of serotonin binding
Current evidence also indicates that serotonin receptor-based mechanisms are involved in the pathophysiology of migraine. In vitro studies have demonstrated that parthenolide displaces radioligand binding from cloned serotonin receptors and from serotonin receptors isolated from rat and rabbit brains, indicating that parthenolide may be a low-affinity antagonist (50).
A chloroform extract of the fresh leaves of Tanacetum parthenium inhibited the contractile response of isolated rings of rabbit aorta to exogenously applied serotonin-receptor agonists (serotonin, angiotensin, phenylephrine, thromboxane mimetic U48819 or thromboxane A2) (51, 52). However, a chloroform extract of the dried leaves which did not contain parthenolide or other sesquiterpene lactones was not active (52).
An in vitro study demonstrated that an extract of the herb or parthenolide was cytotoxic to human peripheral blood mononuclear cells induced by mitogens and synovial cells stimulated by interleukin-1 (53). Parthenolide-induced cytotoxicity was due to the inhibition of thymidine incorporation into DNA (54, 55). Intragastric administration of 100 times the normal daily dose for humans of powdered leaf to rats did not result in loss of appetite or weight (19).
Five randomized, double-blind, placebo-controlled studies have assessed the efficacy of various Herba Tanaceti Parthenii products for the prevention of migraine (21-23, 56, 57). Three of the trials used an encapsulated dried or freeze-dried leaf product (21-23), while one study used a 90% ethanol extract of the herb bound to microcrystalline cellulose (56). The remaining study was reported only as an abstract and the herb preparation used was not defined (57). These five trials were analysed recently by two independent reviewers (24). The data were analysed in a predefined, standardized fashion, and each trial was assessed using the Jadad scoring system. Although the data would suggest that the herb was more effective than a placebo in preventing migraine, a firm conclusion could not be reached given the shortcomings of the trials (such as small sample size, poor definition of inclusion criteria and lack of washout period) (24).
In the first study, 17 patients who had been treating themselves with the fresh leaves of Tanacetum parthenium for 3-4 years for migraine were recruited. Patients were administered an oral dose of 50 mg (concentration of parthenolide was not stated) of a freeze-dried leaf preparation or a placebo daily for 6 months. The average number of migraines in the treatment group was 1.69 over the whole treatment period and 1.50 during the final 3 months of the study, compared with 3.13 and 3.43, respectively, in the placebo group (21). Bouts of nausea and vomiting were reported 39 times in the treatment group, compared with 116 occasions in the placebo group. The reduction in frequency of nausea and vomiting was significant (P < 0.05) (20, 21).
In the second study, 59 patients with a history of migraine attacks were treated daily with either an encapsulated product containing 70-114 mg leaves (equivalent to 0.545 mg parthenolide) or a placebo, after a 1-month placebo runin. During this crossover trial, patients received the leaf product for 4 months and then a placebo for 4 months. During the treatment phase, a 24% decrease was reported in the number of migraines in the treatment group as compared with the number in the placebo group. No change in the duration of the migraine or in the proportion of attacks associated with an aura was observed in the treatment group. However, a significant reduction in the number of bouts of nausea and vomiting associated with the migraine was reported (P < 0.02). Global assessments of efficacy also demonstrated that the leaf product was significantly superior to the placebo in preventing migraines (P < 0.0001) (22).
In the third study, 57 patients were divided into two groups for the initial openlabel phase. Patients were treated with either a placebo or 100 mg encapsulated leaf preparation (standardized to contain 0.2 mg parthenolide) daily for 60 days. After the open-label phase, a randomized, double-blind, placebo-controlled, crossover study was carried out. Patients were again divided into two groups: 30 patients continued to receive 100 mg leaf preparation and 27 patients received a placebo. After 30 days, the treatments were crossed over (i.e. patients who had received the placebo were then given the leaf preparation, or vice versa) for a further 30 days. No washout period was allowed between each phase. Results of the open-label phase showed a significant reduction in pain intensity of migraines and symptoms such as vomiting, or sensitivity to light or noise in patients in the treatment group (P < 0.001). In the double-blind phase, patients in the treatment group reported a significant decrease in the pain intensity of migraines (P < 0.01), while patients in the placebo group noted an increase. Similar results were reported after the crossover. In the double-blind phase, a significant decrease in vomiting (P < 0.001) and light- and noise-sensitivity (P < 0.017) was observed in the treatment group compared with the placebo group (23).
A randomized, double-blind, placebo-controlled, crossover study assessed the efficacy of a 90% ethanol extract of the herb bound to microcrystalline cellulose in the prevention of migraine headache in 44 patients. Diagnosis was carried out using the International Headache Society diagnostic criteria. After an initial 1-month placebo run-in, patients were treated with either 143mg extract standardized to contain 0.5 mg parthenolide or placebo daily for 4 months, then the treatments were crossed over for a further 4 months (56). The average response to the two treatments was the same and the extract did not prevent migraines. Statistical significance was not reported.
A study without controls demonstrated that platelet aggregation in 10 patients who had taken preparations of the herb for 3.5-8.0 years was the same as in a control group of four patients who had stopped taking the herb for at least 6 months prior to being tested (58).
A double-blind, placebo-controlled trial assessed the efficacy of the herb for the treatment of rheumatoid arthritis. Forty women with rheumatoid arthritis were treated with either 70-86 mg of an encapsulated leaf product or a placebo daily for 6 weeks. No beneficial effects were observed (25).
Herba Tanaceti Parthenii is contraindicated in cases of known allergy to plants of the Asteraceae family, and during pregnancy (1, 19, 28).
No information available.
Carcinogenesis, mutagenesis, impairment of fertility
No significant differences were observed in the mean frequency of chromosomal aberrations or sister-chromatid exchange in the circulating peripheral lymphocytes of 30 patients who had taken Herba Tanaceti Parthenii for 11 months or longer. Urine samples from these patients did not induce a significant increase in the number of revertants in the Salmonella/microsome assay with or without metabolic activation (59).
Pregnancy: teratogenic effects
See Contraindications. The use of Herba Tanaceti Parthenii during pregnancy is contraindicated due to its uterotonic activity in vivo (19, 28).
Pregnancy: non-teratogenic effects
No information available on general precautions or precautions concerning drug interactions; drug and laboratory test interactions; nursing mothers; or paediatric use. Therefore, Herba Tanaceti Parthenii should not be administered during lactation or to children without medical supervision.
Dizziness, heartburn, indigestion, inflammation of the mouth and tongue with swelling of the lips, loss of taste, mouth ulceration, and weight gain have been reported (19, 21, 22). Mouth ulceration is a systemic reaction to Herba Tanaceti Parthenii and requires discontinuation of the product. Inflammation of the mouth and tongue with swelling of the lips appears to be a local reaction that may be overcome by using encapsulated herb products. Abdominal bloating, heart palpitations, constipation, diarrhoea, flatulence, increased menstrual flow, nausea and skin rashes have also been reported to a lesser degree (21, 22, 56). Allergic reactions, such as contact dermatitis, have also been reported (19). Cross-sensitivity between pollen allergens of other members of the Compositae family, Parthenium hysterophorus (American feverfew) and Ambrosia species (ragweed), has been reported (60).
Crude drug for decoction; powdered drug or extracts in capsules, tablets, tinctures and drops (2). Store in a well-closed container, protected from light and humidity (3).
(Unless otherwise indicated)
Daily dosage: encapsulated crude drug equivalent to 0.2-0.6mg parthenolide (as a chemical marker) for prevention of migraine (21-23, 27, 32).
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