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Feverfew

Botanical Name: Tanacetum parthenium (L.) Schultz Bip.
Pharmacopoeial Name: Tanaceti partheni herba.
Synonyms: Matricaria parthenium L.; Chrysanthemum parthenium (L.) Bernh.; Leucanthemum parthenium (L.) Gren. and Godron; Pyrethrum parthenium L. Sm.
Common Name: Feverfew.

herb description

Family

Asteraceae.

Parts Used

Aerial herb.

Common Forms

Fresh leaf.

Dried leaf, freeze-dried leaf.

Tincture: 1:5 25% ethanol.¹

Standardized Extract: Not less than 0.2% parthenolide content.

interactions review

Strategic Considerations

The modern use of feverfew as a specific for migraines followed its adoption by physicians at the London Migraine Clinic in the early 1980s, who investigated anecdotal reports of the effectiveness of the fresh leaf as a migraine prophylactic and treatment. ^2,3Following initial studies, its use spread rapidly to North America, and today the herb hovers in the lower ranks of the top-20 best-selling botanicals in the United States, partly because of the large number (29 million) of migraine sufferers seeking effective treatment for the often-refractory condition. This indication was never prevalent in Germany, and the herb is not mentioned by Weiss, ⁴ Wichtl, ⁵ or the German Commission E. ⁶ The first modern-use therapeutic monograph was in the British Herbal Compendium ¹ ; this has been superseded by a comprehensive monograph from the European Scientific Cooperative on Phytotherapy (ESCOP) ⁷ and recent reviews from Mills and Bone ⁸ and McKenna et al. ⁹

Despite its current public popularity, recent systematic reviews of the available controlled trial data suggest that the effectiveness of feverfew for migraine prophylaxis is not conclusively established beyond reasonable doubt, although most trials favor the herb against placebo and suggest it has a good safety profile. ^10,11

Interpretations of the pharmacodynamics of feverfew extracts that stress only the sesquiterpene lactone parthenolide as the active constituent responsible for the anti-inflammatory and antimigraine actions of the herb have been described as controversial, particularly the so-called serotonin-parthenolide hypothesis of migraine prophylaxis. ¹² The recent ESCOP monograph asserts that connections between the constituents of the herb and its migraine prophylactic action should be considered as complex and not definitively established. ⁷ However, a clearer picture may be emerging from recent studies.

Currently, the pharmacology of feverfew is being intensively reexamined after the discovery of the anti–nuclear factor kappa B (NF-κB) properties of parthenolide. ^13-15From an interactions perspective, given the pluripotent activities governed by this transcription factor, inhibition of NF-κB suggests several potentially valuable strategic interactions; these include modulation of adhesion molecule expression, ¹⁶ inhibition of inducible nitric oxide synthase (iNOS), ^17,18and possible targeting of antireperfusion injury, ¹⁹ as well as induction of apoptosis and modulation of drug resistance. ^20,21Parthenolide also appears to be a thiol depleter, which may be part of the mechanism underlying its antiaggregatory effect. ^22,23The induction of apoptosis by parthenolide also involves thiol antioxidant modulation. ^21,24The presence of NF-κB in platelets also suggest that this factor may have a role in aggregation, independently of gene regulation. ²⁵

Parthenolide has recently been shown to be a selective inducer of apoptosis in cells from chronic lymphocytic leukemia (CLL) patients at the relatively low median inhibitory concentration (IC50) of 6.2 µmol. ²⁶ Increasing research interest in the anticancer properties of feverfew and parthenolide are expanding the “herb for migraine” conception of the botanical that characterized feverfew in the late twentieth century.

The official ESCOP monograph lists no known interactions between feverfew and pharmaceuticals, and interactions reports are absent from the literature, although some secondary sources persistently assert an interaction between feverfew and warfarin ^7,27(see Theoretical, Speculative, and Preliminary Interactions Research). An interaction with drugs targeting hemostasis is theoretically more likely with antiplatelet thrombolytics, but depending on context and intent, such interactions are as likely to be beneficial as adverse. Protection against gastropathies induced by nonsteroidal anti-inflammatory drugs (NSAIDs) is a more than theoretically possible interaction, and although evidence for adjunctive interactions in oncological therapies (involving NF-κB–mediated activities) is preliminary, this may be an area of future interest as research evidence continues to emerge.

Pharmacokinetic data on the herb are meager; a recent report suggests that parthenolide and other sesquiterpene lactones exhibit a high degree of protein binding in human plasma. ²⁸ The metabolic fate of parthenolide and its possible modulation of the cytochrome P450 (CYP450) system is unknown, but to date the herb does not appear to be associated with any obvious pharmacokinetic interactions.

herb-drug interactions

Indomethacin and Related Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Evidence: Indomethacin (indometacin; Indocin, Indocin-SR).

Extrapolated, based on similar properties: Nonsteroidal anti-inflammatory drugs (NSAIDs): COX-1 inhibitors:Diclofenac (Cataflam, Voltaren), combination drug: diclofenac and misoprostol (Arthrotec), diflunisal (Dolobid), etodolac (Lodine), fenoprofen (Dalfon), furbiprofen (Ansaid), ibuprofen (Advil, Excedrin IB, Motrin, Motrin IB, Nuprin, Pedia Care Fever Drops, Provel, Rufen), combination drug: hydrocodone and ibuprofen (Reprexain, Vicoprofen), indomethacin (indometacin; Indocin, Indocin-SR), ketoprofen (Orudis, Oruvail), ketorolac (Acular ophthalmic, Toradol), meclofenamate (Meclomen), mefenamic acid (Ponstel), meloxicam (Mobic), nabumetone (Relafen), naproxen (Aleve, Anaprox, Naprosyn), oxaprozin (Daypro), piroxicam (Feldene), salsalate (salicylic acid; Amigesic, Disalcid, Marthritic, Mono Gesic, Salflex, Salsitab), sulindac (Clinoril), tolmetin (Tolectin). COX-2 inhibitor:Celecoxib (Celebrex).

Prevention or Reduction of Drug Adverse Effect

Probability: 3. Possible
Evidence Base:

Preliminary

Effect and Mechanism of Action

The anti-inflammatory effects of feverfew may protect against gastropathic adverse effects of indomethacin and possibly other NSAIDs occurring with chronic use of these agents.

Research

In a rodent model of experimentally induced gastric ulceration by ethanol, oral pretreatment with either feverfew extract or parthenolide 24 hours before ethanol administration created protective effects ranging between 34% and 100% for the extract and 27% and 100% for parthenolide. At doses of 40 mg/kg body weight, the mean ulcer index declined from 4.8 (control) to 1.4 for the extract and 0.5 for parthenolide. ²⁹ The researchers used Tanacetum larvatum(Grisb. ex Pant), a related feverfew species with a higher parthenolide content (1.1%) than T. parthenium,to examine the ulceroprotective effects of the herb against indomethacin-induced ulcers in rodents. They concluded that there was significant reduction of the ulcerogenic effect at 50 mg/kg orally, given after indomethacin (not pretreatment). The same extract significantly reduced NF-κB activation in two assay methods, at levels of 20 µg/mL. They also examined the anti-inflammatory effect of combining indomethacin and the herbal extract on the rat-paw carrageenan model and concluded that although there was slight synergy of effect for the combination, it was not significant. ²⁹

Previous studies on the ulceroprotective effects of dihydroleucodine, a sesquiterpene lactone from Artemisia douglasiana,support the hypothesis that the protective effects are caused by increased mucus secretion, which is significantly reduced by indomethacin. ³⁰ More recently, unrelated investigations have shown that indomethacin markedly activates mucosal NF-κB 48 hours after administration, lending indirect support to the hypothesis that the therapeutic effects of feverfew are mediated through inhibition of this transcription factor. ³¹

Integrative Therapeutics, Clinical Concerns, and Adaptations

The protective effectiveness of feverfew extracts in ameliorating NSAID-induced gastropathy is experimentally established, and positive data are available relating to indomethacin. In practice, unless feverfew is an agent of choice for therapeutic reasons, primarily migraine or arthritis, other botanical agents, such as licorice or aloe, may have a superior cost/risk profile to feverfew for this purpose. Toxicological data on possible mutagenicity of feverfew is controversial, although otherwise the extract has a good safety profile. In addition, additive or synergistic anti-inflammatory effects are therapeutically preferable, and in the case of feverfew and NSAIDs, this synergism has not been clearly demonstrated; a controlled trial of 50 migraine patients found no significant difference between placebo and control groups. ³² However, use of anti-inflammatory medications by patients in the feverfew group showed a decline over the 9-month trial period.

Taxanes: Paclitaxel, Docetaxel

Evidence: Docetaxel (Taxotere), paclitaxel (Paxene, Taxol), paclitaxel, protein-bound (Abraxane).

Extrapolated, based on similar properties: Chemotherapeutic agents that activate NF-κB: Cisplatin ( cis-diaminedichloroplatinum, CDDP; Platinol, Platinol-AQ), daunorubicin (Cerubidine, DaunoXome), doxorubicin (Adriamycin, Rubex), doxorubicin, pegylated liposomal (Caelyx, Doxil, Myocet), epirubicin (Ellence, Pharmorubicin), etoposide (Eposin, Etopophos, Vepesid, VP-16), idarubicin (Idamycin, Zavedos), irinotecan (camptothecin-11, CPT-11; Campto, Camptosar), tamoxifen (Nolvadex), topotecan (Hycamtin), vinblastine (Alkaban-AQ, Velban, Velsar), vincristine (Leurocristine, Oncovin, Vincasar PFS), vinorelbine (Navelbine).

Potential or Theoretical Beneficial or Supportive Interaction, with Professional Management

Probability: 4. Plausible
Evidence Base:

Preliminary

Effect and Mechanism of Action

Parthenolide experimentally increases the sensitivity of breast cancer cells with constitutively active NF-κB expression to apoptosis-inducing effects of taxanes. This is likely a specific case of general chemosensitization by naturally occurring NF-κB inhibitors to chemotherapeutic agents known to have antiapoptotic effects of NF-κB. Clinical support for the interaction is not available.

Research

Parthenolide and feverfew extracts both exhibit NF-κB inhibitory actions. ^13-15 This transcription factor is involved in multiple effects in cancer biology, including cell survival, adhesion, inflammation, proliferation, and metastasis, as well as chemoresistance, and its expression can be modulated by a range of chemopreventive natural compounds. ^33,34 Paradoxically, a number of cytotoxic chemotherapeutic agents activate NF-κB, leading to chemoresistance. ^35,36 Cory and Cory ³⁷ found that parthenolide acted as an augmenter of apoptosis through NF-κB inhibition in a leukemia cell line, and later they studied an NF-κB–expressing subset of breast cancer cells that were chemoresistant to paclitaxel. The sensitivity to the chemotherapeutic agent could be increased in the malignant cells both by I-κB-α superrepressor and parthenolide. The effect was not replicated in nonmalignant cells. The authors suggest that the active ingredients of herbs may be useful in increasing the chemosensitivity of cancers with constitutively active NF-κB. ^20,37

An in vivo and in vitro study using three breast cancer lines found that parthenolide combined with docetaxel increased the antiapoptotic and antimetastatic effects of the taxane, and that the effect was accompanied by lower tumor levels of NF-κB. ³⁸ Another NF-κB–related effect has been demonstrated with tamoxifen resistance reduction and parthenolide in MCF7 cells. ³⁹ Thiol and redox status may also relate to the important differential effects of parthenolide on apoptosis between malignant and normal cells. ^21,24 Parthenolide acted as an in vitro sensitizer to the NSAID sulindac in a pancreatic carcinoma cell line. The effect of the combination was synergistic (greater than either agent alone), suggesting possible preclinical support for combining parthenolide with other NF-κB inhibitors in chemotherapy. ⁴⁰ For example, parthenolide combined with dehydroepiandrosterone (DHEA) attenuated tumor growth in vivo in a murine model compared to either agent alone. ⁴¹ Weak synergistic effects of parthenolide with other constituents of the whole herb on growth inhibition for two breast and one endometrial cancer cell lines were found in the case of the flavonoids apigenin and luteolin by Wu et al. ⁴²

Integrative Therapeutics, Clinical Concerns, and Adaptations

This potential interaction may be of considerable significance, although it currently lacks clinical support and must be regarded as preliminary. Incorporation into chemotherapy protocols at this time should be considered only by practitioners with solid clinical grounding in integrative oncology and may be specifically limited to issues related to chemotherapy-induced NF-κB activation.

Acetylsalicylic Acid, Clopidogrel, Ticlopidine, and Other Antiplatelet Thromboprophylactics

Evidence: Acetylsalicylic acid (acetosal, acetyl salicylic acid, ASA, salicylsalicylic acid; Arthritis Foundation Pain Reliever, Ascriptin, Aspergum, Asprimox, Bayer Aspirin, Bayer Buffered Aspirin, Bayer Low Adult Strength, Bufferin, Buffex, Cama Arthritis Pain Reliever, Easprin, Ecotrin, Ecotrin Low Adult Strength, Empirin, Extra Strength Adprin-B, Extra Strength Bayer Enteric 500 Aspirin, Extra Strength Bayer Plus, Halfprin 81, Heartline, Regular Strength Bayer Enteric 500 Aspirin, St. Joseph Adult Chewable Aspirin, ZORprin); combination drugs: ASA and caffeine (Anacin); ASA, caffeine, and propoxyphene (Darvon Compound); ASA and carisoprodol (Soma Compound); ASA, codeine, and carisoprodol (Soma Compound with Codeine); ASA and codeine (Empirin with Codeine); ASA, codeine, butalbital, and caffeine (Fiorinal).

Extrapolated, based on similar properties: Cilostazol (Pletal), clopidogrel (Plavix), dipyridamole (Permole, Persantine), ticlopidine (Ticlid), combination drug: ASA and extended-release dipyridamole (Aggrenox, Asasantin).

Potential or Theoretical Adverse Interaction of Uncertain Severity

Probability: 5. Improbable
Evidence Base:

Inadequate

Effect and Mechanism of Action

Aspirin (acetylsalicylic acid, ASA) is a well-documented antiplatelet agent acting through inhibition of cyclooxygenase production of thromboxane A ² (TXA ² ). Ticlopidine interacts with glycoprotein IIb/IIIa to inhibit fibrinogen binding to activated platelets and has been used for prevention of thrombosis when aspirin is poorly tolerated. Because of reports of hematological adverse effects associated with ticlopidine, clopidogrel (Plavix) is currently the preferred antiplatelet agent in such cases. As with ticlopidine, clopidogrel is another irreversible antiplatelet drug operating through adenosine diphosphate (ADP) receptor antagonism. The potential interaction is thus a theoretical additive pharmacodynamic increase in antiplatelet activity. Such an additive effect may theoretically increase the likelihood of bleeding disorders related to disturbances of primary hemostasis.

Research

In vitro investigations have demonstrated antiaggregatory actions of feverfew extracts and isolated parthenolide. Several aggregatory stimuli are inhibited by parthenolide, including ADP, collagen, and arachidonate. ^43-46 Platelet secretory activity is also inhibited by parthenolide, reducing 5-hydroxytryptamine (5-HT, serotonin) release. ^44,47,48 Thiol depletion plays a significant role in the mechanism. ^22,49,50 Interestingly, the antiaggregatory effects of feverfew extracts and isolated parthenolide appear to be equivalent in magnitude. ⁵¹

In a comprehensive review of antiplatelet activity of plant compounds, Venton et al. ⁵² stressed that because the relevant assay technologies are currently quite straightforward, many plant extracts and isolated compounds have been screened in vitro for platelet-inhibiting properties. Although many potentially active compounds that inhibit activation by one or more agonists have been identified, none has yet been transformed into a clinically effective antithrombotic drug. ⁵² Other than the pharmacokinetic modeling studies by Boik, ³³ there has been little attempt to create meaningful algorithms to extrapolate in vitro IC ⁵⁰ values from the different study methods into meaningful estimates of likely therapeutic levels of the compounds after therapeutic oral doses of herb.

Reports

There are no preclinical studies or clinical reports confirming this interaction. On the contrary, the original clinical investigators of feverfew at the London Migraine Clinic reported to the Lancetin 1982 that they had tested 10 patients who had taken feverfew for 3½ to 8 years and assayed dose–aggregatory response curves to several platelet agonists, including ADP, thrombin, serotonin, and a prostaglandin analog (U46619). Aggregation responses to ADP and thrombin were identical to controls who had not taken feverfew for 6 months. ⁵³ This was in direct conflict with in vitro findings of Makheja and Bailey ⁴³ published earlier in 1982, confirming that extrapolation from in vitro activity to in vivo effects is problematic.

Clinical Implications and Adaptations

At present, this potential interaction can be considered clinically insignificant, if in fact it exists. Monitoring migraine or arthritis patients who may be combining substantial doses of feverfew chronically with antiplatelet drugs for signs relating to disturbances of primary hemostasis may be prudent (e.g., petechiae, ecchymoses, superficial bleeds at mucous membranes).

theoretical, speculative, and preliminary interactions research, including overstated interactions claims

5-Hydroxytryptamine Receptor Agonists (Triptans)

Almotriptan (Axert), eletriptan (Relpax), frovatriptan (Frova), naratriptan (Amerge), rizatriptan (Maxalt), sumatriptan (Imitrex), zolmitriptan (Zomig).

There is no evidence of interaction between feverfew and the triptan drugs used for prophylaxis and treatment of migraine. Triptans are potent 5-HT agonists, and most triptans undergo metabolism by either monoamine oxidase A or CYP450 1A2 or 3A4. The serotonin hypothesis of feverfew pharmacology is no longer considered credible, and although direct evidence is lacking, obvious effects of the herb on CYP450 enzymes appear unlikely, therefore currently ruling out plausible pharmacokinetic and pharmacodynamic mechanisms for a feverfew-triptan interaction.

Anisindione (Miradon), dicumarol, ethyl biscoumacetate (Tromexan), nicoumalone (acenocoumarol; Acitrom, Sintrom), phenindione (Dindevan), phenprocoumon (Jarsin, Marcumar), warfarin (Coumadin, Marevan, Warfilone).

Although denied by authoritative secondary sources, a warfarin-feverfew interaction has been suggested by some derivative sources, based on in vitro antiplatelet activity previously discussed. Clinical evidence for this interaction is currently lacking.

Citations

1.Bradley P. British Herbal Compendium. 1 vol. Bournemouth, UK: British Herbal Medical Association; 1992.
2.Johnson S. Feverfew—a Traditional Herbal Remedy for Migraine and Arthritis. London: Sheldon Press; 1984.
3.Johnson ES, Kadam NP, Hylands DM, Hylands PJ. Efficacy of feverfew as prophylactic treatment of migraine. Br Med J (Clin Res Ed) 1985;291:569-573.View Abstract
4.Weiss R. Herbal Medicine. Meuss A, Translator. 6th ed. Beaconsfield, UK: Beaconsfield Publishers Ltd; 1988.
5.Bisset N. Wichtl’s Herbal Drugs and Phytopharmaceuticals. 2nd ed. Stuttgart: Medpharm GmbH; 1994.
6.Blumenthal M, Busse W, Goldberg A et al. The Complete German Commission E Monographs. Austin, Texas: American Botanical Council: Integrative Medicine Communications; 1998.
7.ESCOP. Tanceti Partheni Herba. ESCOP Monographs: the Scientific Foundation for Herbal Medicinal Products. 2nd ed. Exeter, UK: European Scientific Cooperative on Phytotherapy and Thieme; 2003:492-498.
8.Mills S, Bone K. Principles and Practice of Phytotherapy. Edinburgh: Churchill Livingstone; 2000.
9.McKenna D, Jones K, Hughes K, Humphrey S. Feverfew. Botanical Medicines. 2nd ed. Binghamton, NY: Haworth Press; 2002:349-373.
10.Ernst E, Pittler MH. The efficacy and safety of feverfew (Tanacetum parthenium L.): an update of a systematic review. Public Health Nutr 2000;3:509-514.View Abstract
11.Pittler M, Ernst E. Feverfew for preventing migraine. Cochrane Database Syst Rev 2004;1:CD002286.View Abstract
12.Awang DVC. Prescribing therapeutic feverfew (Tanacetum parthenium (L.) Schultz Bip., syn. Chrysanthemum parthenium (L.) Bernh.). Integr Med 1998;1:11-13.
13.Rungeler P, Castro V, Mora G et al. Inhibition of transcription factor NF-κB by sesquiterpene lactones: a proposed molecular mechanism of action*1. Bioorg Med Chem 1999;7:2343-2352.View Abstract
14.Koch E, Klaas CA, Rungeler P et al. Inhibition of inflammatory cytokine production and lymphocyte proliferation by structurally different sesquiterpene lactones correlates with their effect on activation of NF-κB1. Biochem Pharmacol 2001;62:795-801.View Abstract
15.Kwok BH, Koh B, Ndubuisi MI et al. The anti-inflammatory natural product parthenolide from the medicinal herb feverfew directly binds to and inhibits IκB kinase. Chem Biol 2001;8:759-766.View Abstract
16.Piela-Smith TH, Liu X. Feverfew extracts and the sesquiterpene lactone parthenolide inhibit intercellular adhesion molecule-1 expression in human synovial fibroblasts. Cell Immunol 2001;209:89-96.View Abstract
17.Fiebich BL, Lieb K, Engels S, Heinrich M. Inhibition of LPS-induced p42/44 MAP kinase activation and iNOS/NO synthesis by parthenolide in rat primary microglial cells. J Neuroimmunol 2002;132:18-24.View Abstract
18.Fukuda K, Hibiya Y, Mutoh M 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.View Abstract
19.Hausenloy DJ, Yellon DM. New directions for protecting the heart against ischaemia-reperfusion injury: targeting the reperfusion injury salvage kinase (RISK) pathway. Cardiovasc Res 2004;61:448-460.View Abstract
20.Cory AH, Cory JG. Augmentation of apoptosis responses in p53-deficient L1210 cells by compounds directed at blocking NF-κB activation. Anticancer Res 2001;21:3807-3811.View Abstract
21.Wen J, You KR, Lee SY et al. Oxidative stress-mediated apoptosis: the anticancer effect of the sesquiterpene lactone parthenolide. J Biol Chem 2002;277:38954-38964.View Abstract
22.Heptinstall S, Groenewegen WA, Spangenberg P, Loesche W. Extracts of feverfew may inhibit platelet behaviour via neutralization of sulphydryl groups. J Pharm Pharmacol 1987;39:459-465.View Abstract
23.Heptinstall S. Feverfew—an ancient remedy for modern times? J R Soc Med 1988;81:373-374.
24.Zhang S, Ong C-N, Shen H-M. Critical roles of intracellular thiols and calcium in parthenolide-induced apoptosis in human colorectal cancer cells. Cancer Lett 2004;208:143-153.View Abstract
25.Liu F, Morris S, Epps J, Carroll R. Demonstration of an activation regulated NF-κB/I-κBα complex in human platelets. Thromb Res 2002;106:199-203.View Abstract
26.Steele AJ, Jones DT, Ganeshaguru K et al. The sesquiterpene lactone parthenolide induces selective apoptosis of B-chronic lymphocytic leukemia cells in vitro. Leukemia 2006;20:1073-1079.View Abstract
27.Heck AM, DeWitt BA, Lukes AL. Potential interactions between alternative therapies and warfarin. Am J Health Syst Pharm 2000;57:1221-1227; quiz 1228-1230.
28.Wagner S, Kratz F, Merfort I. In vitro behaviour of sesquiterpene lactones and sesquiterpene lactone-containing plant preparations in human blood, plasma and human serum albumin solutions. Planta Med 2004;70:227-233.View Abstract
29.Tournier H, Schinella G, de Balsa EM et al. Effect of the chloroform extract of Tanacetum vulgare and one of its active principles, parthenolide, on experimental gastric ulcer in rats. J Pharm Pharmacol 1999;51:215-219.View Abstract
30.Maria AO, Franchi AM, Wendel GH et al. Gastric cytoprotective activity of dehydroleucodine in rats: role of prostaglandins. Biol Pharm Bull 1998;21:335-338.View Abstract
31.Ianaro A, Ialenti A, Maffia P et al. Role of cyclopentenone prostaglandins in rat carrageenin pleurisy. FEBS Lett 2001;508:61-66.View Abstract
32. DeWeerdt C, Bootsma H, Hendricks H. Herbal medicines in migraine prevention. Phytomedicine 1996;3:225-230.
33.Boik J. Natural Compounds in Cancer Therapy. Princeton, Minn: Oregon Medical Press; 2001.
34.Bharti AC, Aggarwal BB. Nuclear factor-kappa B and cancer: its role in prevention and therapy. Biochem Pharmacol 2002;64:883-888.View Abstract
35.Bharti AC, Aggarwal BB. Chemopreventive agents induce suppression of nuclear factor-κB leading to chemosensitization. Ann N Y Acad Sci 2002;973:392-395.View Abstract
36.Pahl HL. Activators and target genes of Rel/NF-κB transcription factors. Oncogene 1999;18:6853-6866.View Abstract
37.Cory AH, Cory JG. Lactacystin, a proteasome inhibitor, potentiates the apoptotic effect of parthenolide, an inhibitor of NF-κB activation, on drug-resistant mouse leukemia L1210 cells. Anticancer Res 2002;22:3805-3809.View Abstract
38.Sweeney CJ, Mehrotra S, Sadaria MR et al. The sesquiterpene lactone parthenolide in combination with docetaxel reduces metastasis and improves survival in a xenograft model of breast cancer. Mol Cancer Ther 2005;4:1004-1012.View Abstract
39. DeGraffenried LA, Chandrasekar B, Friedrichs WE et al. NF-κB inhibition markedly enhances sensitivity of resistant breast cancer tumor cells to tamoxifen. Ann Oncol 2004;15:885-890.View Abstract
40.Yip-Schneider MT, Nakshatri H, Sweeney CJ et al. Parthenolide and sulindac cooperate to mediate growth suppression and inhibit the nuclear factor-kappa B pathway in pancreatic carcinoma cells. Mol Cancer Ther 2005;4:587-594.View Abstract
41.Taguchi T, Takao T, Iwasaki Y et al. Suppressive effects of dehydroepiandrosterone and the nuclear factor-κB inhibitor parthenolide on corticotroph tumor cell growth and function in vitro and in vivo. J Endocrinol 2006;188:321-331.View Abstract
42.Wu C, Chen F, Rushing JW et al. Antiproliferative activities of parthenolide and golden feverfew extract against three human cancer cell lines. J Med Food 2006;9:55-61.View Abstract
43.Makheja AN, Bailey JM. A platelet phospholipase inhibitor from the medicinal herb feverfew (Tanacetum parthenium). Prostaglandins Leukot Med 1982;8:653-660.View Abstract
44.Heptinstall S, White A, Williamson L, Mitchell JR. Extracts of feverfew inhibit granule secretion in blood platelets and polymorphonuclear leucocytes. Lancet 1985;1:1071-1074.View Abstract
45.Loesche W, Mazurov AV, Voyno-Yasenetskaya TA et al. Feverfew—an antithrombotic drug? Folia Haematol Int Mag Klin Morphol Blutforsch 1988;115:181-184.
46.Loesche W, Groenewegen WA, Krause S et al. Effects of an extract of feverfew (Tanacetum parthenium) on arachidonic acid metabolism in human blood platelets. Biomed Biochim Acta 1988;47:S241-243.View Abstract
47.Groenewegen WA, Knight DW, Heptinstall S. Compounds extracted from feverfew that have anti-secretory activity contain an alpha-methylene butyrolactone unit. J Pharm Pharmacol 1986;38:709-712.View Abstract
48.Marles RJ, Kaminski J, Arnason JT et al. A bioassay for inhibition of serotonin release from bovine platelets. J Nat Prod 1992;55:1044-1056.View Abstract
49.Heptinstall S, Groenewegen WA, Spangenberg P, Losche W. Inhibition of platelet behaviour by feverfew: a mechanism of action involving sulphydryl groups. Folia Haematol Int Mag Klin Morphol Blutforsch 1988;115:447-449.View Abstract
50.Till U, Bergmann I, Breddin K et al. Sulfhydryl/disulfide-status of blood platelets: a target for pharmacological intervention? Prog Clin Biol Res 1989;301:341-345.
51.Groenewegen WA, Heptinstall S. A comparison of the effects of an extract of feverfew and parthenolide, a component of feverfew, on human platelet activity in-vitro. J Pharm Pharmacol 1990;42:553-557.View Abstract
52.Venton DL, Kim SO, LeBreton GC. Antiplatelet activity from plants. In: Wagner H, Farnsworth NR, eds. Economic and Medicinal Plant Research. 5 vol. London: Academic Press; 1991:323-351.
53.Biggs MJ, Johnson ES, Persaud NP, Ratcliffe DM. Platelet aggregation in patients using feverfew for migraine. Lancet 1982;2:776.View Abstract

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Clinical Implications and Adaptations