PLANT DESCRIPTION
Tanacetum parthenium is a traditional medicinal herb which is found in many old gardens, and is also occasionally grown for ornament. Tanacetum is derived from the greek "akéomai", heal, and "tànaos" long. Parthenium (Parthenos that takes its meaning from the maiden, virgin) was the name of that medicine called matricarie, used to treat certain vaginal diseases. It is also commonly seen in the literature by its synonyms, Chrysanthemum parthenium, also derives from the greek meaning of the famous "Golden Flower".
Though its earliest medicinal use is unknown, it was documented in the first century (AD) as an anti-inflammatory by the Greek herbalist physician Dioscorides. The ancient Greeks called the herb “Parthenium,” supposedly because it was used medicinally to save the life of someone who had fallen from the Parthenon during its construction in the 5th century BC. Feverfew also was known as “medieval aspirin” or the “aspirin” of the 18th century.
The plant has been used to treat arthritis, asthma, constipation, dermatitis, earache, fever, headache, inflammatory conditions, insect bites, labor, menstrual disorders, potential miscarriage, psoriasis, spasms, stomach ache, swelling, tinnitus, toothache, vertigo, and worms.
ACTIVE MOLECULES DESCRIPTION
The most important biologically active principles are the sesquiterpene lactones, the principal one being parthenolide. More than 30 sesquiterpene lactones have been identified in feverfew. In general, there are 5 different types of sesquiterpene lactones, which may be classified by chemical ring structures. Feverfew contains eudesmanolides, germacranolides, and guaianolides. Parthenolide is a germacranolide. Feverfew (Tanacetum parthenium L.): A systematic review,2011
The following flavonoids have been isolated: 6-hydroxykaempferol 3,6-dimethyl ether, 6-hydroxykaempferol 3,6,4′-trimethyl ether (tanetin), quercetagetin 3,6-dimethyl ether, quercetagetin 3,6,3′-trimethyl ether (accompanied by isomeric 3,6,4′-trimethyl ether), quercetin, apigenin, luteolin
CLASSIFICATION
Tanacetum parthenium (Sch.Bip., 1844) è una pianta della famiglia delle Asteraceae.
INDICATIONS
Anti-inflammatory activity
- Parthenolide binds to and inhibits IκB kinase complex (IKK)β
- Parthenolide inhibits prostaglandine synthetase
- Parthenolide reduces human neutrophil oxidative burst activity
Parthenolide, a sesquiterpene lactone, expresses multiple anti-cancer and anti-inflammatory activities, 2012
Effects on platelets
Extracts of feverfew inhibit platelet 5-HT secretion via neutralization of sulfhydryl groups inside or outside the cell. The sesquiterpenes in feverfew contain the alpha-methylenebutyrolactone unit capable of reacting with sulfhydryl groups. Feverfew extracts are not only potent inhibitors of serotonin release from platelets but also of polymorphonuclear leukocyte granules.
The Feverfew plant-derived compound, parthenolide enhances platelet production and attenuates platelet activation through NF-κB inhibition,2010
Inibition of histamine release
A chloroform extract of feverfew inhibited histamine release from rat peritoneal mast cells in a different manner from established mast cell inhibitors, such as cromoglycate and quercetin. The exact mechanism of action has not been determined but may be mediated by entry of calcium into mast cells. The activity of compounds extracted from feverfew on histamine release from rat mast cells,1987
Anticancer activity
Mechanisms of action may include:
- Cytotoxic action associated with interruption of DNA replication by the highly reactive lactone ring, epoxide, and methylene groups of parthenolide through inhibition of thymidine into DNA
- oxidative stress, intracellular thiol depletion, endoplasmic reticulum stress, and mitochondrial dysfunction.
Suppressed NF-kappaB and sustained JNK activation contribute to the sensitization effect of parthenolide to TNF-alpha-induced apoptosis in human cancer cells,2004
Parthenolide, a sesquiterpene lactone, expresses multiple anti-cancer and anti-inflammatory activities, 2012
Parthenolide and similar lactones displayed anticancer activity against several human cancer cell lines, including human fibroblasts, human laryngeal carcinoma, human cells transformed with simian virus, human epidermoid cancer of the nasopharynx, and anti Epstein–Barr early antigen activity .
Migraine headache, prophylactic treatment
Inhibition of prostaglandin synthesis, decrease of vascular smooth muscle spasm, and blockage of platelet granule secretion. Feverfew for migraine prophylaxis: a systematic review,2009
Effects on vascular smooth muscle
Treatment with parthenolide significantly decreased the [(3)H]thymidine incorporation into DNA by 30%~56%. Addition of parthenolide also increased cell population at G(0)/G(1) phase
and decreased cell population at S phase, which is consistent with its stimulatory effects on p21 and p27. In addition, parthenolide also increased IkappaBalpha expression and reduced Cox-2 expression in a time-dependent manner. Parthenolide inhibits proliferation of vascular smooth muscle cells through induction of G0/G1 phase cell cycle arrest,2009
PHARMACOKINETICS
It 'has been postulated that inactivation through the alpha-methylene groups of glutathione-gamma-lactone typical partenolidi could happen pretty quickly after entering the bloodstream, thereby reducing the relevance of in vitro studies. However it has also been postulated that partenolidi "inactivated" to be turned on at the cellular level through the action of cytochrome P-450.
MOLECULAR MECHANISM
Interaction with Inflammosoma
The inflammasome collectively refers to oligomeric molecular platforms or assemblies that recruit and activate caspase -1, which processes inactive pro-IL-1β3 and pro-IL-18 into the active pro-inflammatory cytokines IL-1β and IL-18, respectively. Inappropriate activation of the NLRP3 inflammasome has been implicated in the pathogenesis of a number of human diseases. In addition, abnormal activation of the NLRP3 inflammasome due to mutations in NLRP3 is responsible for several autoinflammatory diseases. we demonstrate that the NF-κB pathway inhibitors parthenolide and Bay 11-7082 are potent inhibitors of the inflammasome independent of their inhibitory effect on the NF-κB pathway. We show that parthenolide is a direct inhibitor of caspase-1 and NLRP3 whereas Bay 11-7082 and several structurally related vinyl sulfone compounds are selective inhibitors of NLRP3. This study identifies parthenolide as the first natural product that directly targets caspase-1 and the NLRP3 inflammasome and vinyl sulfones as the first small molecules that selectively inhibit activation of the NLRP3 inflammasome, possibly by targeting its ATPase activity. Anti-inflammatory Compounds Parthenolide and Bay 11-7082 Are Direct Inhibitors of the Inflammasome, 2010
The molecular mechanism of activation of the NLRP3 inflammasome by these diverse stimuli is still unclear, but evidence suggests that NLRP3 is activated by a two-step mechanism. In the first step, known as the priming step, NLRP3 is transcriptionally up-regulated by NF-κB-inducing stimuli such as ligands of the Toll-like receptors. However, the induction of NLRP3 protein expression is not sufficient for its activation, and another transcription-independent step (activation step) is required for NLRP3 activation. This step is triggered by stimuli such as ATP. A recent study provided evidence that reactive oxygen species generated by NLRP3 stimuli activate NLRP3 by promoting its association with TXNIP. Once activated, NLRP3 undergoes self-oligomerization to form a molecular platform, which recruits the adaptor protein ASC. Parthenolide is a direct inhibitor of the protease activity of caspase-1 and is also an inhibitor of the ATPase activity of NLRP3. Parthenolide inhibits caspase-1 activity by alkylating critical cysteine residues in the p20 subunit. Similarly, alkylation is likely to be responsible for the inhibitory effect of parthenolide on NLRP3-dependent ATPase activity.
Cytotoxic activity against TICs
STAT3 and JNK, are involved in PTL-induced cytotoxic effects.Interestingly, src activation was decreased upon addition of PTL, in particular we observed an increase in phosphorylation of src at tyrosine-529, which indicates a decrease in src activity. We also saw attenuation of downstream src effectors, including: PI3K, PKCs, CaMKs and MAPK. Src is a gateway signaling protein and is strongly implicated in prostate cancer. It can promote crosstalk between numerous proteins that include G-protein coupled receptors, growth factor receptors (EGFR, PDGF and IGF), cytokine receptors and integrins, all of which have been implicated in cancers. In particular, src has an important role in prostate cancer where it is overexpressed and src inhibitors attenuate cancer cell line growth and proliferation. In addition, src has been implicated in bone metastasis of prostate cancer. PTL’s ability to target TICs is important to future therapies. Phytochemical parthenolide is able to induce cell death in prostate TICs (prostate tumor initiating cells). After 72 hrs of treatment with PTL (10 µM), we determined that it is toxic (>90%) to most of the TICs and non-TICs in both cell lines and primary prostate cancer cells. Effects of the sesquiterpene lactone parthenolide on prostate tumor-initiating cells: an integrated molecular profiling approach,2009
Interaction with DNMT1
Parthenolide inhibits DNA methyltransferase 1 (DNMT1), possibly through alkylation of the proximal thiolate of Cys1226 of the catalytic domain by its γ-methylene lactone, and 2) down-regulates DNMT1 expression possibly associated with its SubG1 cell-cycle arrest or the interruption of transcriptional factor Sp1 binding to the promoter of DNMT1. Modulation of DNA methylation by a sesquiterpene lactone parthenolide,2009
Interaction with HDACI
Co-administration of parthenolide blocked HDACI-mediated phosphorylation/activation of IKK and RelA/p65 in association with increased JNK1 activation in various AML cell types. These events were accompanied by an increase in apoptosis in multiple AML cell lines.
Acute myeloid leukemia (AML) recurrences are attributed to leukemia stem cells (LSCs that are capable of surviving conventional chemotherapy and radiation treatments. The drug parthenolide (PTL) has shown remarkable efficacy in inducing selective apoptosis in LSCs. However, PTL's low water solubility prevents it from reaching therapeutically effective levels in the blood stream. To circumvent this problem, we are developing a novel micelle delivery system to solubilize and target PTL. The NF (Nuclear factor)-κB inhibitor parthenolide interacts with histone deacetylase inhibitors to induce MKK7/JNK1-dependent apoptosis in human acute myeloid leukaemia cells,2010
DRUG INTERACTIONS
Feverfew may alter the effects of some prescription and non-prescription medications. If you are currently being treated with any of the following medications, you should not use feverfew without first talking to your health care provider.
Blood-thinning medications- Feverfew may inhibit the activity of platelets (a substance that plays a role in blood clotting), so individuals taking blood-thinning medications (such as aspirin and warfarin) should consult a health care provider before taking this herb.
SIDE EFFECTS
Feverfew can induce more widespread inflammation of the oral mucosa and tongue, often with lip swelling and loss of taste. Dermatitis has been associated with this plant. Patients who switched to placebo after taking feverfew for several years experienced a cluster of nervous system reactions (eg, headaches, insomnia, joint pain, nervousness, poor sleep patterns, stiffness, tension, tiredness) along with muscle and joint stiffness, often referred to as “postfeverfew” syndrome.
TOXICITY
No studies of chronic toxicity have been performed on the plant and the safety of long-term use has not been established. Pregnant women should not use the plant because the leaves have been shown to possess potential emmenagogue activity. It is not recommended for lactating mothers or for use in children.
RESISTANCE
Are not known forms of resistance.
DEPENDENCE AND WITHDRAW
Tanacetum parthenium is not addictive
DOSAGE
Pedriatic
Feverfew should not be used in children younger than 2 years. In older children, adjust the recommended adult dose to account for the child's weight. Most herbal dosages for adults are calculated on the basis of an average of 150 lb (70 kg) adult. Therefore, if the child weighs 50 lb (20–25 kg), the appropriate dose of feverfew for this child would be 1/3 of the adult dosage.
Adult
For migraine headaches: Take 100–300 mg, up to 4 times daily, standardized to contain 0.2–0.4% parthenolides. Feverfew may be used to prevent or to stop a migraine headache. Feverfew supplements may also be CO2 extracted. For these, take 6.25 mg, 3 times daily, for up to 16 weeks.
For inflammatory conditions (such as arthritis): 60-120 drops, 2 times daily of a 1:1 w/v fluid extract, or 60-120 drops twice a day of 1:5 w/v tincture.
AVAILABLE FORMS
Feverfew supplements are available fresh, freeze-dried, or dried and can be purchased in capsule, tablet, or liquid extract forms. Feverfew supplements with clinical studies contain a standardized dose of parthenolide. Feverfew supplements should be standardized to contain at least 0.2% parthenolide.
