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A few Botanical Names

Tanacetum parthenium (L.) Sch.


Bip.; Fam.: Asteraceae
Pain relieving
properties of Feverfew (Syn.; Chrysanthemum Parthenium Bernh.,
Matricaria parthenium L., Leucanthemum
Tanacetum parthenium (L.) Sch. Bip.
parthenium (L.) Gren. Et Godr.)

Andrea Lugli BSc, (dott. Chim. Ind.), MCPP.

CPP Seminar 27 March 2010 -London

Some European Common Name What our senses, tell us?


•  Strong Aromatic bitter!
•  Pleasent to taste, smell?
Italian: Amarella, Amareggiola, Erba amara vera,
Camomilla bastarda, Matricale, Partenio.
German: Mutterkraut
English: Feverfew
French: Grande Camomille
Spanish: Yerba de Santa Maria

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What we know from history, Historical


tradition, practice.
3 Levels of Knowledge Dioscorides recommended
Feverfew for many
complaints including “all hot
•  Historical inflammations and hot
•  Traditional swellings” (AHP 2007)
•  Modern-traditional

Dioscorides I century. AD

Historical Herbario Novo


Durante, talks about the
emmenagogue actitivity of a
decoction of the flowers
with nutmeg in wine.

“A decoction made with its flowers,


and nutmeg in wine, heat and
“caccia fuori i mestrui = is
emmenagogue”

Castore Durante (1529-1590)

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Historical Historical
According to Berry (1984)

A brief historical outline, according to Jacques Fleurentin


( President de la Sociéteé Francaise
Difficulties in labour,
d’Ethonpharmacologie)
Threatened miscariage,
Fever, Headache, “migraine” Regulation of menses
Greek Medicine: asthma and melanconie
Arabian Medicine: diuretic, emmenagogue
Middle Age (St. Hildegarde): febrifuge
Relieve of stomachache, XIX sec.: stimulant, digestive, antispasmodic,
Toothache,
Insect bite emmenagogue
Fleurentin J. 2007. Les pantes qui nous soignent. Ouest-
France.
Berry MI, 1984. Feverfew faces the
future. Pharm J 232: 611-614.

Traditional Traditional
Feverfew flowers: they are used as a
subtitute of Chamomile in case of L’Antonelli (1941) says that “all the plant is tonic, febrifuge,
dysmenorrhea, and disorder of female stimulant, antispasmodic, emmenagogue and antiflatulent” , he
cycle. Cataplams made with the infusion of says that it was very well known to the old physicians. The
flowers are used in case of contusion/bruise, flowers are used both fresh or dried, particularly in case of
dysmenorrhea.
and skin ulcers (Negri, 1979)
Dosage: herbal tea made with 4-16g/L, 3-4 glasses during the
morning, during the 4-5 days of the menstrual cycle.
The flowers are the part used in case of
aerophagia, headache, dysmenorrhea,
dispepsia... Antonelli G 1941. Le Piante che ridanno la salute. Edizione
Planta Medica, copia anastatica della III edizione "Riveduta ed
aumentata" del 1941.
Dosage: powder, 2-5 g/die; tincture,
30-60gtt, 3-5 times daily (Palma 1964).

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Traditional Physiomedical American Tradition


Grieve (1973) “ An infusion of the flowers
made with boiling water and alowed to become
cold, will allay any distressing sensitivenenss
to pain in a higly nervous subject, and will
afford relief to the face-ache or earache of a
dyspeptic or rheumatic person”.
Fluid extract, dose: 3,5-7ml

- Physiomedical dispensatory of Cook (1869):


14g in around 1liter of boiling water, 250 ml
(equivalent to 3-4g herb), every 30 minutes or
more frequently.

Traditional Modern-traditional
(Experience Based Phytotherapy- EBP)

2.
1. A.  In prophylaxis of migraine
American Indian Mahuna used Used in case of: B.  As symptomatic antinflammatory/painkiller
Headache,
Feverfew internally as
Dysmenorrhea,
antirheumatic. Rheumatic disorders
Moermann (1998)

3.
As a symptomatic the
Dosage is quite high
(around 2g/die of drug)

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Modern-traditional: a look at the Monographs: part used, indications,


dosage. dosage
•  Two teaspoonfuls as herbal tea. 2-3 cups before meals, regularly for a Monograph Part used Indications Dosage
few months. prophylaxis of
Wichtl M (ed.) 2004. Herbal Drugs and Phytopharmaceuticals. Handbook for a practice on a scientific basis. ESCOP 2003 aerial parts
migraine
50-120 mg/die
3rd edition. Stuttgart, medoharm Scientific publishers.
prophylaxis of
•  Up to 1800g/die (starting at the first sign of migraine) migraine fresh leaves:1-3 l. daily;
Mitchell WA. 2003. Plant medicine in practice. Churchill Livingstone
American Herbal (supported by powder 100 mg daily;
leaves or aerial
clinical trial); tincture (1:5) 10-40 gtt
•  “ …higher doses of up to 2g/day may be required for acute treatment of Pharmacopoeia (AHP) parts
others... every 2-3 hrs as
migraine or for inflammatory conditions”. (experienced indicated
based)
Hoffmann D 2003. Medical Herbalism - The science and practice of herbal medicine. Healing Art Press.
Rochester, Vermont.
prophylaxis of
migraine
•  About powder “…doses of 200mg bid are often recommended”. (supported by prevention of
Tincture 1:5 0,25-0,5ml tid (equivalent to max: 300mg) leaves or aerial clinical trial); migraine: drug
Trickey R, 1998. Women hormones and the menstrual cycle. Allen Unwin
WHO vol.II (2002) parts others... equivalent to 0,2-0,6 mg
(traditional/ of parthenolide
•  1-3 ml/day of 1:5 tincture (equivalent to around 0,2-1 g/day of leaf). experienced
based)
Bone K 2003. A clinical guide to blending liquid herbs. Churchill Livingstone.

Phytochemistry Phytochemistry strongly dependent


on…

•  Variety
Costonulide
Parthenolide •  Harvesting time

Santin

Centaureidin

Apigenin

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The Phytocomplex Phytochemistry

Sesquiterpenlactones Parthenolide distribution in the different parts of the plant


(i.e. Parthenolide)
Feverfew Part of the Plant Concentration of Parthenolide (%)
Phytocomplex
Flavonoids Flowers 1,38
Leaves 0,95
Others: Stems 0,08
- Essential oil
Root 0,01
- Polyphenols (dicaffeoylchinic Source: Heptinstall et al., 1992
acids)
- Tannins, Melatonin (very low) The content of Parthenolide in the flower maybe up to 4 times that
one in the leaves.

Lypophilic flavonoids identified in different part


Sesquiterpenlactones in Feverfew: not only Parthenolide of Feverfew 1/2
Leaf Disc Ligule
Germacranolide Parthenolide,
Costunolide, Artemorin, Flavonols
Crisantemomin
6-hydroxy kampferol
Guaianolide Artecanin, Crisatemin A e
3,6-dimethyl ether + (+) -
B, Crisantemolide,
Partholide 3,6,4’-trimethyl ether (Santin) +++ +++ ++

Eudesmolide Magnolialide, Reinosin,


Santamarin, 1-β-hydroxi Quercetagetin
arbuscolin, 5-β- 3,6-dimethylether + ++ -
hydroxireinosin. 3,6,3’-trimethylether (Jaceidin) ++ +++ +

The activity of Parthenolide is 1/24 of the activity of an extract 3,6,4’ trimethylether (Centaureidin) ++ +++ +

obtained from a drug rich in flowers.


Quantity: +++, major; ++, medium +, minor; (+), trace.
Costunolide is more active as antinflammatory than perthenolide. Source: modifided from Williams et al., 1999
(Koo TH, Lee JH, et al., 2001. A sesquiterpene lactone, costunolide, from Magnolia grandiflora inhibits NF-kappa B by targeting I kappa B
phosphorylation. Planta Med. Mar;67(2):103-7; Kassuya CA, Cremoneze A, et al., 2009. Antipyretic and anti-inflammatory properties of the
ethanolic extract,dichloromethane fraction and costunolide from Magnolia ovata (Magnoliaceae).J Ethnopharmacol. Jul 30;124(3):369-76. Epub
2009 Jun 12.

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Lypophilic flavonoids identified in different part


of Feverfew 2/2
Leaf Disc Ligule
Feverfew and inflammation
Flavones - Hall IH et al., 1979. Antinflammatory activity of sesquiterpenlactones and related
compounds. J Pharm Sci 68:537-542.
Apigenin (+) + +
Luteolin - ++ - NF-kB
Chrysoeriol - (+) - Parthenolide
Apigenin 7-glucuronide +
Luteolin 7-glucuronide + iNOS
(inducible nitric oxide
synthase
Quantity: +++, major; ++, medium +, minor; (+), trace.
Source: modifided from Williams et al., 1999
Inhibition of agrecan
Inhibition of synovial
Different profile also in the watersoluble flavonoids catabolism induced by TNF-α.
Fibroblast proliferation
(in vitro chondrocyte
(Parada-Turska et al., 2008)
Osteoarthritis model)
(Zhonghua Yi Xue Za Zhi. 2008

Feverfew and inflammation Feverfew and inflammation

NF-kB
•  Recently (Wu et al., 2007)
Parthenolide
Flavonoids
indentified different
iNOS dicaffeoylchinic acids
(inducible nitric oxide
synthase with elevated antioxidant
Inhibition of synovial action.
Fibroblast proliferation
(Parada-Turska et al., 2008)
Direct inhibition
Inhibition of agrecan Of COX-2 and
catabolism induced by TNF-α. Lypoxygenase
(in vitro chondrocyte
Osteoarthritis model)
(Zhonghua Yi Xue Za Zhi. 2008

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Extracts Pharmacology An interesting study


•  An extract DEPLETED of
parthenolide showed
antinflammatory activity:

•  direct inhibition of lypoxygenase


•  inhibition of release of different
inflammatory mediators (PGE2, NO,
TNF- α, IL-2 etc. )

Sur R, Martin K, Liebel F, Lyte P, Shapiro S, Southall M. 2009. Anti-inflammatory activity of parthenolide-depleted
Feverfew (Tanacetum parthenium). Inflammopharmacology. Feb;17(1):42-9.

Going back to the origin of the


The Original Sin…
“Evidence Based Dosage” (?!)
•  Johnson ES, Kadam NP et al., 1985. Efficacy of feverfew as
prophylactic treatment of migraine. BMJ 291:569- 573.

•  RCT, double blind, placebo controlled


•  20 subjects (City of London Migraine Clinic) that were used to self
treating with feverfew fresh leaves.

COULD THEY HAVE USED THE FLOWERS?

…and the City of London

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The Beginning or Going back to the


Modern-traditional
dosage
“ Each freeze dried leaf containing five leaflets weighed a mean of 25.7 •  Two teaspoonfuls as herbal tea. 2-3 cups before meals, regularly for a
few months.
mg”. Wichtl M (ed.) 2004. Herbal Drugs and Phytopharmaceuticals. Handbook for a practice on a scientific basis.
3rd edition. Stuttgart, medoharm Scientific publishers.

“The mean daily dose of feverfew used by patients before entry to the •  Up to 1800g/die (starting at the first sign of migraine)
Mitchell WA. 2003. Plant medicine in practice. Churchill Livingstone
study was 2.44 leaves (roughly 60mg). We therefore decided that
the dose of each capsule should be fixed at 25 mg and that each •  “ …higher doses of up to 2g/day may be required for acute treatment of
patient should receive two capsules daily.” migraine or for inflammatory conditions”.
Hoffmann D 2003. Medical Herbalism - The science and practice of herbal medicine. Healing Art Press.
Rochester, Vermont.

Today recommended dosage: powder: 50-120 mg/die •  About powder “…doses of 200mg bid are often recommended”.
Tincture 1:5 0,25-0,5ml tid (equivalent to max: 300mg)
Trickey R, 1998. Women hormones and the menstrual cycle. Allen Unwin

Roughly: 5-20 times lower than the traditional dosage •  1-3 ml/day of 1:5 tincture (equivalent to around 0,2-1 g/day of leaf).
Bone K 2003. A clinical guide to blending liquid herbs. Churchill Livingstone.

Summary of Pharmacological studies on a Summary of Pharmacological studies on a


extract from Aerial part rich of flowers. extract from Aerial part rich of flowers.

To test antinflammatory and pain reducing


properties in acute.

•  it is 3-30 times more active (in different


animal models) than extracts from leaves or
“normal” aerial parts).
•  it is 3 times more active than extracts from
leaves in a specific model of migraine (c-fos).
Foto Sara Mercati ©

Foto Sara Mercati ©

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Summary of Pharmacological studies on a


extract from Aerial part rich of flowers. CONCLUSION
•  FROM Historical and traditional data and
information:
–  leaves, aerial part, or flowers could be used.
•  Content of parthenolide correlates with –  dosage can be quite high (specifically in acute
activity only in the migraine model. conditions)
•  Content of total flavonoids, by itself, does
not correlate with activity and does not explain •  The dosage supported by clinical trial in the
the difference in activity of different extracts. prophylaxis of migraine
–  is not based on traditional use but on a very specific
and unusual one.
–  It is very low due to the fact that patients ate fresh
leaves. (They could very difficulty could ate other
parts!)

CONCLUSION
•  Phytochemistry shows that many active
constituents (es. different kind of
sesquiterpenlactones or flavonoids) make the
phytocomplex of flowers similar but not equal to THE END
that one of leaves and standard aerial parts.

Thanks for your kind attention


•  It would be possibile that extracts from a drug
based or rich in flowers is more/the most
active in acute conditions and at high dosage.

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