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Abstract

Achillea millefoilum L. (Yarrow) is an important species of Asteraceae family with common utilization in traditional medicine of several cultures from Europe to Asia for the treatment of spasmodic gastrointestinal disorders, hepatobiliary, gynecological disorders, against inflammation and for wound healing. An extensive review of literature was made on A. millefoilum L. using ethno botanical text books, published articles in peer-reviewed journals, unpublished materials and scientific databases. The Plant List, International Plant Name Index and Kew Botanical Garden databases were used to authenticate the scientific names. Monoterpenes are the most representative metabolites constituting 90% of the essential oils in relation to the sesquiterpenes, and a wide range of chemical compounds have also been reported. Different pharmacological experiments in many in-vitro and in-vivo models have proved the potential of A. millefoilum with antiinflammatory, antiulcer, anticancer activities etc. lending support to the rationale behind numerous of its traditional uses. Due to the noteworthy pharmacological activities, A. millefoilum will be a better option for new drug discovery. The present review will comprehensively summarize the pharmacognosy, phytochemistry and ethnopharmacology of A. millefoilum reported to date, with emphasis on more in vitro, clinical and pathological studies needed to investigate the unexploited potential of this plant. Copyright © 2017 John Wiley & Sons, Ltd.
REVIEW
Pharmacognosy, Phytochemistry and
Pharmacological Properties of Achillea
millefolium L.: A Review
Sofi Imtiyaz Ali, B. Gopalakrishnan and V. Venkatesalu*
Department of Botany, Annamalai University, Annamalainagar 608 002Tamil Nadu, India
Achillea millefoilum L. (Yarrow) is an important species of Asteraceae family with common utilization in
traditional medicine of several cultures from Europe to Asia for the treatment of spasmodic gastrointestinal
disorders, hepatobiliary, gynecological disorders, against inflammation and for wound healing. An extensive
review of literature was made on A. millefoilum L. using ethno botanical text books, published articles in
peer-reviewed journals, unpublished materials and scientific databases. The Plant List, International Plant Name
Index and Kew Botanical Garden databases were used to authenticate the scientific names. Monoterpenes are
the most representative metabolites constituting 90% of the essential oils in relation to the sesquiterpenes, and
a wide range of chemical compounds have also been reported. Different pharmacological experiments in many
in-vitro and in-vivo models have proved the potential of A. millefoilum with antiinflammatory, antiulcer,
anticancer activities etc. lending support to the rationale behind numerous of its traditional uses. Due to the
noteworthy pharmacological activities, A. millefoilum will be a better option for new drug discovery. The present
review will comprehensively summarize the pharmacognosy, phytochemistry and ethnopharmacology of A.
millefoilum reported to date, with emphasis on more in vitro, clinical and pathological studies needed to
investigate the unexploited potential of this plant. Copyright © 2017 John Wiley & Sons, Ltd.
Keywords: Achiella millefoilum; pharmacognosy; phytoconstituents; ethnopharmacology; traditional uses; drug discovery.
INTRODUCTION
Natural products, especially those derived from plants,
continue to provide new and important leads in the drug
discovery process (Balunas and Kinghorn, 2005). The
first step in drug discovery is to document traditionally
used materials to treat an ailment. The knowledge of
medicinally used important plants and practices are
passed verbally from one generation to another, and
because of this tradition, there is fear that indigenous
knowledge about traditional medicine is slowly being
lost (Bhatia et al., 2014). Documentation of such
knowledge may help in conservation and facilitate
future research on medicinal plant safety and efficacy
to validate. Therefore, such plants should be
investigated to better understand their properties, safety
and efficiency (Bunalema et al., 2014) as well as prevent
the destructive changes in the knowledge of medicinal
plants during transmission between generations
(Khoshbakht and Hammer, 2005).
The genus Achillea belongs to the family Asteraceae,
comprises over 130 perennial herb species indigenous to
the Northern Hemisphere from Europe to Asia and
grows in temperate climates in dry or semi-dry habitats
(Si et al., 2006). Achillea millefolium L. (yarrow or
milfoil), the best-known and most widespread species,
is listed among the most commonly used plant species
in both folk and conventional medicine for over
3000 years (Radusiene and Gudaityte, 2005). It is
commonly known as Yarrow in English and has
different vernacular names in India like Biranjasipha,
Gandana, Gandrain, Puthkanda, Bhut Kesi (Hindi),
Bimjasif (Joshimath), Rajmari (Konkani), Rojmaari
(Marathi), Achchilliya (Tamil), Tukhm gandana,
Buiranjasif and Brinjasuf (Urdu). A diversity of
pharmacological properties is ascribed to A.
millefolium, such as spasmolytic, antiinflammatory,
analgesic, haemostatic, antidiabetic, cholagogue,
antitumor, antioxidant, antifungal, antiseptic and liver
protective effects attributed due to the presence of
several chemical constituents viz., essential oils,
sesquiterpenes, phenolic compounds etc
(Karamenderes and Apaydin, 2003; Stojanovic et al.,
2005; Cavalcanti et al., 2006; Si et al., 2006; Tajik et al.,
2008; Lazarevic et al., 2010; Fierascu et al., 2015).
The flowering tops containing essential oil are the
most active part of the plant, used mainly for the
treatment of influenza, hemorrhage, dysmenorrhea,
diarrhea and as a haemostatic (Baser et al., 2002;
Benedek et al., 2008). Tea from A. millefolium is also
used to treat diseases of gastrointestinal tract like
dyspepsia, flatulence, abdominal pain, diarrhea,
stomachache and digestive complaints. Recently, in a
double-blind randomized clinical trial, it has been shown
that tea prepared from powder of the flowers of A.
* Correspondence to: V. Venkatesalu, Department of Botany, Annamalai
University, Annamalainagar 608 002, Tamil Nadu, India.
E-mail: venkatesalu@yahoo.com
PHYTOTHERAPY RESEARCH
Phytother. Res. (2017)
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/ptr.5840
Copyright © 2017 John Wiley & Sons, Ltd.
Received 15 December 2016
Revised 03 May 2017
Accepted 04 May 2017
millefolium relieved the severity of pain in primary
dysmenorrheal (Jenabi and Fereidoony, 2015).
Nowadays, it can be found in herbal pharmacies as
tinctures and capsules containing dry flowers or aerials.
The plant is also used as a component of a variety of
industrial tea mixtures and an ingredient of
phytoremedies (e.g. Amersan) (David et al., 2010). A.
millefolium can be used as an essential oil, infusion or
alcohol extract, decoction, hydroalcoholic, methanolic
and aqueous extract (Dias et al., 2013).
A. millefolium is of great concern as evidenced by the
ample research carried out by different researchers in
the recent past. The present review is intended to pile
up the widespread information on the pharmacognosy,
phytochemistry and pharmacology of A. millefolium to
explore its therapeutic potential and evaluate future
research opportunities.
BOTANY
Plant occurrence
Asteraceaeous plants are distributed throughout the
world and most common in the arid and semi-arid
regions of subtropical and lower temperate latitudes.
Achillea contains around 130 flowering and perennial
species, found in Europe and temperate areas of Asia
and America. Achillea is represented in Turkey with
46 taxa, of which 25 are endemic, and in Iran with 19
species, of which seven species are endemic
(Mozaffarian, 2009). A. millefolium is native to Europe
and western Asia but is also widespread in most
temperate regions including North America and is
represented by about 85 species mostly found in
Europe, Asia and in North America (Anne et al.,
2006). A. millefolium grows at 3500MSL and is often
found in grasslands and open forests. The plant
commonly flowers from May through June, and active
growth occurs in the spring.
Botanical description
A. millefolium belongs to family Asteraceae which is the
largest family of vascular plants. It is an erect
herbaceous perennial plant that grows up to 50 cm tall,
with a slender cropping rootstock throwing numerous
roots and stolons with a blunt, succulent scale at each
node. The leaves are 520 cm long, bipinnate or
tripinnate, almost feathery, having varying degrees of
hairiness (pubescence) and arranged spirally near the
middle and bottom of the stem. The flowers are typically
white, but either pink or pale purple flowers with
corymbose, ovoid, flat-topped heads at the end of stems
and branches, having densely arranged petals in
flattened clusters. Fruits are 2-mm, shiny, oblong
achenes, with broadly winged margins and no pappus
(Akram, 2013) (Fig. 1).
A. millefoliuma polyploid complex
A. millefolium is one of the most diverse polyploid
complexes of the Northern hemisphere in terms of
morphological, genetic and ecological features (Guo
et al., 2005, 2008 and 2012; Ehrendorfer and Guo,
2006). This group includes A. millefolium, together with
a set of Eurasian and North American related lineages
(Guo et al., 2005), some of them naturalized in
temperate and cold areas of other continents but its
basal diploids are limited to Eurasia (with four species
in Europe and three in Asia). The complexity of the
aforementioned group is the result of multiple processes
of hybridization, polyploidization and evolution linked
with different types of habitats. The existence of
different autopolyploids and allopolyploids representing
four ploidy levels (2×, 4×, 6× and 8×) is widely
documented (Guo et al., 2012), and analysis of genetic
diversity carried out using AFLP markers revealed
substantial polymorphism, significantly higher in
polyploid than in diploid strains (Guo et al., 2008). The
polyploidy species are mostly difficult to define; their
number varies depending on the authorities and may
reach 17 or more.
Separation of A. millefolium agg. from other
members of sect. Achillea was not possible by ITS and
trnL-Fs sequences (Guo et al., 2004). By contrast, the
AFLP data clearly characterize the polyploidy complex
as a clade, with mostly well separated 2× species, but
with a rather diffuse superstructure of 4× and 6× taxa.
By morphological, phytochemical, DNA analytical and
ecogeographical criteria, A. millefolium agg. appears as
the most apomorphic, polymorphic, diverse and wide-
spread, highly polyploid (2×, 4×, 6×, 8×) but
nevertheless monophyletic crown groupof the genus
(Guo et al., 2005).
Taxonomy
A. millefolium is native to Europe and includes three
subspecies: subsp. millefolium (small white flowers),
pink flowered subsp. alpestris (Wimm. & Grab.) and
subsp. ceretanum Sennen. (large white flowers) confined
to Spain and southern France (Applequist and
Moerman, 2011). Several closely related species or
microspecies belong to A. millefolium species complex,
Figure 1. Achiella mellifolium L. [Colour figure can be viewed at
wileyonlinelibrary.com]
S.I. ALI ET AL.
Copyright © 2017 John Wiley & Sons, Ltd. Phytother. Res. (2017)
with Achillea collina J. Becker ex Reichenb. and
Achillea pannonica Scheele. most frequently treated as
subspecies of A. millefolium, though usually excluded
today. Ploidy level is informative in the recognition of
species; for example, A. millefolium is hexaploid, while
A. collina is tetraploid and A. pannonica are usually
reported to be octoploid (Applequist and Moerman,
2011).
Additionally, the common native North American A.
millefolium has been recognized at the species level as
A. lanulosa Nutt. (Itself sometimes divided into multiple
species) or at the subspecific level as A. millefolium
subsp. lanulosa (Nutt.) Piper. As narrowly defined, this
taxon is tetraploid (Ehrendorfer, 1973; Gervais, 1977),
while North American populations recognized by some
authorities as A. borealis Bong. may be tetraploid or
hexaploid (Ehrendorfer1973; Ramsey, 2007). Guo et al.
(2005) concluded from AFLP data that the North
American polyploids were genetically from A.
millefolium, having a closer or more direct relationship
to diploid Achillea asiatica Serg. Gharibi et al. (2011)
assessed extensive genetic differentiation among A.
millefolium subsp. elbursensis and A. millefolium subsp.
millefolium from the Northern regions of Iran by using
ISSR and morphological markers.
HISTORY
The name of the genus Achillea originates from the
ancient use as a wound-healing remedy by the Trojan
hero Achilles, a powerful warrior in Greek mythology
(Benedek et al., 2007b). A. millefolium is one of the
oldest known botanicals used by humans (sensu lato):
it is among the six medicinal plants whose pollen was
found in a Homo neanderthalensis grave at Shanidar,
dated to 65 000 B.P. (Leroi, 1975; Solecki, 1975).
Although it is impossible to know whether usage since
then has been continuous, but it has certainly been
persistent over a prolonged period, as it has been
broadly accepted as a medicine by many recent cultures
within its range. Duke has repeatedly argued (Duke and
Ayensu, 1985; Duke, 1986) that plants used by unrelated
groups for similar purposes are likely to be potent, given
the statistical unlikelihood that multiple cultures would
randomly adopt and retain the same use for an inert
plant (Moerman, 2007), a plant whose use is
independently adopted and retained by multiple
cultures has increased likelihood of being genuinely
bioactive.
The oldest surviving texts to record the use of A.
millefolium in the European classical medical tradition
are by Pliny the Elder and Dioscorides, both during
the first century AD. These texts set a lower limit on
the age of A. millefolium used by western cultures,
although, as for most botanicals, folk use is an oral
tradition may have long preceded the plants appearance
in scholarly medicine. A necessary caveat is that,
although most authorities have interpreted these
references as being to A. millefolium, the traditional
assignments of Linnean names to plants in classical texts
are seldom certain: if, for example, a classical common
name were later used for another species with similar
appearance, range and uses, errors would result.
Dioscorides described the herb achilleios, or millefolium
(among other names), as being useful to stop bleeding,
including from wounds and abnormal menstrual
bleeding and reduce inflammation; a decoction could
be used as a douche for menstrual bleeding and be
drunk for dysentery (Osbaldeston and Wood, 2000).
Plinys natural history indicated that a plant probably
identifiable as yarrow was known by names including
achilleos, sideritis and millefolia. Some people also used
the former two names for several other species, some
quite different in description, with all being considered
valuable for wounds (Jones, 1956).
The literary record has recently been supported by
marine archeology. A. millefolium is among plants
reported, using DNA analysis, to be present in two
pressed tablets of plant material recovered in the 1980s
from a collection of medical supplies in a Roman ship
Table 1. Traditional uses of A. millefolium in different cultures
S. no. Culture Treatment Reference
1. European Gastrointestinal disorders, loss of appetite,
menstrual problems, as a diaphoretic, skin
inflammations, wounds and external bleeding
Wichtl (2004) and Willuhn (2002)
2. Iranian Inflammation, pain and gastrointestinal
disturbances, hemorrhoids, dyspepsia,
dysmenorrhea and gastritis
Miraldi et al. (2001)
3. Italy Menstrual problems, as a diuretic or for
urinary problems, toothache, as a sedative
and gastrointestinal disorders
Applequist and Moerman (2011)
4. Hungary Internal ailments as well as for burns and wounds Applequist and Moerman (2011)
5. Peru Gastritis, diabetes, cholesterol and skin infections Bussmann et al. (2007)
6. Brazil Wounds, skin problems, diarrhea and
gastrointestinal problems
Pires et al. (2009) and Baggio et al. (2008)
7. Britain and Ireland Wounds, nosebleeds, uterine hemorrhage, high
blood pressure, respiratory infections, fevers and
rheumatic complaints
Allen and Hatfield (2004)
8. China Snakebite, wounds, hemorrhoids, varicose veins,
dysmenorrhea and tuberculosis
Applequist and Moerman (2011)
9. India Gastric problems and fever Sharma et al. (2004)
ACHILLEA MILLEFOLIUM L.: A REVIEW
Copyright © 2017 John Wiley & Sons, Ltd. Phytother. Res. (2017)
that sunk off the coast of Tuscany between 140 and
120 BC. The DNA analysis organized by Alain
Touwaide and Emanuela Appetiti of the Institute for
the Preservation of Medical Traditions and performed
by Robert Fleischer at the Smithsonian Institution.
Their investigation tentatively identified several of the
tablets ingredients, all considered in writings of the time
to be medicinal; in addition to yarrow, the study found
DNA evidence of carrot, radish, parsley, celery, wild
onion and cabbage (Applequist and Moerman, 2011).
TRADITIONAL USES
A. millefolium, a very important medicinal plant in
Unani (Greco-Arab) system of medicine under the
name of Biranjasif (Applequist and Moerman, 2011),
has been used in traditional medicine for hundreds of
years internally as herbal teas for headaches, hepato-
biliary disorder, gastrointestinal complaints and as an
appetite enhancing drug and externally as lotions and
ointments against skin inflammations, wounds, cuts
and abrasions (Cavalcanti et al., 2006; Benedek et al.,
2007a & 2008; Nadim et al., 2011) (Table 1).
A. millefolium has a long history of use as traditional
herbal medicine even in veterinary medicine (Eghdami
and Sadeghi, 2010). Preparations in the form of
infusions, decoctions or fresh juices have been used
against anorexia, stomach cramps, flatulence, gastritis,
enteritis, internal and external bleeding (coughing
blood, nosebleed, hemorrhoidal and menstrual
bleeding, bloody urine), wounds, sores, skin rash, as
well as dog and snake bites. It has been used internally,
usually as a tea, and externally as a lotion, ointment or
poultice (Grieve, 1971; Chandler et al., 1982a).
The aerial parts of A. millefolium, a well-known
species among other members of Achillea, are
commonly used in European and Asian traditional
medicine for the treatment of gastrointestinal
disorders and hepatobiliary complaints, as well as for
wound healing and skin inflammations (Jaradat, 2005;
De et al., 2007; Ugulu et al., 2009). The ancient
Europeans called it Herba Militaris, the military herb,
an ointment made from it was used as vulnerary drug
on battle wounds. A. millefolium flower was formerly
official in the United States Pharmacopeia. In
European folk, A. millefolium is used for
gastrointestinal disorders, loss of appetite, for
menstrual problems, as a diaphoretic, for skin
inflammations, wounds and external bleeding
(Willuhn, 2002 Wichtl, 2004).
A. millefolium is widely used in Iranian folk medicine
to treat diverse diseases including inflammation, pain
and gastrointestinal disturbances. However, the infusion
of dried flowers is considered suitable for the treatment
of hemorrhoids, dyspepsia, dysmenorrhea and gastritis
(Miraldi et al., 2001). In Italy, A. millefolium is used
for a variety of conditions like menstrual problems, as
a diuretic or for urinary problems, for toothache and
as a sedative but primarily for gastrointestinal disorders
(Passalacqua et al., 2007). In Hungary, the plant is
known as cickafark (kitten tail) and has been used for
internal ailments as well as for burns and wounds
(Applequist and Moerman, 2011).
Bussmann et al. (2007) reported that A. millefolium
is used in Peru under the names of Milenrama and
Chonchón, for gastritis, diabetes, cholesterol and
mainly for skin infections. Likewise, it is used in
Brazil, under the names of mil-folhas and erva de
cortadura, to treat wounds, skin problems, diarrhea
and other gastrointestinal problems (Baggio et al.,
2008; Pires et al., 2009), although plant infusion or
the decoction of the aerial parts of the plant is
indication for calmness (Manfrini et al., 2009). This
latter indication is also seen in Mexico (Molina-
Hernandez et al., 2004). One third of the 125 records
of folk use of A. millefolium in Britain and Ireland
were for wounds, nosebleeds, uterine hemorrhage,
high blood pressure, respiratory infections, fevers and
rheumatic complaints (Allen and Hatfield, 2004). In
China, A. millefolium has been used to stop bleeding,
snakebite, wounds, hemorrhoids, varicose veins,
dysmenorrhea and tuberculosis (Applequist and
Moerman, 2011). A. millefolium has also been listed
in the Indian Ayurvedic Pharmacopeia for fevers and
wound healing. In India, the leaves and flowers are
used for gastric problems and fever in Parvati valley
of Himalayan region (Sharma et al., 2004).
CHEMICAL CONSTITUENTS OF A. millefolium
Studies on the chemical constituents of A. millefolium
could be traced back to 19th century, and many
compounds have been found until now. Active
ingredients reported in A. millefolium are summarized
below, and chemical properties of major phytochemicals
present in A. mellifolium are shown in Table 2.
Phenols
Choline (Borrelli et al., 2012), 1,3-dicaffeoylquinic acid
(DCQA), 1,4-DCQA, apigenin 4-O-glucoside and
luteolin 4-O-glucoside (Vitalini et al., 2011), 3,4-DCQA
(Benedek et al., 2007c; Vitalini et al., 2011), 3,5-DCQA
(Innocenti et al., 2007; Benedek et al., 2007c; Fraisse
et al., 2011; Vitalini et al., 2011), 1, 5-DCQA (Fraisse
et al., 2011), 4, 5, DCQA (Benedek et al., 2007c; Fraisse
et al., 2011), chlorogenic acid (Tunón et al., 1994;
Innocenti et al., 2007; Benetis et al., 2008; Fraisse et al.,
2011; Vitalini et al., 2011), luteolin-7-β-D-Oglucuronide
(Benedek et al., 2007c), caffeic acid (Tunón et al., 1994;
Wojdyłoet al., 2007; Yassa et al., 2007; Pires et al.,
2009), p-coumaric acid and neochlorogenic acid
(Wojdyłoet al., 2007), ferulic acid (Tunón et al., 1994;
Wojdyłoet al., 2007) and stachydrine, carboxylic acid,
salicylic acid, pyrocatechol, adenine, mandelic acid,
methyl esters of caprylic-linolenic- and undecylenic acid
(Tunón et al., 1994) are the phenols reported from
different parts of A. mellifolium.
Flavonoids
The various flavonoids reported from A. mellifolium
include resveratrol, morin, myricetin, naringin and
naringenin (Keser et al., 2013), quercetin and
kaempferol (Greger, 1969; Wojdyłoet al., 2007; Keser
S.I. ALI ET AL.
Copyright © 2017 John Wiley & Sons, Ltd. Phytother. Res. (2017)
Table 2. Chemical properties of major phytochemicals present in A. millefolium
S. no. Compounds Molecular formula 2DStructure Systematic name Average mass Structure ID
01. Cynaroside C21H20O11 2-(3,4-Dihydroxyphenyl)-5-
hydroxy-7-[(2S,3R,4S,5S,6R)-
3,4,5-trihydroxy-6-
(hydroxymethyl)oxan-
2-yl]oxychromen-4-one
448.377 Da ChemSpider ID-4444241
Pubchem CID-5280637
02. Cosmosiin C21H20O10 5-Hydroxy-2-(4-hydroxyphenyl)
-7-[(2S,3R,4S,5S,6R)-3,4,5-
trihydroxy-6-(hydroxymethyl)
oxan-2-yl]oxychromen-4-one
432.378 Da ChemSpider ID-4444290
Pubchem CID-5280704
03. Casticin C19H18O8 5-Hydroxy-2-(3-hydroxy-4-
methoxyphenyl)-3,6,7-
trimethoxychromen-4-one
374.341 Da ChemSpider ID-4474632
Pubchem CID-5315263
04. Centaureidin C18H16O8 5,7-Dihydroxy-2-(3-hydroxy-
4-methoxyphenyl)-
3,6-dimethoxychromen-4-one
360.315 Da ChemSpider ID-4474997
Pubchem CID-5315773
05. Apigenin C15H10O5 5,7-Dihydroxy-2-(4-hydroxyphenyl)-
4H-chromen-4-one
270.237 Da ChemSpider ID-4444100
Pubchem CID-5280443
06. Luteolin C15H10O6 2-(3,4-Dihydroxyphenyl)-5,7-
dihydroxychromen-4-one
286.236 Da ChemSpider ID-4444102
Pubchem CID-5280445
07. Artemetin C20H20O8 2-(3,4-Dimethoxyphenyl)-
5-hydroxy-3,6,7-
trimethoxychromen-4-one
388.368 Da ChemSpider ID-4478461
Pubchem CID-5320351
08. Thymol C10H14O 5-Methyl-2-propan-2-ylphenol 150.218 Da ChemSpider ID-21105998
Pubchem CID 6989
09. Carvacrol C10H14O 2-Methyl-5-propan-2-ylphenol 150.218 Da ChemSpider ID-21105867
Pubchem CID-10364
10. Limonene C10H16 (4R)-1-Methyl-4-prop-1-en-
2-ylcyclohexene
136.234 Da ChemSpider ID-20939
Pubchem CID-440917
11. Camphene C10H16 3,3-Dimethyl-2-methylidenebicyclo
[2.2.1]heptane
136.234 Da ChemSpider ID-6364
Pubchem CID-6616
12. Caffeic acid C9H8O4 (2E)-3-(3,4-Dihydroxyphenyl)
prop-2-enoic acid
180.157 Da ChemSpider ID-600426
Pubchem CID-689043
(Continues)
ACHILLEA MILLEFOLIUM L.: A REVIEW
Copyright © 2017 John Wiley & Sons, Ltd. Phytother. Res. (2017)
Table 2. (Continued)
S. no. Compounds Molecular formula 2DStructure Systematic name Average mass Structure ID
13. Achillinin A C15H20O6 (3aS,6R,6aR,6bR,7aS,8R,8aS)
-6,6a,8-Trihydroxy-6,8-dimethyl-
3 methylenedecahydrooxireno
[1,2]azuleno[4,5-b]furan-2(3H)-one
296.316 Da ChemSpider ID-28289151
Pubchem CID-101805792
14. Rutin C27H30O16 2-(3,4-Dihydroxyphenyl)
-5,7-dihydroxy-
4-oxo-4H-chromen-3-yl 6-O-
(6-deoxy-α-L-mannopyranosyl)
-β-D-glucopyranoside
610.518 Da ChemSpider ID-4444362
Pubchem CID-5280805
15. 1,8-cineole C10H18O2 1,3,3-Trimethyl-
2-oxabicyclo[2.2.2]octane
154.249 Da ChemSpider ID-2656
Pubchem CID-2758
16. Bisabolol C15H26O (2S)-6-Methyl-2-[(1S)-
4-methylcyclohex-
3-en-1-yl]hept-5-en-2-ol
222.366 Da ChemSpider ID-10141
Pubchem CID-442343
17. α-pinene C10H16 4,6,6-Trimethylbicyclo[3.1.1]hept-
3-ene
136.234 Da ChemSpider ID-6402
Pubchem CID-6654
18. β-pinene C10H16 6,6-Dimethyl-4-methylidenebicyclo
[3.1.1]heptane
136.234 Da ChemSpider ID-14198
Pubchem CID-14896
19. Germacrene D C15H24 (1Z,6Z)-1-Methyl-5-methylidene-8-
propan-2-ylcyclodeca-1,6-diene
204.351 Da ChemSpider ID-28288426
Pubchem CID-5373727
20. Camazulene C14H16 7-Ethyl-1,4-dimethylazulene 184.277 Da ChemSpider ID-10268
Pubchem CID-10719
S.I. ALI ET AL.
Copyright © 2017 John Wiley & Sons, Ltd. Phytother. Res. (2017)
et al., 2013), Ten 1,10-secoguaianolides viz., millifolide
A, millifolide B, millifolide C, iso-secotanapartholide,
arteludooicinolide A, 3-acetyl-iso-seco-tanapartholide,
3-methoxytanapartholide, seco-tanapartholide A, seco-
tanapartholide, and 5-epi-secotanapartholide A (Li
et al., 2012a), achillinin A (Li et al., 2011), apigenin 7-
O-glucoside (cosmosiin) and luteolin 7-O-glucoside
(cynaroside) (Vitalini et al., 2011; Benedek et al.,
2007c; Yassa et al., 2007; Horhammer, 1961; Michaluk,
1962; Horhammer et al., 1964; Oswiecimska and
Miedzobrodzka, 1966; Kaloshina and Neshta, 1973;
Schulz and Albroscheit, 1988), apigenin and luteolin
(Csupor et al., 2009; Innocenti et al., 2007; Benedek
et al., 2007c; Wojdyłoet al., 2007; Guédon et al., 1993),
centaureidin (Csupor et al., 2009), casticin (Csupor
et al., 2009; Haidara et al., 2006; Falk et al., 1975),
luteolin-3,7-di-O-glucoside and vicenin-2 (Benetis
et al., 2008), artemetin (Csupor et al., 2009; Falk et al.,
1975; Ivancheva et al., 2002), rutin (Vitalini et al., 2011;
Pires et al., 2009; Benedek et al., 2007c; Innocenti et al.,
2007; Neshta et al., 1972; Kaloshina and Neshta, 1973),
dihydrodehydrodiconiferyl alcohol 9-O-β-D-
glucopyranoside, apigenin-7-O-β-D-glucopyranoside,
luteolin-7-O-β-D-glucopyranoside and luteolin-4-O-β-
D-glucopyranoside (Innocenti et al., 2007), 5-hydroxy
3,40, 6,7 tetramethoxy flavones (Gadgoli and Mishra,
2007; Falk et al., 1975), isorhamnetin (Wojdyłoet al.,
2007; Falk et al., 1975; Greger, 1969) and acacetin
(Greger, 1969).
Flavonoid aglycones and flavonoid glycosidesC-
glycosylflavones, flavonol and flavones O-glycosides
are also found in A. mellifolium. The flavonoid
aglycones include chrysophenol-D, salvigenin,
quercetagetin, centaureidin, hispidulin, cirsimarin and
nepetin. The flavonoid glycosides include vitexin,
vicenine, swertjponin and swertisin. The flavonol and
flavones O-glycosides contain quercetin-3-O-glycoside,
quercetin-3-O-rhamnoglycoside, luteolin-7-O-glycoside,
diosmetin-7-O-glycoside and kaempferol-3-O-glycoside
(Ivancheva et al., 2002).
Sesquiterpenoids
The sesquiterpenoids identified in A. millefolium are
sesquiterpene lactone ester A, sesquiterpene lactone
ester B and sesquiterpene lactone-diol (Farooq et al.,
2012), seco-pseudo guaianolides viz., paulitin,
isopaulitin, psilostachyin C, desacetylmatricarin and
sintenin (Csupor et al., 2009), achimillic acids A, B
and C (Tozyo et al., 1994), isoachifolidiene (Rucker
et al., 1992), 8-acetyl egelolide and 8-angeloyl egelolide
(Ochir et al., 1991), austricin (deacetylmatricarin),
millefin, 8-hydroxyachillin and artelesin (Konovalov
and Chelombitko, 1991), α-peroxyachifolid, β-
peroxyisoachifolid (Hausen et al., 199; Rucker et al.,
1991), achillifolin, dihydroparthenolide and
dihydroreynosin (Ulubelen et al., 1990), azulenogene
sesquiterpene lactones viz., 8-acetoxy-artabsine, 8-
angeloxy-artabsine and 2, 3-dihydro-desavetoxy-
matricin (Verzar-Petri et al., 1980), acetylbalchanolide
and millefolide (Hochmannová et al., 1961). The sterols
identified include, β-sitosterol, stigmasterol,
campesterol and cholesterol while triterpenes identified
are α-amyrin, β-amyrin, taraxasterol and
pseudotaraxasterol (Chandler et al., 1982b).
Essential oils
Monoterpenes are the most representative metabolites
constituting 90% of the essential oil of A. millefolium
in relation to the sesquiterpenes. However, variation in
the composition of essential oil may be due to various
factors related to chemotype, ecotype, phenophases,
altitude and variations in environmental conditions such
as temperature, photoperiod, relative humidity and
irradiance. Moreover, genetic background may be the
factor responsible for affecting the chemistry of
secondary metabolites of the plants (Zahara et al.,
2014).
Hydrocarbon monoterpenes
Cis-chrysanthenol (Judzentiene, 2016), α-pinene, β-
pinene and β-phellandrene (Sevindik et al., 2016;
Kazemi, 2015; Costescu et al., 2014; Falconieri et al.,
2011; Nadim et al., 2011; Conti et al., 2010; Bimbiraite
et al., 2008; Anne et al., 2001 & 2006; Nemeth, 2005;
Boskovic et al., 2005; Rohloff et al., 2000; Hofmann
et al., 1992), p-cymene (Ebadollahi et al., 2016;
Yousefzadeh and Zeinivand, 2013; Nadim et al., 2011;
Anne et al., 2006; Jaimand et al., 2006), α-thujane, α-
terpinene and γ-terpinene (Mazandarani et al., 2013),
camphene and limonene (Kazemi, 2015; Nadim et al.,
2011; Bimbiraite et al., 2008) and sabinene (Nadim
et al., 2011; Conti et al., 2010; Boskovic et al., 2005) are
the hydrocarbon monoterpenes identified in A.
millefolium.
Oxygenated monoterpenes
Oxygenated monoterpenes including camphor, borneol
and bornyl acetate (Sevindik et al., 2016; Ebadollahi
et al., 2016; Kazemi, 2015; Mazandarani et al., 2013;
Conti et al., 2010; Rahimmalek et al., 2009; Boskovic
et al., 2005; Candan et al., 2003), piperitone (Ebadollahi
et al., 2016), carvacrol and carvone (Kazemi, 2015), 1, 8-
cineole (Sevindik et al., 2016; Yousefzadeh and
Zeinivand, 2013; Nadim et al., 2011; Judzentiene and
Mockute, 2010; Conti et al., 2010; Rahimmalek et al.,
2009; Anne et al., 2006; Candan et al., 2003; Bezic
et al., 2003), α-terpineol and terpinen-4-ol (Sevindik
et al., 2016; Nadim et al., 2011; Candan et al., 2003),
artemisia ketone (Mazandarani et al., 2013; Conti et al.,
2010), α-thujone, β-thujone, linalool and fenchyl acetate
(Mazandarani et al., 2013; Anne et al., 2006),
dihydrocarveol and chrysanthenyle acetate
(Yousefzadeh and Zeinivand, 2013), trans-thujone and
trans-crhysanthenyl acetate (Falconieri et al., 2011) and
myrecene (Bezic et al., 2003) were isolated from A.
millefolium.
Sesquiterpene hydrocarbons
(E)-β-caryophyllene (Sevindik et al., 2016; Costescu
et al., 2014; Conti et al., 2010; Anne et al., 2006; Bezic
et al., 2003), β-cubebene (Costescu et al., 2014),
germacrene-D (Costescu et al., 2014; Rahimmalek
et al., 2009; Bimbiraite et al., 2008; Santoro et al., 2007;
Nemeth, 2005; Boskovic et al., 2005; Anne et al., 2001;
ACHILLEA MILLEFOLIUM L.: A REVIEW
Copyright © 2017 John Wiley & Sons, Ltd. Phytother. Res. (2017)
Hofmann et al., 1992; Lourenco et al., 1999), α-asarone
and β-bisabolene (Falconieri et al., 2011),
bicyclogermacrene (Rahimmalek et al., 2009), α-
humulene and cadinene (Bimbiraite et al., 2008),
germacrene-B (Jaimand et al., 2006), γ-muurolene
(Anne et al., 2006) and α-elemene, trans-β-farnesene,
α-cadinene, germacrene-D-4-ol (Lourenco et al., 1999)
are the sesquiterpene hydrocarbons reported from A.
millefolium.
Oxygenated sesquiterpenes
Oxygenated sesquiterpenes include Umbelulone
(Yousefzadeh and Zeinivand, 2013), viridiflorol, 10-
epi-γ-eudesmol and selin-11-en-4α-ol (Judzentiene,
2016), bisabolol-oxides (Costescu et al., 2014; Nemeth,
2005; Anne et al., 2001), caryophyllene oxide (Sevindik
et al., 2016; Judzentiene and Mockute, 2010; Conti
et al., 2010; Boskovic et al., 2005; Anne et al., 2006),
nerolidol and eudesmol (Judzentiene and Mockute,
2010), spathulenol (Rahimmalek et al., 2009), β-
bisabolol (Anne et al., 2006) and α-bisabolol, β-
eudesmol, γ-eudesmol, bisabolol oxide II and
bisabolone oxide (Candan et al., 2003).
Proazulenes
Chamazulene (Costescu et al., 2014; Mazandarani et al.,
2013; Nadim et al., 2011; Rahimmalek et al., 2009;
Santoro et al., 2007; Nemeth, 2005; Anne et al., 2006;
Jaimand et al., 2006; Anne et al., 2001; Hofmann et al.,
1992) are the proazulenes reported from A. millefolium.
PHARMACOLOGICAL ACTIVITIES
Various active compounds have been reported from A.
millefolium containing wide range of medicinal
activities viz., choleretic, antimalarial, antioxidant,
Table 3. Phytochemicals from A. millefolium linked to various pharmacological properties
S. no. Phytochemical Pharmacological effect References
1. Centaureidin, casticin,
paulitin, isopaulitin, psilostachyin C,
desacetylmatricarin and sintenin
Antiproliferative Cuspor et al. (2009)
2. 3,5-DCQA (dicaffeoylquinic acid),
1,5-DCQA and 4,5-DCQA
Antioxidant Fraisse et al. (2011)
3. Neochlorogenic acid, ferulic acid,
thymol, carvacrol, bornyl acetate,
limonene, camphene, eucalyptol,
α-pinene and β-terpineol
Antioxidant Aneta et al. (2007)
4. Terpinolene, 1,8-cineole,
γ-terpinene and thujone
Antibacterial Masumeh et al. (2009)
5. Camphor and borneol Antibacterial and antioxidant Masumeh et al. (2009)
6. Rutin Antinociceptive and antioxidant Pires et al. (2009) and
Vitalini et al. (2011)
7. Apigenin 7-O-glucoside and
luteolin 7-O-glucoside
Antiplasmodial, antioxidant
and antiinflammatory
Vitalini et al. (2011) and
Yassa et al., (2007)
8. Quercetin Antispasmodic Lemmens-Gruber et al. (2006)
9. Salicylic acid and pyrocatechol Antiparasitic Tunón et al. (1994)
10. Seco-tanapartholide A
(Ten 1,10-secoguaianolides)
Anticancer Li et al. (2012a)
11. Achimillic acids A, B and C, Antitumor Tozyo et al. (1994)
12. Achillinin A Antiproliferative Li et al. (2011)
13. Apigenin and luteolin Antispasmodic; antioxidant,
antiproliferative and estrogenic
Lemmens-Gruber et al. (2006);
Vitalini et al. (2011);
Aneta et al. (2007);
Cuspor et al. (2009);
Innocenti et al. (2007)
14. Caffeic acid, Antiparasitic and antioxidant Tunón et al. (1994) and
Aneta et al. (2007)
15. Chlorogenic acid Antioxidant and antiparasitic Fraisse et al. (2011) and
Tunón et al. (1994)
16. Luteolin-7-O-beta-D-glucuronide Choleretic Benedek et al. (2005)
17. Dihydrodehydrodiconiferyl alcohol
9-O-beta-D-glucopyranoside
Estrogenic Innocenti et al. (2007)
18. 5-Hydroxy 3,4, 6,7-
tetramethoxy flavone
Hepatoprotective Gadgoli and Mishra (2007)
19. Artemetin Hypotensive, vasodilatory,
bronchodilatory and antiproliferative
De Souza et al. (2011)
and Cuspor et al. (2009)
20. Bisabolol Immunosuppressive Saeidnia et al. (2004)
S.I. ALI ET AL.
Copyright © 2017 John Wiley & Sons, Ltd. Phytother. Res. (2017)
antihypertensive, antimicrobial, antispasmodic,
hepatoprotective, gastroprotective, etc. using different
in-vitro and in-vivo methods. The different
pharmacological activities of the A. millefolium extracts
and its isolated phytoconstituents are summarized in
Table 3.
Antiulcer
Hydroalcoholic extract of A. millefolium was
evaluated on locomotor activity of ileum. The ileum
contractions of Wister rats were induced by 60 mM
KCl (18.83 ± 4.91%) or 1-μM acetyl choline
(18.31 ± 11.12%). However, addition of 1% of the
extract decreased the contraction in ileum induced by
KCl (59.96 ± 11.8%) or acetyl choline
(54.16 ± 12.06%) (p>0.05), and this may be due to
flavonoids especially quercetin and apigenin (Sedighi
et al., 2013).
The effect of aqueous extract obtained from A.
millefolium flowering tops (AME) on gastric motility
was evaluated on the resting tone of the isolated gastric
antrum and on gastric emptying in vivo both in control
mice and in cisplatin-treated mice. It was observed that
the AME (130 000 μgmL
1
) contracted the isolated
mouse and human gastric strips in a concentration-
dependent manner, with an effective threshold
concentration of 100 μgmL
1
. The contractile effect of
AME was unaffected by hexamethonium
(3 × 10
4
mol L
1
) and tetrodotoxin (3 × 10
7
mol
L
1
) but strongly reduced by atropine (10
6
mol L
1
).
Among various chemical ingredients in A. millefolium,
choline (5.62 × 10
4
mol L
1
threshold concentration),
but not the flavonoids rutin and apigenin, mimicked
the action of AME. The prokinetic effect of A.
millefolium extract observed in vivo could provide the
pharmacological basis underlying its traditional use in
the treatment of dyspepsia (Borrelli et al., 2012).
Oral administration (30, 100 and 300 mg/kg) of the
hydroalcoholic extract of A. millefolium aerial part
inhibited ethanol-induced gastric lesions by 35, 56 and
81%, respectively. However, oral treatment of 1 and
10 mg/kg reduced the chronic gastric ulcers induced by
acetic acid exposure by 43 and 65%, respectively, and
promoted significant regeneration of the gastric mucosa
after ulcer induction denoting increased cell
proliferation. A. millefolium treatment (10 mg/kg p.o.)
also decreased glutathione (GSH) and superoxide
dismutase (SOD) activity by 53 and 37% after acetic
acid-induced chronic gastric lesions. The results
suggested that the antioxidant properties of the
hydroalcoholic extract may contribute to its
gastroprotective activity (Potrich et al., 2010).
Baggio et al. (2008) investigated that a hot-water
aqueous extract of A. millefolium protected rats
against gastric ulcers induced by ethanol and
restraint-in-cold stress, but not against indomethacin
induced ulcers. The inhibitory dose 50% (ID
50
) for
the aqueous extract of A. millefolium was 900 mg/kg,
p.o when tested against gastric ulcers induced by
ethanol and or indomethacin. Antiulcer activity of A.
millefolium may be either due to inhibition of gastric
secretion or increase in protective factors (such as
blood flow) in gastric mucosa.
Cavalcanti et al. (2006) reported that aqueous extract
of A. millefolium efficiently heals the chronic ulcers
induced by acetic acid (ED
50
= 32 mg/kg, p.o.) in
rodents. The mucosal damage was reduced up to 75%
after seven days of treatment (100 mg/kg/day dose)
and by 90% at 300 mg/kg/day dose. Additionally, acute
administration of A. millefolium extract, concomitant
to ulcer-inducing treatment with 70% ethanol or
indomethacin, significantly reduced mucosal damage.
Hepatoprotective
Zolghadri et al. (2014) investigated the effect of
ethanol extract of A. millefolium aerial parts on IL-
1βand iNOS gene expression of pancreatic tissue in
the Streptozotocin (STZ) induced diabetic rats.
Streptozotocin (45 mg/kg body) was injected
intraperitoneal (IP) for inducing diabetes in rats.
Real-time PCR was used for determining quantity of
pancreatic IL-1βand iNOS mRNA. Body weight, IL-
1βand iNOS genes expression (about 56 and 55%,
respectively) in STZ-diabetic rats was restored after
administration of A. millefolium extract (100 mg/kg/
day). This may be due to amelioration of IL-1βand
iNOS gene over expression which can have a β-cell
protective effect.
Antihepatotoxic activity of 5-hydroxy 3, 40,6,7-
tetramethoxy flavone isolated from the aqueous extract
of A. millefoliumn aerial parts on fasted Wistar rats was
assessed by estimating Serum Transaminases viz.
Glutamyl Pyruvate Transaminase (GPT) and Glutamyl
Oxaloacetate Transaminases (GOT), alkaline
phosphatase and total bilirubin. Hepatotoxicity was
induced by using carbon tetrachloride (CCl
4
) and
paracetamol (PCL). Pretreatment with the isolated
compound, 5-hydroxy 3, 40, 6, 7 tetramethoxy flavone,
at 20 mg/kg b.w.i.p. significantly reduced GPT levels
(101.28 and 141.98%), while GOT levels reduced to
99.8 and 110.12%, alkaline phosphatase (39.2 and
17.97%) and total bilirubin (55.28 and 43.64%) as
compared with CCl
4
and PCL respectively, which is
similar with Silymarin (50 mg/kg b. w. i. p.). The results
confirmed the medicinal value of A. millefolium used in
indigenous systems of medicines in India (Gadgoli and
Mishra, 2007).
The aqueousmethanol extract of A. millefolium
aerial parts was studied for its possible hepatoprotective
effect against d-galactosamine (d-GalN) and
lipopolysaccharide (LPS) -induced hepatitis in mice to
rationalize some of the folklore uses. Co-administration
of d-GalN (700 mg/kg) and LPS (25 μg/kg) produced
100% mortality in mice. However, pre-treatment with
A. millefolium extract (300 mg/kg) reduced the
mortality to 40%. Co-administration of d-GalN
(700 mg/kg) and LPS (1 μg/kg) significantly raised the
plasma alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) levels compared with values
in the control group (p<0.05). Pre-treatment of mice
with A. millefolium extract (150600 mg/kg)
significantly prevented the toxins induced rise in plasma
ALT and AST (p<0.05). These results indicate that the
A. millefolium exhibit a hepatoprotective effect, which
may be partly attributed to its observed calcium channel
blocking activity (Yaeesh et al., 2006).
ACHILLEA MILLEFOLIUM L.: A REVIEW
Copyright © 2017 John Wiley & Sons, Ltd. Phytother. Res. (2017)
Anticancer/Antitumor
Ten 1,10-secoguaianolides isolated from the
methanolic extract of A. millefolium flower, were
studied for their growth inhibitory activity in vitro
against the human tumor (MCF7WT) and human
prostatic cancer cell line (PC3). 3-(4,5-
Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
(MTT) assay was used for estimating cell survival.
The results showed that only Seco-tanapartholide A
exhibited moderate cell growth inhibitory activity
against the human cancer cell line MCF7WT
(IC
50
= 5:51 μm) (Li et al., 2012a).
Cytotoxic and genotoxic effects of A. millefolium leaf
aqueous extract on Lactuca sativa (lettuce) root tip
meristem cells were examined. Lettuce seeds were
treated for 72 h with different concentrations of A.
millefolium aqueous extracts (5, 10, 20 and 30 mg/mL)
for analyzing percentage of germination, root
development and cellular behavior. The results showed
that the 30 mg/mL of aqueous extract reduced the
mitotic index, seed germination, root development and
also induced chromosome aberrations and cellular
death in the root cells of L. sativa. Although A.
millefolium has a beneficial effect as a medicinal plant,
serious problems and damages on cells by incorrect
usage can be observed (Saulo and Viccini, 2011).
Hemmati et al. (2011) investigated the anticancer
effect of hydroalcoholic extract of A. millefolium
flowers on bleomycin-induced (7.5 IU/kg) lung fibrosis
in Sprague Dawley rat. They were treated with
different doses of A. millefolium extract (400, 800,
1600 mg/kg/day P.O.) for two weeks. Histopathological
examination of bleomycin-treated animals showed
marked alveolar thickening associated with fibroblasts,
myofibroblasts proliferation and collagen production
in interstitial tissue leading to pulmonary fibrosis.
However, no toxicological or histopathological
abnormalities were exhibited in rats after oral
treatment of A. millefolium extract and less
contraction of lung strips was also observed at
1600 mg/kg of the extract.
Anticancer potential of ethanol extract of A.
millefolium aerial part was assayed on HFFF (normal
fibroblast cell line) and six cancerous cell lines viz,
AGS (human caucasian gastric adenocarcinoma),
MCF7 (human breast ductal carcinoma), SW742
(human colorectal adenocarcinoma), SKLC6 (human
lung carcinoma), A375 (human melanoma cancer)
and PLC/?PRF/5 (human liver hepatoma). Cell lines
were treated with 10 mg of evaporated ethanol extract
dissolved in DMSO and ethanol (50%). The highest
IC
50
value of 66.000 μg/mL was observed against
PLC/?PRF/5, followed by MCF7 (64.058 μg/mL),
A537 (49.438 μg/mL), SW742 (40.279 μg/mL), HFFF
(34.431 μg/mL), SKLC6 (24.106 μg/mL) and AGS cell
lines (22.051 μg/mL). The findings may point at
selectivity effect of extract in inducing cytotoxicity on
cancerous cell lines (Ghavami et al., 2010).
De Santanna et?al. (2009) investigated the genotoxic
activity of A. millefolium flower oil on heterozygous
diploid strain of Aspergillus nidulans (A757//UT448
with green conidia). The genotoxic evaluation was
performed at 0.13, 0.19 and 0.25 μL/mL concentrations.
A significant increase in number of yellow and white
mitotic recombinants, per colony of the diploid strain,
was reported after oil treatment with 0.19 and 0.25 μL/
mL. The genotoxicity of the oil was associated with the
induction of mitotic non-disjunction or crossing-over
by oil. The present results pointed to the necessity of
testing the ability of A. millefolium essential oil to
interfere with the recombinational process in
mammalian cells and also suggested that the oil should
be used carefully.
Casticin isolated from A. millefolium was studied for
antitumor potential through cell cycle and apoptotic
signaling pathways in two MCF-7 sub-lines MN1 and
MDD2. Both cell lines were found sensitive to Casticin
at concentrations above 0.25 μM, and they display a
similar 50% inhibitory concentration (IC
50
)of2μM.
Casticin results in cell growth arrest in G2/M phase
and induced apoptotic death by acting as a tubulin-
binding agent (TBA). It also induced p21which in turn
inhibited Cdk1 and down regulated the cyclin A
expression (Haidara et al., 2006).
The cytotoxic activity of A. millefolium leaf and
flower ethanol extracts was investigated on human
breast cancer (SK-Br-3, MDA-MB-435) and leukemia
cell lines (U937 and K562). The inhibition of cell
proliferation was measured by using MTT colorimetric
assay. A. millefolium extract at 10 μg/mL concentration
caused 50% inhibition in growth of SK-Br and K562
cells (most sensitive cells to the effect), and the
proliferation of these cells was strongly decreased at
400 μg/mL (>87% inhibition). However, with increase
in concentration, the proliferation activity of these cells
was increased by 10 to 100 μg/mL (%inhibition range
48.8 at 10 μg/mL to 6.25 at 100 μg/mL) and suppressed
(%inhibition range 6.25 and 27.6% at 400 μg/mL)
(Amirghofran and Karimi, 2002).
In-vivo antitumor activity of three sesquiterpenoids,
achimillic acids A, B and C, isolated from methanol
extract of A. millefolium flower was studied against
mouse P-388 leukemia cells.Test compounds were
administrated as a single IP injection on the day
following the tumor inoculation at a dose of 1, 2, 5, 20
and 50 mg/kg. The compounds were found to be active
against mouse P-388 leukemia cells in a concentration-
dependent manner (Tozyo et al., 1994).
Antiinflammatory
David et al. (2010) examined the effects of A.
millefolium aqueous extract on the inflammatory
responses of RAW 264.7 murine macrophages cell line
challenged with LPS. Cell viability was not affected at
the concentration of 25300 μg/mL of extract.
Lipopolysaccharide-induced NO production was
strongly suppressed in a dose-dependent manner by
down regulating the expression inducible nitric oxide
synthase (iNOS), an enzyme directly involved in LPS-
stimulated NO synthesis. However, no significant effect
was observed in PGE
2
synthesis, protein COX-2 and IL-
6 levels and dose-dependent inhibition was observed in
secretion of GM-CSF and IL-10. At 200 μg/mL, the
production of TNF-and IL-10 was significantly
enhanced. The present study clearly suggested the
potential of A. millefolium to combat acute and chronic
inflammation and may be a novel source for drug
discovery.
S.I. ALI ET AL.
Copyright © 2017 John Wiley & Sons, Ltd. Phytother. Res. (2017)
In-vitro antiinflammatory activity of A. millefolium
aerial part methanol and aqueous extracts inhibited
the inflammation-related proteases, viz, neutrophil
elastase (HNE) and matrix metalloproteinases
(MMP-2 and -9). Besdes extracts, two fractions
enriched in flavonoids and DCQAs, were tested in
order to evaluate their contribution to the
antiphlogistic activity of the plant. The extract and
the flavonoid-enriched fraction inhibited HNE at
IC
50
value of 20 μg/mL, while a DCQA-enriched
fraction inhibited HNE at IC
50
value of 72 μg/mL.
Dicaffeoylquinic acid fraction was more potent to
inhibit MMP-2 and MMP-9 at IC
50
values ranged from
600 to 800 μg/mL then the flavonoid fraction and the
extract. The obtained results give further insights into
the pharmacological activity of A. millefolium and
confirm the traditional application as antiphlogistic
drug (Benedek et al., 2007c).
Three glycosylated phenolic compounds, luteolin-7-
O-glucoside, apigenin-7-O-glucoside and caffeic acid
glucoside were isolated from the methanol extract of
A. millefolium aerial part, and the immunological
properties of different fractions of plant extract were
studied on humoral immune system of BALB/c albino
female mice using microhaemagglutination test. The test
compounds at 125 and 61.5 mg/kg showed a significant
decrease in the anti-SRBC (sheep red blood cell) titer
of mice. The immunological properties of the fractions
may be attributed to glycosylated derivatives of caffeic
acid (Yassa et al., 2007).
Lopes et al. (2005) studied the effects of A.
millefolium leaf essential oil and commercial azulene in
peritoneal macrophage cell cultures from Swiss mice.
Three dilutions of the essential oil (1:50, 1:100 and
1:200) and commercial azulene (1:100) were tested for
H
2
O
2
and TNF-αdetermination by using MTT assay.
Higher viability level of 70% was observed in 1:100
and 1:200 dilutions. However, 66.86% viability of the
cells was found in the presence of commercial azulene.
The essential oil was also able to stimulate peritoneal
macrophages to produce H
2
O
2
and TNF-αwithout
causing an overproduction of these compounds, but it
is lower than that of commercial azulene. The results
suggested that the A. millefolium can modulate
macrophages activation.
Lopes et al. (2003) determined the release of nitric
oxide in peritoneal macrophages cultures of Swiss mice
in the presence of crude essential oil and 70% crude
ethanolic extract obtained from the leaves of A.
millefolium. Among different dilutions of the essential
oil tested (1:50, 1: 100 and 1: 200), only the 1: 100
dilution produced a greater amount of nitric oxide
(NO). In relation to the 70% ethanolic extract, higher
NO production was observed in the more concentrated
samples (6, 8 and 10 mg/mL). It was found that both
the essential oil and the 70% crude ethanolic extract of
A. millefolium are macrophage activation modulating
agents at concentrations of 20, 10 and 5 mg/mL, when
compared with LPS (LPS-potent stimulator of NO
production).
Antiinflammatory activity of different fractions
isolated from an aqueous extract of the dry flower heads
of A. millefolium was measured by the mouse paw
edema test. The most active fraction isolated (XII)
reduced inflammation by 35% at a dose level of
40 mg/kg (Goldberg et al., 1969).
Antiproliferative
Antiproliferative activity of methanolic extract of A.
millefolium aerial parts (MEA) alone or combined with
bleomycin was investigated on human prostate cancer
(DU-145) and human nonmalignant fibroblast cell lines
(HFFF2) by using MTT assay. Both the cell lines were
treated with MEA at various concentrations (20, 100,
500, 1000 and 2000 μg/mL). The extract considerably
improved cytotoxicity induced by bleomycin showing
60 and 49% survival rate at doses of 1000 and
2000 μg/mL, respectively. The survival rate reached
85% in bleomycin-treated cells. MEA did not exhibit
any cytotoxicity on HFFF2 cells. The enhanced cell
toxicity induced by bleomycin in the prostate cancer cell
without any significant toxicity on normal cells may be
due to cytotoxic flavonoids such as casticin and
sesquiterpenoids, but the mechanisms remain to be
elucidated (Shahani et al., 2015).
In-vitro antiproliferative activity of Achillinin A
isolated from the flower of A. millefolium was evaluated
against five human lung tumor cell lines
(adenocarcinomic human alveolar basal epithelial
A549, human lung adenocarcinoma RERF-LC-kj,
human lung carcinoma QG-90, QG-56, PC-3) and
compared with that of cisplatin. The results showed that
Achillinin A exhibited potential antiproliferative
activity to adenocarcinomic human alveolar basal
epithelial A549, human lung adenocarcinoma RERF-
LC-kj and human lung carcinoma QG-90 cells with
50% inhibitory concentration (IC
50
) values of 5.8, 10
and 0.31 μM, respectively, and the activity was stronger
than that of cisplatin (Li et al., 2011).
Five flavonoids (apigenin, luteolin, centaureidin,
casticin and artemetin) and five sesquiterpenoids
(paulitin, isopaulitin, psilostachyin C,
desacetylmatricarin and sintenin) isolated and identified
from chloform extract of aerial parts of A. millefolium
were investigated for their antiproliferative activities
on three human tumor cell lines (HeLa, MCF-7 and
A431 cells) by using MTT assay. Centaureidin was the
most effective constituent having high cell growth
inhibitory activities on HeLa (IC
50
value of
0.0819 μM) and MCF-7 (IC
50
value of 0.1250 μM) cells.
Casticin and paulitin were also highly effective against
all three tumor cell lines (IC
50
1.2864.76 μM), while
apigenin, luteolin and isopaulitin proved to be
moderately active (IC
50
value of 6.9532.88 μM).
Artemetin, psilostachyin C, desacetylmatricarin and
sintenin did not show antiproliferative effects against
these cell lines (Csupor et al., 2009).
Antispermatogenic effect
Takzare et al. (2011)studied the effect of ethanol extract
of A. millefolium flowers on spermatogenesis in adult
male wistar rats. A dose of 200, 400 and 800 mg/kg/day
of extract were administered by IP injection or through
gavage for 22 days, on every other day. At a dose of
400 mg/kg/day (IP), scattered immature cells on basal
membrane in seminiferous tubules were found, and also
a significant decrease in cell accumulation and
vacuolization in seminiferous tubule was seen.
However, a dose of 800 mg/kg (IP) caused thickeness
in seminiferous tubules on basal membrane, decrease
ACHILLEA MILLEFOLIUM L.: A REVIEW
Copyright © 2017 John Wiley & Sons, Ltd. Phytother. Res. (2017)
in cell accumulation in seminiferous tubule, severe
disarrangement, degenerative cells and severe decrease
in sperm count. Oral administration of 800 mg/kg/day
of extract showed thickness in basal membrane and
the disarrangement in cells. The present results suggest
that the A. millefolium exhibit temporary antifertile
activity in adult male animals.
Oral administration of alcoholic extract of A.
millefolium flowers caused significant decrease in
fertility parameters (fertility indices, body and
reproductive organs weight) in male rats. At the doses
of 200 and 400 mg/kg/day for 50 days, no significant
difference in body weight, sperm motility and sperm
viability was observed. However, significant decrease
was observed in epedidymis weight, epididymal sperm
reserve (ESR), daily sperm production (DSP) and
testosterone concentration at 200 mg/kg of body weight.
The results suggested that alcoholic extract of A.
millefolium flowers had antifertility effect, but its
mechanism is not clear, and it may be due to the
presence of chemical composition of A. millefolium
(Parandin and Ghorbani, 2010).
Montanari et al. (1998) studied the effect of an
ethanolic extract (200 mg/kg/day, intraperitoneally, for
20 days) and a hydroalcoholic extract (300 mg/kg/day,
orally, for 30 days) of A. millefolium flowers on the
spermatogenesis of Swiss mice. A. millefolium, at the
dose of 200 mg/kg/day for 20 days or at the dose of
300 mg/kg/day for 30 days, did not cause any significant
difference in body weight gain or in testis and seminal
vesicle weight. However, macroscopic alterations were
observed in the reproductive organs of animals treated
with 200 mg/kg/day, intraperitoneally, for 20 days, and
giant multinuclear cells were found in the vacuolized
seminiferous tubules of animals treated with
300 mg/kg/day of the extract. The results clearly
suggested further studies with A. millefolium as an
antifertility agent.
Antioxidant
Various compounds isolated from the essential oil of
aerial part of A. millefolium were examined for their
antioxidant activity using DPPH assay. The highest free
radical scavening activity against DPPH was shown by
thymol (IC
50
12.0 ± 0.1 μg/mL), followed by carvacrol
(IC
50
13.43 ± 0.0 μg/mL), and the lowest activity was
exhibited by bornyl acetate (IC
50
25 ± 0.1 μg/mL).
However, similar activity was observed in α-pinene
(20 ± 0.1 μg/mL), limonene (20 ± 0.3 μg/mL) and
camphene (20.01 ± 0.3 μg/mL). The results suggested
that the antioxidant activity of the essential oil is mainly
due to the action of thymol and carvacrol (Kazemi,
2015).
Georgieva et al. (2015) studied the antioxidant
activity (DPPH, ABTS, FRAP and CUPRAC assays)
of A. millefolium (leaves and stems). The highest free
radical scavenging activity was observed against
CUPRAC (55.08 ± 0.85 to 148.99 ± 1.94 μM TE/g dw),
followed by FRAP (38.16 ± 0.47 to 132.71 ± 1.86 μM
TE/g dw), DPPH (24.15 ± 0.15 to 116.74 ± 0.21 μM
TE/g dw) and ABTS (18.59 ± 0.22 to 125.75 ± 2.24 μM
TE/g dw). However, decoction extract showed
two/three times higher activity than the other extracts
studied.
Ethanol and aqueous extracts of A. millefolium
leaves, flowers and seeds were studied for their
antioxidant activity by using ferric thiocyanate and
H
2
O
2
radical scavenging assays. At 100 μg, both the
extracts exhibited scavenging activity (17.75 to
40.63%) on H
2
O
2
. However, α-tocopherol and BHA
(control) exhibited 44.58% and 39.26% H
2
O
2
scavenging activity. The highest H
2
O
2
scavenging
activity was observed in A. millefolium aqueous seed
extract (17.75%) and the lowest (40.57%) in ethanol
flower extract (Keser et al., 2013).
The antioxidant activity of the methanol extract of A.
millefolium aerial part and its compounds were
evaluated by using DPPH, total antioxidant capacity
(TAC), copper reducing power and TBARS assays.
Methanol extract showed significant activity against all
the assays. However, among compounds, rutin (IC
50
1.50 ± 0.11 mEq uric acid for DPPH and
0.35 ± 0.07 mEq uric acid for TAC at 1 μM), luteolin
7-O-glucoside (IC
50
1.10 ± 0.09 mEq uric for DPPH
and 0.11 ± 0.03 mEq uric acid for TAC at 1 μM) and
chlorogenic acid (IC
50
1.58 ± 0.11 mEq uric for DPPH
and 0.30 ± 0.05 mEq uric acid for TAC at 1 μM) showed
the highest activity. While luteolin-7-O-glucoside and
apigenin-7-O-glucoside showed the maximum inhibition
of TBARS formation (Vitalini et al., 2011).
Fraisse et al. (2011) assessed the contribution of five
main caffeoyl derivatives to the antioxidant activity of
the A. millefolium determined by DPPH assay. Total
antioxidant capacity of A. millefolium aerial parts was
8.29%, and main caffeoyl derivatives showed 61.80%
of the total with chlorogenic acid (10.01%), 3,5-DCQA
(33.17%), 1,5-DCQA (13.63%) and 4,5-DCQA
(4.99%). The main caffeoyl derivatives among
polyphenols can be considered as the major antioxidant
compounds of aerial parts of A. millefolium.
Wojdyłoet al. (2007) isolated five phenolic
compounds (caffeic acid, neochlorogenic acid, ferulic
acid, luteolin and apigenin) from A. millefolium and
studied their antioxidant activity by using ABTS, DPPH
and FRAP assays. The highest activity was observed
against DPPH (200 ± 3.33 μM trolox/100 g dw),
followed by FRAP (191 ± 4.51 μM trolox/100 g dw)
and ABTS (11.2 ± 0.77 μM trolox/100 g dw).
In-vitro antioxidant activity of borneol, camphor,
eucalyptol, α-pinene and β-terpineol isolated from
essential oil of A. millefolium aerial parts strongly
reduced the diphenylpicrylhydrazyl radical (DPPH)
(IC
50
= 1.56 μg/mL) and exhibited hydroxyl radical
scavenging effect in the Fe
3+
EDTAH
2
O
2
deoxyribose
system (IC
50
= 2.7 μg/mL). It also inhibited the
nonenzymatic lipid peroxidation of rat liver
homogenate (IC
50
= 13.5 μg/mL). Observations
confirmed that A. millefolium essential oil possessed
strong antioxidative activity (Candan et al., 2003). The
results suggested that A. millefolium may be used as
an easily accessible source of natural antioxidants and
also as a possible food supplement or in pharmaceutical
industry.
Antimicrobial
Antifungal activity of the essential oil from aerial parts
of A. millefolium was evaluated against Candida
albicans,Candida tropicalis,Candida krusei,Candida
S.I. ALI ET AL.
Copyright © 2017 John Wiley & Sons, Ltd. Phytother. Res. (2017)
guillermondii,Candida parapsilosis,Cryptococcus
neoformans,Trichophyton rubrum,Trichophyton
mentagrophytes,Trichophyton verrucosum,
Microsporum canis,Microsporum gypseum,
Epidermophyton floccosum,Aspergillus niger,
Aspergillus fumigates and Aspergillus flavus. The oil
showed the highest activity against the tested strains,
with MIC values ranging from 0.321.25 μLmL
1
(Falconieri et al., 2011).
Antibacterial activity of essential oil from aerial parts
of A. millefolium was studied against Shigella dysenteria,
Pseudomonas aeruginosa,Escherichia coli,Bacillus
cereus,Salmonella typhimurium,Staphylococcus aureus,
Staphylococcus epidermidis,Enterococcus faecalis and
Kelebsiella pneumoniae. The highest antibacterial
activity was observed against S. epidermidis and S.
aureus (33.6 ± 0.5 mm; MIC 12.6 μg/mL and
31.4 ± 0.8 mm; MIC 15.4 μg/mL) (Mazandarani et al.,
2009).
Different extracts (hexane, petroleum ether and
methanol) of A. millefolium aerial parts was tested
against S. aureus,E. coli,K. pneumoniae,P. aeruginosa,
Salmonella enteritidis,A. niger and C. albicans. The
mean zones of inhibition ranged between 15 and
17 mm, and the highest zone was observed in P.
aeruginosa (Stojanovic et al., 2005). Methanol extract
of A. millefolium aerial parts was active against
Helicobacter pylori at a MIC of 50 μg/mL (Mahady et al.,
2005).
The methanolic extracts (both water-soluble and
water-insoluble fractions) and the essential oil of A.
millefolium aerial parts were screened for antimicrobial
activity against S. aureus,Streptococcus pneumoniae,
Moraxella catarrhalis,B. cereus,Acinetobacter lwoffii,
Enterobacter aerogenes,E. coli,K. pneumoniae,Proteus
mirabilis,P. aeruginosa,Clostridium perfringens,
Mycobacterium smegmatis,C. albicans and C. krusei by
agar well-diffusion method.The significant activity was
shown by water-insoluble fractions against Candida
perfringens and the yeasts as compared with water-
soluble fractions which exhibited slight or no activity.
Essential oil possessed strong activity against the tested
strains as compared with the extracts. The MIC value
ranged from 4.5 mg/mL (w/v) to 72.00 mg/mL (w/v) with
the lowest MIC value against S. pneumoniae, C.
perfringens and C. albicans at 4.5 mg/mL (w/v). The
highest zone of inhibition was recorded against C.
albicans and C. krusei (21 and 16 mm) (Candan et al.,
2003).
Ethanol extract of aerial parts of A. millefolium was
screened for antimicrobial activity against E. coli, B.
cereus, P. aeruginosa, S. enteritidis and C. albicans. The
highest MIC value of 62.50 mg/mL was observed against
B. cereus and S. enteritidis. However, no activity was
observed in other three tested strains (Kokoska et al.,
2002). These studies confirmed the
ethnopharmacological use of A. millefolium and place
them among the most promising indigenous drug to
treat microbial infections.
Antiparasitic
Ebadollahi and Ashouri (2011) determined the
fumigant toxicity of essential oil from A. millefolium
against adults of Plodia interpunctella. The 100%
mortality rate was achieved at 50, 65 and 80-μL
concentrations. The LC
50
value was 34.80 μL/L after
24 h of fumigation, and it decreased with increase of
exposure time.
Methanolic extract and compounds isolated from
methanolic extract of A. millefolium were screened for
antiplasmodial activity in CQ-sensitive (D10) and CQ-
resistant (W2) strains of Plasmodium falciparum. The
methanol extract did not induce 50% mortality in the
D10 strain but showed a measurable activity against
the CQ-resistant W2 strain, with an IC
50
value of
44.6 ± 8.8 μg/mL. However, among the isolated
compounds, apigenin 7-O-glucoside (IC
50
10.1 ± 1.3 in
D10 and 6.1 ± 3.8 μg/mL in W2) and luteolin 7-O-
glucoside (IC
50
26.2 ± 13.5 in D10 and 26.8 ± 3.6 μg/
mL in W2) were the most active against both strains of
P. falciparum (Vitalini et al., 2011).
Essential oil extracted from the leaves and flowers
of A. millefolium were tested for their in-vitro
antileishmanial activity against Leishmania
amazonensis and murine macrophages (J774G8 cell
line). The IC
50
value of L. amazonensis promastigotes
was 7.8 μg/mL whereas the survival of amastigotes of
this pathogen within peritoneal murine macrophages
was halved by treatment with the oil at 6.5 μg/mL.
The mean cytotoxic value of the oil measured against
adherent (uninfected) J774G8 macrophages was
72.0 μg/mL (i.e. 9.2 and 11.0 times higher than the
IC
50
against the promastigotes and intracellular
amastigotes). Scanning electron microscopy revealed
that the oil caused morphological changes in the
treated parasites, including alterations in their shape
and size. In transmission electron microscopy,
promastigotes treated with the oil (at IC
50
of 7.8 μg/
mL) showed ultrastructural alterations (Santos et al.,
2010).
A study was conducted to investigate the efficacy of
11 flavonoids to inhibit the growth of the
intraerythrocytic malarial parasite viz., chloroquine-
sensitive (3D7) and chloroquine-resistant (7G8) strains.
All flavonoids showed activity against 7G8 strain, and
only eight exhibited activity against 3D7 strain, and
luteolin was the most effectual in preventing the
parasitic growth (Lehane and Saliba, 2008).
Nilforoushzadeh et al. (2008) evaluated the efficacy of
A. millefolium, propolis hydroalcoholic extract and
systemic glucantime against Cutaneous leishmaniasis in
Balb/c mice. Mean of ulcer size reduction observed in
glucantime was 22.57%, A. millefolium (43.29%) and
propolis groups (43.77%). However, A. millefolium
and propolis hydroalcoholic extract were more effective
than glucantime.
Essential oil from A. millefolium was investigated for
their antitrypanocidal activity against epimastigotes and
trypomastigotes forms of Trypanosoma cruzi. Results
showed a dose-dependent growth inhibition with IC
50
of 145.5 and 228 g/mL after 24 h, respectively (Santoro
et al., 2007).
Antimalarial and antibabesial activities (Babesia
gibsoniis is a tick-transmitted canine protozoan parasite
that destroys red blood cells) of 24 aqueous extracts of
traditionally used plants for the treatment of malaria in
Java were investigated. A. millefolium was one of the
six species found to exhibit strong inhibitory activity
(over 80% inhibition at 1 mg/mL) (Murnigsih et al.,
2005).
ACHILLEA MILLEFOLIUM L.: A REVIEW
Copyright © 2017 John Wiley & Sons, Ltd. Phytother. Res. (2017)
A. millefolium flower, leaf and stem ethanolic extracts
showed repellant activity against Aedes aegypti. The
nitrogen-containing compound stachydrine, the
carboxylic acids, caffeic acid, chlorogenic acid, salicylic
acid and the phenolic compound pyrocatechol, were
most active among 35 compounds isolated from
fractions of the extracts. They showed a distance and
contact-repelling activity similar to the well-known
repellent N,N-diethyl-toluamide (DEET) (Tunón et al.,
1994).
A. millefolium methanol extract exhibited activity
against 24-h-old larvae of Aedes triseriatus. The active
principle was found to be N-(2-methlpropyl)-(E, E)-2,
4-decadienamide. At 5 ppm, isolated and synthesized
amides resulted in 98 and 100% mortality of 24-h-old
A. triseriatus larvae. The N-(2-methylpropyl)-amides of
decanoic and (E)-2-decenoic acids showed the same
order of antilarval activity as N-(2-methylpropyl)-(E,
E)-2, 4-decadienamide, but N-(2-methylpropyl)
sorbamide was inactive (Lalonde et al., 1980).
Antispasmodic
Moradi et al. (2013) studied the effect of hydroalcoholic
extract of A. millefolium aerial parts on contraction and
relaxation of isolated ileum in rat. The inhibitory effect
of the extract on contractions induced by KCl and
acetylcholine was not significantly affected neither by
propranolol (1 μM) nor by Nω-Nitro-L-arginine
methylester hydrochloride (100 μM). However, A.
millefolium extract reduced KCl and acetylcholine-
induced contraction of ileum, which may be due to the
blockade of voltage-dependent calcium channels and
can be used for eliminating intestinal spasms.
Babaei et al. (2007) studied the effect of A.
millefolium hydro-alcoholic extract on the contractile
responses of the isolated guinea-pig ileum. It was found
that the contractile response was repressed by the
extract in a dose-dependent manner (EC
50
= 1.5 mg/
mL). The results confirmed that in-vitro effect of A.
millefolium extract in inhibiting the electrical induced
contractions of the guinea-pig ileum.
Several flavonoid agycones viz, quercetin, luteolin
and apigenin showed potent antispasmodic activities
on isolated terminal guinea pig ilea in vivo. The
aglycones quercetin, luteolin and apigenin exhibited
the highest antispasmodic activities with IC
50
values of
7.8, 9.8 and 12.5 μmol/L, respectively. However, rutin
and the flavonoid metabolites, homoprotocatechuic acid
and homovanillic acid showed no significant effects on
contractility of the terminal ilea (Lemmens-Gruber
et al., 2006).
Immunosuppressive
Yassa et al. (2007) studied the immunosuppressive
activity of methanol extract and some fractions of A.
millefolium aerial parts on humoral immunity in
BALB/c mice by microhaemagglutination test. Only
two fractions at 125 and 61.5 mg/kg showed significant
decrease in the anti-SRBC titer of mice. The
immunological properties of A. millefolium may be
due to the presence of glycosylated derivatives of caffeic
acid isolated from the active fraction of A. millefolium.
Saeidnia et al. (2004) studied the effects of A.
millefolium essential oil on humoral immune responses
in BALB/c mice. The essential oil decreased the anti-
SRBC antibody titer in mice and accounts for the
different immunological effects of this plant. However,
a sesquiterpene bisabolol was the main compound
isolated from A. millefolium essential oil.
Cardiovascular
DallAcqua et al. (2011) investigated the effect of
methanol extract of A. millefolium aerial parts extract
in vitro on the growth of primary rat vascular smooth
muscle cells (VSMC) under different conditions of cell
seeding density (2000 or 8000 SMC/well) and incubation
time (24 or 48 h) using the MTS assay. A. millefolium
extract was found to enhance primary rat VSMC by
partly acting through estrogen receptors and impairing
NF-κB signaling in human umbilical vein endothelial
cells at a concentration below 60 μg/mL by about 30
40%.
Niazmand and Saberi (2010) investigated the
inotropic and chronotropic effects of aqueousethanol
extract of A. millefolium on 24 wistar rats isolated
heart. The extract was infused to the heart at three
different concentrations (0.01, 0.0125, 0.02 mg/mL) for
30 s. The extract showed negative inotropic and
chronotropic effects on the heart during the infusion.
However, the negative choronotropic of A. millefolium
was stronger than its negative inotropic effect. This
supports some of the traditional uses of A. millefolium
and may induce novel potential actions in the
cardiovascular system.
Analgesic effect
Noureddini and Rasta (2008) studied the analgesic
effects of aqueous extract of A. millefolium flowers in
the rats formalin test. Aqueous extract of A.
millefolium (5, 27, 40, 80, 160 and 320 mg/kg, p.o.) was
injected 30 min before formalin injection.
Antinociception during 05 min (first phase) and 15
60 min (second phase) after formalin injection was
recorded. The highest antinociceptive was observed at
a dose of 160 mg/kg, and larger dose (320 mg/kg) did
not further effect in the formalin test. The results of
the present study justified the traditional use of the A.
millefolium for treating pain.
Role in appetite
Nematy et al. (2017) studied the orexigenic effect of
hydro-alcoholic extract of A. millefolium on 30 male
wistar rats by measuring plasma ghrelin level. A dose
of 50, 100 or 150 mg/kg of A. millefolium extract was
given to rats for 7 days via gavage. The extract at the
concentrations of 50 and 100 mg/kg showed significant
increase in food intake by rats during 24 h, while at
the 150 mg/kg no significant effect was observed. The
reason for decrease in appetite after administration of
150 mg/kg of extract is not clear. However, it may be
due to some side effects of A. millefolium at high doses.
S.I. ALI ET AL.
Copyright © 2017 John Wiley & Sons, Ltd. Phytother. Res. (2017)
This study indicated that A. millefolium had positive
dose-related effects on appetite in rats.
Estrogenic
Innocenti et al. (2007) reported the in-vitro estrogenic
activity of A. millefolium aerial parts in an assay using
recombinant MCF-7 cells. Active constituents
(dihydrodehydrodiconiferyl alcohol 9-O-beta-D-
glucopyranoside, apigenin and luteolin) isolated from
aerial part of A. millefolium are considered as estrogenic
agents. Apigenin activated estrogen receptor α(ERα)at
a minimum concentration of 1.50 × 10
2
g/L, while
luteolin was inactive. However, apigenin and luteolin
activated ERβat minimum concentrations of
3.70 × 10
3
g/L and 2.20 × 10
3
g/L.
Choleretic activity
The efficiency of 20% methanol extract fraction
enriched in 3,4-DCCA, 3,5-DCCA and 4,5-DCCA and
luteolin-7-O-β-D-glucuronide of A. millefolium aerial
parts was investigated for their choleretic potential in
isolated perfused rat liver. The fraction caused a dose-
dependent increase in bile flow of 23.1% (±6.9), 44.1%
(±17.2) and 47% (±12.2), compared with the internal
standard cynarin, which showed an increase of 5.1%
(±2.0), 15.9% (±3.6) and 21.6% (±8.9) at the same
concentrations (10, 20 and 40 mg/L). The combined
effect of DCCAs and luteolin-7-O-β-D glucuronide
stimulated bile flow more effectively than the single
compound cynarin. Due to their polar structure, these
compounds are quantitatively extracted into teas and
tinctures and are active choleretic principles in the
traditional applications of A. millefolium (Benedek
et al., 2006).
Anxiolytic activity
Hydroalcoholic extract of aerial parts of A. millefolium
was evaluated for their potential anxiolytic-like effect
in mice subjected to the elevated plus-maze, marble-
burying and open-field tests. Flumazenil (1.0 mg/kg)
and picrotoxin (1.0 mg/kg) were administered
intraperitoneally 30 min before the administration of
the hydroalcoholic extract of A. millefolium (300 mg/
kg). A. millefolium exerted anxiolytic-like effects in the
elevated plus-maze and marble-burying test after acute
and chronic (25 days) administration at doses that did
not alter locomotor activity. The effects of A.
millefolium in the elevated plus-maze were not altered
by picrotoxin pretreatment but were partially blocked
by flumazenil. A. millefolium did not induce any
changes in [(3)H]-flunitrazepam binding to the
benzodiazepine (BDZ) site on the GABA(A) receptor
indicating that the anxiolytic-like effects were likely
not mediated by GABA(A)/BDZ neurotransmission
and may be a promising candidate for future
development as a new anxiolytic drug (Baretta et al.,
2012).
Antinociceptive
The hydroalcohol extract of A. millefolium was
evaluated by the hot plate, writhing, formalin and
intestinal transit tests to confirm their folk use as
analgesic, antiinflammatory and antispasmodic agents.
Abdominal contortions were significantly inhibited by
65 and 23% at 500 and 1000 mg/kg of the extract due
to the presence of flavonoid glycoside rutin as a
principal constituent. A high content of caffeic acid
derivatives was also found in A. millefolium. None of
the extracts produced differences in the intestinal transit
in mice, nor in the response time in the hot plate or in
the immediate or late responses in the formalin test
(Pires et al., 2009).
Hypotensive, vasodilatory and bronchodilatory
activities
The oral administration of aqueous ethanol extract of A.
millefolium aerial parts (100300 mg/kg),
dichloromethane fractions (1030 mg/kg) significantly
reduced the mean arterial pressure (MAP) of
normotensive rats, but not ethylacetate fraction
(10 mg/kg) and butanolic fraction (50 mg/kg). The
dichloromethane fractions were found to contain high
amounts of artemetin and when administered by either
oral (1.5 mg/kg) or intravenous (0.151.5 mg/kg) routes
in rats caused dose-dependent reduce in MAP, up to
11.47 ± 1.5 mmHg (1.5 mg/kg, i.v.). Intravenous
injection of artemetin (0.75 mg/kg) significantly reduced
the hypertensive response to angiotensin-I, while
increasing the average length of bradykinin-induced
hypotension. Artemetin (1.5 mg/kg, p.o.) was also able
to reduce plasma (about 37%) and vascular (up to
63%) angiotensin-converting enzyme activity in vitro,
compared with control group (De Souza et al., 2011).
The aqueousmethanol extract of A. millefolium
aerial parts caused a dose-dependent (1100 mg/kg)
decrease in arterial blood pressure of rats under
anesthesia. In spontaneously beating guinea pig atrial
tissues, the extract exerted negative inotropic and
chronotropic effects. In isolated rabbit aortic rings, the
extract (0.310 mg/mL) relaxed phenylephrine (1 mM)
and high K
+
(80 mM) induced contractions. In guinea
pig tracheal strips, the extract suppressed carbachol
(1 mM) and K
+
induced contractions. These results
indicated that A. millefolium exhibits hypotensive,
cardiovascular inhibitory and bronchodilatory effects,
thus explaining its medicinal use in hyperactive
cardiovascular and airway disorders, such as
hypertension and asthma (Khan and Gilani, 2011).
Skin-rejuvenating activity
Pain et al. (2011) evaluated the effect of A. millefolium
extract on the expression pattern of various epidermal
differentiation markers in normal human skin biopsies
using quantitative image analysis and second to evaluate
its capacity to rejuvenate the appearance of skin surface
in vivo. Study showed that A. millefolium extract
improved the expression profile of various epidermal
differentiation markers (cytokeratin 10,
transglutaminase-1 and filaggrin) in cultured skin
ACHILLEA MILLEFOLIUM L.: A REVIEW
Copyright © 2017 John Wiley & Sons, Ltd. Phytother. Res. (2017)
biopsies as well as increased epidermal thickness. In
vivo, a 2-month treatment with 2% A. millefolium
extract significantly improved the appearance of
wrinkles and pores compared with placebo.
Cyclophosphamide toxicity amelioration activity
Jalali et al. (2012) assessed whether A. millefolium
inflorescences aqueous extract with antioxidant and
antiinflammatory activities could serve as a protective
agent against reproductive toxicity during
cyclophosphamide treatment induced in male Wistar
rats. A. millefolium aqueous extract was given at a dose
of 1.2 g/kg/day orally 4 h after cyclophosphamide
administration (at dose of 5 mg/kg/day for 28 days by
oral gavages). Cyclophosphamide-treated rats showed
significant decrease in the body, testes and epididymides
weights as well as many histological alterations.
Stereological parameters, spermatogenic activities and
testicular antioxidant capacity along with epididymal
sperm count and serum testosterone concentration were
also significantly decreased by cyclophosphamide. Co-
treatment with A. millefolium extract caused a partial
recovery in above-mentioned parameters.
Anticonflict behavior activity
Molina-Hernandez et al. (2004) found that anticonflict-
like behavior actions of aqueous extract of A.
millefolium flowers in female Wistar rats may vary
according to the oestrous cycle phase. During late
proestrus, conflict behavior was reduced at doses of
8.0, 10.0 or 12.0 mg/kg. Conversely, during diestrus, only
the dose of 12.0 mg/kg reduced conflict behavior.
During late proestrus, control rats displayed reduced
conflict behavior compared with diestrus. Diazepam
(2.0 mg/kg; IP) reduced conflict behavior both during
late proestrus or diestrus. It was found that the
anticonflict-like actions of A. millefolium may vary
according to the estrous cycle phase.
Anthelmintic activity
Tariq et al. (2008) evaluated the anthelmintic efficacy of
aqueous and ethanolic extracts of A. millifolium against
the gastrointestinal nematodes of sheep. The worm
motility inhibition assay was used for in-vitro studies,
and fecal egg count reduction assay was used for in-vivo
studies. In-vitro studies revealed significant anthelmintic
effects of A. millefolium extracts on live Haemonchus
contortus worms as evident from their paralysis and
death at 8 h post exposure. Both the extracts resulted
in a mean worm motility inhibition of 94.44 and
88.88%. The mean mortality index (MMI) of both
extracts was 0.95 MMI and 0.9 MMI and LC
50
was
0.05 mg/mL for aqueous extract and 0.11 mg/mL for
ethanol extract. The in-vivo anthelmintic activity of
aqueous and ethanol extracts of A. millefolium
demonstrated the highest (88.40%) nematode egg count
reduction in sheep treated with aqueous extract at 2 g/kg
body weight on day 15 after treatment and 76.53%
reduction in fecal egg count for the ethanol extract at
the same concentration. A. millefolium possesses
significant anthelmintic activity and could be a potential
alternative for treating cases of helminth infections in
ruminants.
Table 4. Clinical trials of A. millefolium
S. no.Study type Number of
participants
Disease Main outcome Main conclusion Adverse
effect
Reference
1. Double-blind
clinical trial
140 Episiotomy Reduce perineal
pain level, redness,
edema and
ecchymosis of
episiotomy wound
Episiotomy wound
healing improver in
primiparous women
Hajhashemi
et al. (2016)
2. Double-blind
randomized
clinical trail
91 Primary
dysmenorrheal
Significant decrease
in primary
dysmenorrheal pain
Pharmacologic
alternative
for primary
dysmenorrheal pain
Jenabi and
Fereidoony (2015)
3. Randomized
controlled trial
56 Oral
mucositis
Significantly reduced
severity of oral
mucositis
Chemotherapy-
induced oral
mucositis drug
Miranzadeh
et al. (2015)
4. Randomized
controlled trial
31 Chronic
kidney
disease
Decrease in
plasma nitrite and
nitrate
concentrations
Higher doses or longer
duration of plant
administration
may make these
changes more
significant
Skin
rashes
Vahid et al. (2012)
5. Double blind,
placebo-controlled
randomized trial
49 Atopic
dermatitis
Same effect as
that of treatment
with placebo
Clinical use is not
recommended
Shapira et al.
(2005)
6. Randomized
double-blind
clinical trial
36 Liver
cirrhosis
Significant decrease
in ChildPugh score
and ascites
Hepatoprotective
effect in cirrhotic
patients
Huseini et al.
(2005)
S.I. ALI ET AL.
Copyright © 2017 John Wiley & Sons, Ltd. Phytother. Res. (2017)
CLINICAL DATA
Herbal remedies continue to be an accepted
complementary medical option throughout the world.
However, the majority of adverse effects come into the
light subsequently including herbdrug interactions,
through spontaneous case reports, case series and post
marketing surveillance studies from herbal remedies
due to the presence of pharmacologically active
molecules. Assessing the safety and efficacy of herbal
medicines remain problematic, with inadequate or
inconsistent methods being used. The clinical evidences
on herbal medicine depend on the totality of the
available clinical data (randomized controlled trials,
case reports, post-marketing surveillance studies and
spontaneous reporting schemes) that can be grouped
in systematic reviews to provide reliable information
on herbal medicines safety. Moreover, randomized
controlled trial (double blind) is the most meticulous
system for evaluating the efficacy of drugs (Izzo et al.,
2016). Different clinical trials performed on A.
millefolium are mentioned in Table 4.
Hajhashemi et al. (2016) assessed the efficacy of A.
millefolium ointments on episiotomy wound healing in
140 primiparous women by doing double-blind clinical
trial. Healing process was assessed by five specifications:
redness, ecchymosis, edema, discharge and wound
dehiscence at 7th, 10th and 14th day after delivery, and
pain level was assessed by means of visual analogue
scale. A significant difference in reducing pain severity
was observed between the groups (P<0.05), as pain
level, redness, edema and ecchymosis were less and
more effective due to A. millefolium ointments than
control groups. But discharge and dehiscence incidence
showed no significant difference between groups
(P>0.05). The results clearly suggested the use of A.
millefolium as episiotomy wound healing improver in
primiparous women.
Jenabi and Fereidoony (2015) assessed the
effectiveness of A. millefolium flowers on relief of
primary dysmenorrheal in 91 female students (ranging
between 10 and 15 years) by conducting double-blind
randomized clinical trial. The subjects were randomly
divided into two equal groups and were given either
placebo or A. millefolium in tea bag form for three days
in two menstruation cycles, and severity of pain was
graded by using a visual analogue scale. It was observed
that the mean change in pain score in the A. millefolium
group was significantly greater than that in the placebo
group at 1 month (P= .001) and 2 months (P<.0001)
after treatment.
Miranzadeh et al. (2015) investigated the effect of A.
millefolium distillate solution in the treatment of
chemotherapy-induced oral mucositis (OM) in 56
cancer patients. The experimental group gargled
15 mL of a mixture of routine solution and distilled A.
millefolium 4 times a day for 14 days, while the control
group gargled 15 mL of routine solution. The severity
of OM was assessed at three times before, 7 and 14 days
after intervention. It was observed that mean severity
score of OM was 2.39 ± 0.875 in both groups at start of
the study that was changed to 1.07 ± 0.85 and
0.32 ± 0.54 in the intervention group in days 7 and 14
(p<0.001). However, the severity of OM was increased
to 2.75 ± 0.87 and 2.89 ± 0.956 in the control group,
respectively, (p<0.001). The results clearly suggested
the use in patients with chemotherapy-induced OM.
Vahid et al. (2012) studied the possible effect of A.
millefolium on plasma nitric oxide concentration in 31
chronic kidney disease patients by randomized
controlled trial. Out of 31 patients, 16 patients received
1.5 g of powdered A. millefolium flower three days a
week for two months, and 15 received placebo for the
same period. Plasma nitrite and nitrate concentrations
decreased (0.82 ± 0.51 μmol/L to 0.63 ± 0.42 μmol/L
and 50.55 ± 17.92 μmol/L to 44.09 ± 17.49 μmole/L,
respectively) after 2-month administration of A.
millefolium without any overdose symptoms, but
adverse reaction of skin rashes was observed in one
female subject who was excluded from the study.
However, these concentrations were slightly increased
in the placebo group. Higher doses or longer duration
of administration may make these changes more
significant.
Ramadan et al. (2006) reported that when healthy
human volunteers were given 500 mg of matricin (one
of the proazulenic sesquiterpene lactone prodrugsin
yarrow) orally, micromolar levels of its
antiinflammatory metabolite, chamazulene carboxylic
acid, were found in their plasma. Another human study
has found that use of yarrow leaf extract significantly
reduces biting by Aedes mosquitoes (Jaenson et al.,
2006).
Huseini et al. (2005) studied the efficacy of herbal
medicine Liv-52 (herbal extract of A. millefolium)on
liver cirrhosis in 36 cirrhotic patients by randomized
double-blind clinical trial. All the patients underwent
clinical examination for the ChildPugh score, ascites,
serum alanine aminotransferase (ALT), aspartate
aminotransferase (AST), total billirubin, albumin,
prothrombin time, platelet and white blood cells counts
before and after 6 months of drug or placebo treatment.
The results demonstrated that the hepatoprotective
effect in cirrhotic patients treated with Liv-52 for
6 months had significantly better ChildPugh score,
decreased ascites, decreased serum ALT and AST, thus,
suggesting the possible use of Liv-52 in the treatment of
cirrhotic patients.
Shapira et al. (2005) tested the efficacy of tri-herbal
combination (Sibirian ginseng,A. millefolium and
Lamium album) on atopic dermatitis in a randomized
placebo-controlled trial in 49 patients (22 were treated
with the study medication and 22 with placebo). It was
observed that treatment with tri-herbal combination
for atopic dermatitis does not differ from treatment with
placebo. Therefore, the study does not support clinical
use of tri-herbal combination.
SAFETY AND TOXICOLOGY
Health hazards associated with long-term exposure to
A. millefolium extracts are not well established. Despite
the fact that, Food and Drug Administration has
classified the plant as non-poisonous and has approved
its utilization in alcoholic drinks (Guédon et al., 1993),
some toxic effects had been reported after its use by
humans and in animal experiments.
A. millefolium essential oil exhibited genotoxicity in a
heterozygous diploid strain of A. nidulans, named
ACHILLEA MILLEFOLIUM L.: A REVIEW
Copyright © 2017 John Wiley & Sons, Ltd. Phytother. Res. (2017)
A757//UT448 with green conidia at concentrations of
0.13, 0.19 and 0.25 μL/mL. A statistically significant
increasing number of yellow and white mitotic
recombinants per colony of the diploid strain were
reported after oil treatment with 0.19 and 0.25 μL/mL
concentrations. The genotoxicity of the oil was
associated with the induction of mitotic non disjunction
or crossing over. Therefore, the results pointing to the
necessity of testing the ability of A. millefolium essential
oil to interfere with the recombinational process in
mammalian cells; they also suggested that the oil should
be used with caution (De Santanna et al., 2009).
Cavalcanti et al. (2006) studied biochemical and
histopathological examinations in Wistar rats by giving
A. millefolium aqueous extract up to 10 g/kg orally and
up to 3 g/kg intraperitoneally, and no signs of deaths
were observed. In longer-term studies, no signs of
relevant toxicity were observed at doses of up to 1.2 g/
kg/day by gavage for up to 90 days. However, slight
changes in liver weight, blood cholesterol and glucose
levels, neither correlated with dose or period of
exposure nor suggestive of toxicity were observed.
Dalsenter et al. (2004) evaluated the toxicity of the
exposure to the aqueous extract from leaves of A.
millefolium on reproductive endpoints (reproductive
organ weights, sperm and spermatid numbers as well as
sperm morphology) in Wistar rats. Adult male rats were
treated daily with yarrow extract (0.3, 0.6 and 1.2 g/kg/
day) during 90 days by oral gavage. A significant increase
in the percentage of abnormal sperm with the highest
dose of A. millefolium extract was detected with no other
important changes in the other reproductive endpoints
studied in the male rats. Furthermore, a possible
estrogenic/antiestrogenic activity of the extract screened
after a 3-day treatment of immature female rats which
did not show any uterotrophic effects. The results clearly
showed that no long-term reproductive toxicological risk
would occur with the doses of A. millefolium commonly
consumed by humans.
Teixeira et al. (2003) determined the effects of the
infusions of A. millefolium on chromosomes and the cell
cycle. Allium cepa L. root-tip cells (A. millefolium3.5
and 35.0 mg/mL) and Wistar rat bone marrow cells (A.
millefolium3.5and35.0mg/100gbodyweight)were
used as in-vivo plant and animal test systems, respectively.
While as, human peripheral blood lymphocytes (A.
millefolium0.35 and 3.5 mg/mL culture medium) were
used as in-vitro test system. No statistically significant
alterations were found, as compared with untreated
controls, in either the cell cycle or the number of
chromosome alterations, after treatments with A.
millefolium, in rat cells or in cultured human lymphocytes.
These results regarding the cytotoxicity and mutagenicity
of A. millefolium provide valuable information about the
safety of using them as therapeutic agents.
A. millefolium ethanolic extract given at 2.8 g/kg/day
on days 18or815 of pregnancy in rats, which is 56
times the allegedly recommended daily human dose of
50 mg/kg (of body weight) showed neither
contraceptive, abortifacient nor teratogenic activity
(Boswell-Ruys et al., 2003).
In male rodents, A. millefolium has some effects on
spermatogenesis, at least at extreme dosages. In mice,
an ethanolic extract of yarrow, delivered
intraperitoneally at 200 mg/kg/day, and a hydroalcoholic
extract delivered orally at 300 mg/kg/day impaired
spermatogenesis; morphological changes observed
included germ cell necrosis (Montanari et al., 1998).
A somatic mutation and recombination test using
Drosophila melanogaster was performed to determine
the genotoxic potential of A. millefolium (20 and 40%)
herbal tea extract. It was found that A. millefolium tea
was weakly genotoxic, and the effect could have been
due to the presence of flavonoids (Graf et al., 1994).
A. millefolium has been reported to cause allergic
contact dermatitis in some people due to the presence
of sensitizing compounds such as guaianolides (a
subcategory of sesquiterpenoid) and especially alpha-
peroxyachifolid, which is present at variable
concentrations in fresh material of up to 0.6% in
blossoms and 0.05% in leaf (Hausen et al., 1991; Rucker
et al., 1991; Rucker et al., 1994). The concentration may
diminish in dried or processed material due to
degradation of the compounds (Rucker et al., 1994).
FUTURE PERSPECTIVES OF A. millefolium
Aromatic plants have a significant role to combat
diseases from the dawn of civilization, and several
researches are being performed in the area of herbal
drugs for exploring newer and safer alternatives in order
to combat against several diseases. The pharmacological
properties of A. millefolium propose them as natural
drug for clinical uses in different diseases and
pathological conditions including inflammation, cancers,
dyspepsia, bacterial, viral, parasitic, helminth infections,
etc. However, further studies are required to find the
exact mechanism lying behind some of their
pharmacological properties viz., antifertility agent, in
promotion of gastric motility and treatment of gastric
ulcer, cytotoxic and genotoxic effects, cardiovascular
diseases and fumigant toxicity for the management of
stored pests. Moreover, many pharmacological effects
of the plant have not yet been scientifically neither
proven nor attributed to any plant constituents.
Regarding toxicity, A. millefolium seems to be almost
safe in customary doses, but there are not enough clinical
studies about A. millefolium safeties. Therefore, active
constituents especially casticin; luteolin 7-O-glucoside;
apigenin 7-O-glucoside; achimillic acids A, B and C;
luteolin; apigenin; rutin and 1,8-cineole can be used in
clinical trials for the other pharmacological properties
viz., antiviral, antimicrobial, anticancer, antiulcer,
hepatoprotective, immunomodulatory, neuroprotective,
etc., and the efficacy of these compounds needs to be
evaluated in humans. However, interaction with other
drugs is the aspect of study which must be considered in
clinical use of A. millefolium. The results of in-vitro and
preclinical studies need to be critically evaluated and
integrated into the practical applications of A. millefolium.
This review brings together the most recent studies in the
field of A. millefolium research; therefore, it will help to
provide greater accessibility to the established
experimental and clinical data and will promote further
studies aimed at confirming the observed effects.
Conflict of Interest
Declared none.
S.I. ALI ET AL.
Copyright © 2017 John Wiley & Sons, Ltd. Phytother. Res. (2017)
REFERENCES
Akram M. 2013. Mini review on Achillea millefolium Linn. J
Membrane Biol 246: 661663.
Allen DE, Hatfield G. 2004. Medicinal Plants in Folk Tradition.
Timber Press: Portland, Oregon.
Amirghofran Z, Karimi MH. 2002. Cytotoxic activity of Thymus
vulgaris, Achillea millefolium and Thuja orientalis on different
growing cell lines. Med J Islam Repub Iran 15: 149154.
Anne O, Elmar A, Ain R. 2006. Phytochemical analysis of the
essential oil of Achillea millefolium L. from various European
countries. Nat Prod Res 20: 10821088.
Anne O, Tiiu K, Kaire L. 2001. Composition of the essential oil from
Achillea millefolium L. from Estonia. J Essent Oil Res 13:
290294.
Applequist WL, Moerman DE. 2011. Yarrow (Achillea millefolium
L.): a neglected panacea? A review of ethnobotany, bioactivity
and biomedical research. Econo Bot 65: 209225.
Babaei M, Abarghoei ME, Akhavan MM, et al. 2007. Antimotility
effect of hydroalcoholic extract of yarrow (Achillea
millefolium) on the guinea-pig ileum. Pak J Biol Sci 10:
36733677.
Baggio HC, Otofuji GDM, Freitas CS, Torres LMB, Marques MCA,
Vela SM. 2008. Brazilian medicinal plants in gastrointestinal
therapy. In Botanical Medicine in Clinical Practice. CABI:
Oxon, United Kingdom; 4651.
Balunas MJ, Kinghorn AD. 2005. Drug discovery from medicinal
plants. Life Sci J 78: 431441.
Baretta IP, Felizardo RA, Bimbato VF, et al. 2012. Anxiolytic-like
effects of acute and chronic treatment with Achillea
millefolium L. extract. J Ethnopharmacol 140:4654.
Baser KH, Demirci B, Demirci F, et al. 2002. Composition and
antimicrobial activity of the essential oil of Acillea multifida.
Planta Med 68: 941943.
Benedek B, Geisz N, Jager W, Thalhammer T, Kopp B. 2006.
Choleretic effects of yarrow (Achillea millefoliums) in the
isolated perfused rat liver. Phytomedicine 13: 702706.
Benedek B, Kopp B. 2007a. Achillea millefolium L. revisited: recent
findings confirm the traditional use. Wien Med Wochenschr
157: 312331.
Benedek B, Gjoncaj N, Saukel J, Kopp B. 2007b. Distribution of
phenolic compounds in Middleeuropean Taxa of the Achillea
millefolium L. aggregate. Chem Biodivers 4: 849857.
Benedek B, Kopp B, Melzig MF. 2007c. Achillea millefolium.is
the anti-inflammatory activity mediated by protease
inhibitors? J Ethnopharmacol 113: 312317.
Benedek B, Rothwangl WK, Rozema E, et al. 2008. Yarrow
(Achillea millefolium); pharmaceutical quality of commercial
samples. Pharmazie 63:2326.
Benetis R, Radusiene J, Janulis V. 2008. Variability of phenolic
compounds in flowers of Achillea millefolium wild populations
in Lithuania. Medicina 44: 774781.
Bezic N, Skocibusic M, Dunkic V, Radonic A. 2003. Composition
and antimicrobial activity of Achillea clavennae L. essential
oil. Phytother Res 17: 10371040.
Bhatia H, Sharma YP, Manhas RK, Kumar K. 2014. Ethnomedicinal
plants used by the villagers of district Udhampur, J & K, India.
J Ethnopharmocol 151: 10051018.
Bimbiraite K, Ragazinskiene O, Maruska A, Kornysova O. 2008.
Comparison of the chemical composition of four yarrow
(Achillea millefolium L.) morphotypes. Biologija 54: 208212.
Borrelli F, Romano B, Fasolino I, et al. 2012. Prokinetic effect of a
standardized yarrow (Achillea millefolium) extract and its
constituent choline: studies in the mouse and human
stomach. Neurogastroenterol Motil 24: 164171.
Boskovic Z, Radulovic N, Stojanovic G. 2005. Essential oil
composition of four Achillea species from the balkans and its
chemotaxonomic significance. Chemi Nat Comp 41:
555558.
Boswell-Ruys CL, Ritchie HE, Brown-Woodman PD. 2003.
Preliminary screening study of reproductive outcomes after
exposure to yarrow in the pregnant rat. Birth Defects Res B
Dev Reprod Toxicol 68: 416420.
Bunalema L, Obakiro S, Tabuti JRS, Waako P. 2014. Knowledge on
plants used traditionally in the treatment of tuberculosis in
Uganda. J Ethnopharmacol 151: 9991004.
Bussmann RW, Sharon D, Vandebroek I, Jones A, Revene Z. 2007.
Health for sale: the medicinal plant markets in Trujillo and
Chiclayo, Northern Peru. J Ethnobiol Ethnomed 3: 37.
Candan F, Unlu M, Tepe B, et al. 2003. Antioxidant and
antimicrobial activity of the essential oil and methanol extracts
of A. millefolium.J Ethnopharmacol 87: 215220.
Cavalcanti AM, Baggio CH, Freitas CS, et al. 2006. Safety and
antiulcer efficacy studies of Achillea millefolium L. after
chronic treatment in Wistar rats. J Ethnopharmacol 107:
277284.
Chandler RF, Hooper SN, Harvey MJ. 1982a. Ethnobotany and
phytochemistry of yarrow, Achillea millefolium, Compositae.
Econ Bot 36: 203223.
Chandler RF, Hooper SN, Hooper DL, Jamieson WD, Flinn CG, Safe
LM. 1982b. Herbal remedies of the Maritime Indians: sterols
and triterpenes of Achillea millefolium L. (Yarrow). J Pharm
Sci 71: 690693.
Conti B, Canale A, Bertoli A, Gozzini F, Pistelli L. 2010. Essential oil
composition and larvicidal activity of six Mediterranean
aromatic plants against the mosquito Aedes albopictus
(Diptera: Culicidae).Parasitol Res 107: 14551461.
Costescu CI, Radoi BP, Hadaruga NG, et al. 2014. Obtaining and
characterization of Achillea millefolium L. extracts. J
Agroaliment Proc Technol 20: 142149.
Csupor LB, Hajdu Z, Zupko I, et al. 2009. Antiproliferative effect of
flavonoids and sesquiterpenoids from Achillea millefolium on
cultured human tumour cell lines. Phytother Res 23: 672676.
DallAcqua S, Bolego C, Cignarella A, Gaion RM, Innocenti G.
2011. Vasoprotective activity of standardized Achillea
millefolium extract. Phytomedicine 18: 10311036.
Dalsenter PR, Cavalcanti AM, Andrade AJ, Araujo SL, Marques
MC. 2004. Reproductive evaluatioin of aqueous crude extract
of A. millefolium L. (Asteraceae) in Wistar rats. Reprod Toxicol
18: 819823.
David RB, Zbigniew AC, Sasha MD. 2010. Aqueous extract of
Achillea millefolium L. (Asteraceae) inflorescences suppresses
lipopolysaccharide-induced inflammatory responses in RAW
264.7 murine macrophages. J Med Plants Res 4: 225234.
De AUP, Muniz DMP, De AAL, et al. 2007. Medicinal plants of the
Caatinga (semi-arid) vegetation of NE Brazil: a quantitative
approach. J Ethnopharmacol 114: 325354.
De Santanna JR, Franco CC, Miyamoto CT, et al. 2009.
Genotoxicity of Achillea millefolium essential oil in diploid cells
of Aspergillus nidulans.Phytother Res 23: 231235.
De Souza P, Gasparotto A Jr, Crestani S, et al. 2011. Hypotensive
mechanism of the extracts and artemetin isolated from
Achillea millefolium L. (Asteraceae) in rats. Phytomedicine
18: 819825.
Dias MI, Barros L, Dueñas M, et al. 2013. Chemical composition of
wild and commercial Achillea millefolium L. and bioactivity of
the methanolic extract, infusion and decoction. Food Chem
141: 41524160.
Duke JA. 1986. Isthmian Ethnobotanical Dictionary, 3rd edn.
Scientific Publishers, Jodhpur: India; 205.
Duke JA, Ayensu ES. 1985. Medicinal Plants of China. Reference
Publications: Algonac, Michigan; 750.
Ebadollahi A, Ashouri S. 2011. Toxicity of essential oils isolated
from Achillea millefolium L., Artemisia dracunculus L. and
Heracleum persicum Desf. against adults of Plodia
interpunctella (Hübner) (Lepidoptera: Pyralidae) in Islamic
Republic of Iran. Ecol Balk 3:4148.
Ebadollahi A, Sendi JJ, Razmjou J. 2016. Toxicity and
phytochemical profile of essential oil from Iranian Achillea
mellifolium L. against Tetranychus urticae Koch (Acari:
Tetranychidae). Toxin Rev 35:2428.
Eghdami A, Sadeghi F. 2010. Determination of total phenolic and
flavonoids contents in methanolic and aqueous extract of
Achillea millefolium.Org Chem J 2:8184.
Ehrendorfer F. 1973. New chromosome numbers and remarks on
the Achillea millefolium polyploid complex in North America.
Oesterr Bot Z 122: 133143.
Ehrendorfer F, Guo YP. 2006. Multidisciplinary studies on Achillea
sensu lato (Composit aeAnthemideae): new data on
systematics andphylogeography. Willdenowia 36:6987.
Falconieri D, Piras A, Porcedda S, et al. 2011. Chemical
composition and biological activity of the volatile extracts of
Achillea millefolium.Nat Prod Commun 6: 15271530.
Falk AJ, Smolenski SJ, Bauer L, Bell CL. 1975. Isolation and
identification of three new flavones from Achillea millefolium
L. J Pharm Sci 64: 18381842.
ACHILLEA MILLEFOLIUM L.: A REVIEW
Copyright © 2017 John Wiley & Sons, Ltd. Phytother. Res. (2017)
Farooq U, Khan A, Khan SS, et al. 2012. Isolation and structure
determination of three new sesquiterpenoids from Achillea
millefolium.Z Naturforsch B Chem Sci 67: 421425.
Fierascu I, Ungureanu C, Avramescu SM, et al. 2015. In vitro
antioxidant and antifungal properties of Achillea millefolium
L. Rom Biotech Lett 20: 1062610636.
Fraisse D, Felgines C, Texier O, Lamison JL. 2011. Caffeoyl
derivatives: major antioxidant compounds of some wild herbs
of the Asteraceae family. Food Nutr Sci 2: 181192.
Gadgoli C, Mishra SH. 2007. Antihepatotoxic activity of 5-hydroxy
3, 40, 6, 7-tetramethoxy flavone from Achillea millefolium.
Pharmacologyonline 1: 391399.
Georgieva L, Gadjalova A, Mihaylova D, Pavlov A. 2015. Achillea
millefolium L. phytochemical profile and in vitro antioxidant
activity. Int Food Res J 22: 13471352.
Gervais C. 1977. Cytological investigation of the Achillea
millefolium complex (Compositae) in Quebec. Can J Bot 55:
796808.
Gharibi S, Rahimmalek M, Mirlohi A, Majid MM, Tabatabaei BES.
2011. Assessment of genetic diversity in Achillea millefolium
subsp. millefolium and Achillea millefolium subsp. elbursensis
using morphological and ISSR markers. J Med Plants Res 5:
24132423.
Ghavami G, Sardari S, Shokrgozar MA. 2010. Anticancerous
potentials of Achillea species against selected cell lines. J
Medi Plan Res 4: 24112417.
Goldberg AS, Mueller EC, Eigen E, Desalva SJ. 1969. Isolation of
the anti-inflammatory principles from Achillea millefolium
(Compositae). J Pharm Sci 58(8): 938941.
Graf U, Moraga AA, Castro R, Diaz CE. 1994. Genotoxicity testing
of different types of beverages in the Drosophila wing somatic
mutation and recombination test. Food Chem Toxicol 32:
423430.
Greger H. 1969. Flavonoide und Systematik der Anthemideae.
Naturwissenschaften 56: 467468.
Grieve M. 1971. A Modern Herbal, 2 Vols. Penguin/Dover
Publications: New York; 919.
Guédon D, Abbe P, Lamaison JL. 1993. Leaf and flower head
flavonoids of Achillea millefolium L. subspecies. Biochem Syst
Ecol 21: 607611.
Guo YP, Ehrendorfer F, Samuel R. 2004. Phylogeny and
systematics of Achillea (AsteraceaeAnthemidae) inferred
from nrITS and plastid trnL-F DNA sequences. Taxon 53:
657672.
Guo YP, Saukel J, Ehrendorfer F. 2008. AFLP trees versus
scatterplots: evolution and phylogeography of the polyploid
complex Achillea millefolium agg. (Asteraceae). Taxon 57:
153169.
Guo YP, Saukel J, Mittermayr R, Ehrendorfer F. 2005. AFLP
analyses demonstrate genetic divergence, hybridization, and
multiple polyploidization in the evolution of Achillea
(AsteraceaeAnthemidae). New Phytol 166: 273289.
Guo YP, Wang SZ, Vogl C, Ehrendorfer F. 2012. Nuclear and plastid
haplotypes suggest rapid diploid and polyploid speciation in
the N Hemisphere Achillea millefolium complex (Asteraceae).
BMC Evol Biol 12. https://doi.org/10.1186/14712148122.
Haidara K, Zamir L, Shi QW, Batist G. 2006. The flavonoid casticin
has multiple mechanisms of tumor cytotoxicity action. Cancer
Lett 242: 180190.
Hajhashemi M, Ghanbari Z, Movahedi M, Rafieian M, Keivani A,
Haghollahi F. 2016. The effect of Achillea millefolium and
Hypericum perforatum ointments on episiotomy wound
healing in primiparous women. J Matern Fetal Neonatal Med
27:120.
Hausen BM, Breuer J, Weglewski J, Rücker G. 1991. α-
Peroxyachifolid and othernew sensitizing sesquiterpene
lactones from yarrow (Achillea millefolium L., Compositae).
Contact Derm 24: 274280.
Hemmati AA, Arzi A, Adineh A, Mostofi NE, Mozaffari AR, Jalali A.
2011. Yarrow (Achillea millefolium L.) extract impairs the
fibrogenic effect of bleomycin in rat lung. J Med Plants Res
5: 18431849.
Hochmannová J, Herout V, Sorm F. 1961. Isolation and structures
of [three crystalline] sesquiterpenic lactones from yarrow
(Achillea millefolium). Collect Czechoslov Chem Commun
26: 18261831.
Hofmann L, Fritz D, Nitz S, Kollmannsberger H, Drawert F. 1992.
Oil composition of three polyploids in the Achillea millefolium
Complex. Phyrochemistry 31: 537542.
Horhammer L. 1961. Ober den qualitativen und quantitativen
Flavongehalt von Arzneipflanzen im Hinblick aufihre
spasmolytische Wirkung. Congr Sci Farm Conf Commun 21:
578588.
Horhammer L, Farkas L, Wagner H, Ostermayer J. 1964. Isolierung
des Luteolin-7-glucosids aus Achillea millefolium L. und eine
neue Synthese des Glucosids. Acta Chim Hung 40: 463469.
Huseini HF, Alavian SM, Heshmat R, Heydari MR, Abolmaali K.
2005. The efficacy of Liv-52 on liver cirrhotic patients: a
randomized, double-blind, placebo-controlled first approach.
Phytomedicine 12: 619624.
Innocenti G, Vegeto E, DallAcqua S, et al. 2007. In vitro
estrogenic activity of Achillea millefolium L. Phytomedicine
14: 147152.
Ivancheva S, Tomas-Barberan F, Tsvetkova R. 2002. Comparative
analysis of flavonoids in Achillea sp. sect. millefolium and
sect. ptarmica. Compt Rend LAcad Bulgare Sci 55:4346.
Izzo AA, Hoon-Kim S, Radhakrishnan R, Williamson EM. 2016. A
critical approach to evaluating clinical efficacy, adverse events
and drug interactions of herbal remedies. Phytother Res 30:
691700.
Jaenson TG, Pålsson K, Borg-Karlson AK. 2006. Evaluation of
extracts and oils of mosquito (Diptera: Culicidae) repellent
plants from Sweden and Guinea-Bissau. J Med Entomol 43:
113 119.
Jaimand K, Rezaee MB, Mozaffarian V. 2006. Chemical
constituents of the leaf and flower oils from Achillea
millefolium ssp. from Iran rich in Chamazulene. J Essent Oil
Res 18: 293295.
Jalali AS, Hasanzadeh S, Malekinejad H. 2012. Achillea
millefolium inflorescence aqueous extract ameliorates
cyclophosphamide-induced toxicity in rat testis: stereological
evidences. Chin J Nat Med 10: 247254.
Jaradat NA. 2005. Medical plants utilized in Palestinian folk
medicine for treatment of diabetes mellitus and cardiac
diseases. J Al-Aqsa Univ 9:128.
Jenabi E, Fereidoony B. 2015. Effect of Achillea millefolium on
relief of primary dysmenorrhea: a double-blind randomized
clinical trial. J Pediatr Adolesc Gynecol 28: 402404.
Jones WHS. 1956. Pliny Natural History (Index of Plants). Harvard
University Press: Volume VII, Books; 2427.
Judzentiene A. 2016. A typical chemical profiles of wild yarrow
(Achillea millefolium L.) essential oils. Rec Nat Prod 10:
262268.
Judzentiene A, Mockute D. 2010. Essential oil composition of two
yarrow taxonomic forms. Cent Eur J Biol 5: 346352.
Kaloshina NA, Neshta DI. 1973. Flavonoids of Achillea millefolium.
Chem Nat Compd 9: 261.
Karamenderes C, Apaydin S. 2003. Antispasmodic effect of
Achillea nobilis L. subsp. sipylea (O. Schwarz) Bässler on the
rat isolated duodenum. J Ethnopharmacol 84: 175179.
Kazemi M. 2015. Phytochemical and antioxidant properties of
Achillea millefolium from the eastern region of Iran. Int J Food
Prop 18: 21872192.
Keser S, Celik S, Turkoglu S, Yilmaz O, Turkoglu I. 2013.
Antioxidant activity, total phenolic and flavonoid content of
water and ethanol extracts from Achillea millefolium L. Turk
J Pharm Sci 10: 385392.
Khan AU, Gilani AH. 2011. Blood pressure lowering,
cardiovascular inhibitory and bronchodilatory actions of
Achillea millefolium.Phytother Res 25: 577583.
Khoshbakht K, Hammer K. 2005. Savadkouh (Iran)an
evolutionary center for fruit trees and shrubs. Genet Resour
Crop Evol 53: 641651.
Kokoska L, Polesny Z, Rada V, Nepovim A, Vanek T. 2002.
Screening of some Siberian medicinal plants for antimicrobial
activity. J Ethnopharmacol 82:5153.
Konovalov DA, Chelombitko VA. 1991. Sesquiterpene lactones
from Achillea millefolium.Chem Nat Compd 27: 640641.
Lalonde RT, Wong CF, Hofstead SJ, Morris CD, Gardner LC.
1980. N-(2-methylpropyl)-(E, E)-2, 4-decadienamide a
mosquito larvicide from Achillea millefolium L. J Chem Ecol
6:3548.
Lazarevic J, Radulovic N, Zlatkovic B, Palic R. 2010. Composition
of Achillea distans Willd. subsp. distans root essential oil.
Nat Prod Res 24: 718731.
Lehane AM, Saliba KJ. 2008. Common dietary flavonoids inhibit
the growth of the intraerythrocytic malaria parasite. BMC
Res Notes 1:2630.
S.I. ALI ET AL.
Copyright © 2017 John Wiley & Sons, Ltd. Phytother. Res. (2017)
Lemmens-Gruber R, Marchart E, Rawnduzi P, Engel N, Benedek B,
Kopp B. 2006. Investigation of the spasmolytic activity of
the flavonoid fraction of Achillea millefolium on isolated
guinea-pig ilea. Arzneimittelforschung 56: 582588.
Leroi GA. 1975. The flowers found with Shanidar IV, a Neanderthal
burial in Iraq. Science 190: 562564.
Li Y, Ni ZY, Zhu MC, et al. 2012a. Millifolides AC. New 1, 10-
seco-guaianolides from the flowers of Achillea millefolium.Z
Naturforsch 67: 438446.
Li Y, Zhang ML, Cong B, et al. 2011. Achillinin A, a cytotoxic
guaianolide from the flower of yarrow, Achillea millefolium.
Biosci Biotechnol Biochem 75: 15541556.
Lopes FCM, Benzatti FP, Junior CMJ, Moreira RRD, Carlos IZ. 2005.
Effect of the essential oil of Achillea millefolium L. in the
production of hydrogen peroxide and tumor necrosis factor-α
in murine macrophages. Braz J Pharm Sci 4:401405.
Lopes FCM, Benzatti FP, Moreira RRD, Santos LE, Carlos IZ. 2003.
Evaluation of the immunological activity of Achillea
millefolium L. Rev Bras Farmacogn 13:1113.
Lourenco PML, Figueiredo AC, Barroso JG, et al. 1999. Essential
oils from hairy root cultures and from plant roots of Achillea
millefolium.Phytochemistry 51: 637642.
Mahady GB, Pendland SL, Stoia AF, et al. 2005. In vitro
susceptibility of Helicobacter pylori to botanical extracts used
traditionally for the treatment of gastrointestinal disorders.
Phytother Res 19: 988991.
Manfrini AC, Ribeiro JJR, Tavares AS. 2009. Reconhecimento e
potencialidades de plantas medicinais ayurvédicas utilizadas
na medicina popular pela comunidade da Costa de Cima,
Lagoa do Peri, Florianópolis/SC (Recognition and Potentialities
of Ayurvedic Medicinal Plants used in Folk Medicine by the
Community of Costa de Cima, Lagoa do Peri,
Florianopolis/SC). Universidade Federal de Santa Catarina:
Florianópolis; 62.
Mazandarani M, Mirdeilami SZ, Pessarakli M. 2013. Essential oil
composition and antibacterial activity of Achillea millefolium
L. from different regions in North east of Iran. J Medi Plant
Res 7: 10631069.
Michaluk A. 1962. Identification of flavones in the baskets of
Achillea millefolium L. Diss Pharm 14: 347353.
Miraldi E, Ferri S, Mostaghimi V. 2001. Botanical drugs and
preparations in the traditional medicine of West Azerbaijan
(Iran). J Ethnopharmacol 75:7787.
Miranzadeh S, Adib-Hajbaghery M, Soleymanpoor L, Ehsani M.
2015. Effect of adding the herb Achillea millefolium on
mouthwash on chemotherapy induced oral mucositis in cancer
patients: a double-blind randomized controlled trial. Eur J
Oncol Nurs 19: 207213.
Moerman DE. 2007. Agreement and meaning: rethinking
consensus analysis. J Ethnopharmacol 112: 451460.
Molina-Hernandez M, Tellez-Alcantara NP, Diaz MA, Perez GJ, Olivera-
Lopez JI, Jaramillo MT. 2004. Anticonflict actions of aqueous
extracts of flowers of A. millefolium L. vary according to the
estrous cycle phases in Wistar rats. Phytother Res 18:915920.
Montanari T, de Carvalho JE, Dolder H. 1998. Antispermatogenic
effect of Achillea millefolium L. in mice. Contraception 58:
309313.
Moradi MT, Rafieian-Koupaei M, Imani-Rastabi R, et al. 2013.
Antispasmodic effects of yarrow (Achillea millefolium L.)
extract in the isolated ileum of Rat. Afr J Tradit Complement
Altern Med 10: 499503.
Mozaffarian V. 2009. A Dictionary of Iranian Plant Names. Tehran:
Farhang Moaser Pub; 596.
Murnigsih T, Subeki MH, Takahashi K, et al. 2005. Evaluation of
the inhibitory activities of the extracts of Indonesian traditional
medicinal plants against Plasmodium falciparum and Babesia
gibsoni.J Vet Med Sci 67: 829831.
Nadim MM, Malik AA, Ahmad J, Bakshi SK. 2011. The essential oil
composition of Achillea millefolium cultivated under tropical
condition in India. W J Agri Sci 7: 561565.
Nematy M, Mazidi M, Jafari A, Baghban S, Rakhshandeh H, et al.
2017. Renal injury, the effect of hydro-alcoholic extract of
Achillea millefolium on appetite hormone in rats. Avicenna J
Phytomed (Epub ahead of print).
Nemeth E. 2005. Essential oil composition of species in the genus
Achillea. J Essent Oil Res 17: 501512.
Neshta ID, Kaloshina NA, Zapesochnaya GG, Bankovskii AI.
1972. Rutin from Achillea millefolium.Chem Nat Compd 8:
664.
Niazmand S, Saberi Z. 2010. The chronotropic and inotropic
effects of aqueousethanolic extract of Achillea millefoliumon
rats isolated heart. Pharmacologyonline 3: 791798.
Nilforoushzadeh MA, Shirani-Bidabadi L, Zolfaghari-Baghbaderani
A, Saberi S, Siadat AH, Mahmoudi M. 2008. Comparison of
Thymus vulgaris (Thyme), Achillea millefolium(Yarrow) and
propolis hydroalcoholic extracts versus systemic glucantime
in the treatment of cutaneous leishmaniasis in balb/c mice. J
Vector Borne Dis 45: 301306.
Noureddini M, Rasta VR. 2008. Analgesic effect of aqueous
extract of Achillea millefolium L. on RatsFormalin Test.
Pharmacologyonline 3: 659664.
Ochir G, Budesinsky M, Motl O. 1991. 3-Oxa-guaianolides from
Achillea millefolium.Phytochemistry 30: 41634165.
Osbaldeston TA, Wood RPA. 2000. Dioscorides: De Materia
Medica. Ibidis Press: Johannesburg.
Oswiecimska M, Miedzobrodzka J. 1966. Flavonoid compounds in
the polyploidal complex of Achillea millefolium.Diss Pharm
Pharmacol 18: 601606.
Pain S, Altobelli C, Boher A, et al. 2011. Surface rejuvenating effect
of Achillea millefolium extract. Int J Cosmet Sci 33: 535542.
Parandin R, Ghorbani R. 2010. Effects of alcoholic extract of
Achilea millefolium flowers on fertility parameters of male
rats. Int J Pharm Tech Res 2: 24922496.
Passalacqua NG, Guarrera PM, De FG. 2007. Contribution to the
knowledge of the folk plant medicine in Calabria region
(Southern Italy). Fitoterapia 78:5268.
Pires JM, Mendes FR, Negri G, Duarte-Almeida JM, Carlini EA.
2009. Antinociceptive peripheral effect of A. millefolium L.
and Artemisia vulgaris L.: both plants known popularly by
brand names of analgesic drugs. Phytother Res 23: 212219.
Potrich FB, Allemand A, da Silva LM, et al. 2010. Antiulcerogenic
activity of hydroalcoholic extract of antiulcerogenic activity
of hydroalcoholic extract of Achillea millefolium L. J
Ethnopharm 130:8592.
Radusiene J, Gudaityte O. 2005. Distribution of proazulenes in
Achillea millefoliums wild populations in relation to
phytosociological dependence and morphological characters.
Plant Genet Resource 3: 136143.
Rahimmalek M, Tabatabaei SBE, Etemadi N, Goli SAH, Arzani A,
Zeinali H. 2009. Essential oil variation among and within six
Achillea species transferred from different ecological
regions in Iran to the field conditions. Ind Crops Prod 29:
348355.
Ramadan M, Goeters S, Watzer B, et al. 2006. Chamazulene
carboxylic acid and matricin: a natural profen and its natura
prodrug, identified through similarity to synthetic drug
substances. J Nat Prod 69: 10411045.
Ramsey J. 2007. Unreduced gametes and neopolyploids in natural
populations of Achillea borealis (Asteraceae). Heredity 98:
143150.
Rohloff J, Skagen EB, Steen AH, Iversen TH. 2000. Production of
yarrow (Achillea millefolium L.) in Norway: essential oil
content and quality. J Agric Food Chem 48: 62056209.
Rucker G, Kiefer A, Breuer J. 1992. Isoachifolidiene, a precursor of
guaianolide peroxides from Achillea millefolium L. Planta Med
58: 293295.
Rucker G, Manns D, Breuer J. 1991. Peroxides as plant
constituents. 8. Guaianolide-peroxides from yarrow, Achillea
millefolium L., a soluble component causing yarrow
dermatitis. Arch Pharm 324: 979981.
Saeidnia S, Yassa N, Rezaeipoor R. 2004. Comparative
investigation of the essential oils of A. talagonica Boiss and
A. millefolium L, chemical composition and immunological
studies. J Essent Oil Res 16: 262264.
Santoro GF, Cardoso MG, Guimaraes LG, Mendonça LZ, Soares
MJ. 2007. Trypanosoma cruzi: activity of essential oils from
Achillea millefolium L., Syzygium aromaticum L. and Ocimum
basilicum L. on epimastigotes and trypomastigotes. Exp
Parasitol 116: 283290.
Santos AO, Santin AC, Yamaguchi MU, et al. 2010.
Antileishmanial activity of an essential oil from the leaves
and flowers of Achillea millefolium.Ann Trop Med Parasitol
104: 475483.
Saulo MS, Viccini LF. 2011. Cytotoxic and genotoxic activity of
Achillea millefolium aqueous extracts. Braz J Pharm Sci 21:
98104.
Schulz H, Albroscheit G. 1988. High-performance liquid
chromatographic characterization of some medical plant
ACHILLEA MILLEFOLIUM L.: A REVIEW
Copyright © 2017 John Wiley & Sons, Ltd. Phytother. Res. (2017)
extracts used in cosmetic formulas. J Chromatogr 442:
353361.
Sedighi M, Nasri H, Rafieian kM, Mortazaei S. 2013. Reversal
effect of Achillea millefolium extract on ileum contractions. J
Herb Med Pharmacol 2:58.
Sevindik E, Abaci ZT, Yamaner C, Ayvaz M. 2016. Determination
of the chemical composition and antimicrobial activity of the
essential oils of Teucrium polium and Achillea millefolium
grown under North Anatolian ecological conditions.
Biotechnol Biotechnol Equip 30: 375380.
Shahani S, Hamzkanlu N, Zakeri N, Hosseinimehr SJ. 2015.
Synergistic anti-tumoral effect of Achillea millefolium combined
with bleomycin on prostate cancer cells. Res Mol Med 3:1015.
Shapira MY, Raphaelovich Y, Gilad L, Or R, Dumb AJ, Ingber A.
2005. Treatment of atopic dermatitis with herbal combination
of Eleutherococcus,Achillea millefolium and Lamium album
had no advantage over placebo: a double blind, placebo-
controlled, randomized trial. J Am Acad Dermatol 52:
691693.
Sharma PK, Chauhan NS, Lal B. 2004. Observations on the
traditional phytotherapy among the inhabitants of Parvati valley
in western Himalaya, India. J Ethnopharmaco l 92: 167176.
Si XT, Zhang ML, Shi QW, Kiyota H. 2006. Chemical constituents
of the plants in the genus Achillea.Chem Biodivers 3:
11631118.
Solecki RS. 1975. Shanidar IV, a Neanderthal flower burial in
northern Iraq. Science 190: 880881.
Stojanovic G, RadulovićN, Hashimoto T, PalićR. 2005. In vitro
antimicrobial activity of extracts of four Achillea species: the
composition of Achillea clavennae L. (Asteraceae) extract. J
Ethnopharmacol 101: 185190.
Tajik H, Jalali FSS, Sobhani A, Shahbazi Y, Zadeh MS. 2008. In
vitro assessment of Antimicrobial efficacy of alcoholic extract
of Achillea millefolium in comparison with Penicillin
derivatives. J Anim Vet Adv 7: 508511.
Takzare N, Hosseini MJ, Hamideh Mortazavi S, Safaie S, Moradi R.
2011. The effect of Achillea millefolium extracts on
spermatogenesis of male wistar rats. Hum Exp Toxicol 30:
328334.
Tariq KA, Chishti MZ, Ahmad F, Shawl AS. 2008. Anthelmintic
efficacy of Achillea millefolium against gastrointestinal
nematodes of sheep: in vitro and in vivo studies. J Helminthol
82: 227233.
Teixeira RO, Camparoto ML, Mantovani MS, Vicentini VEP. 2003.
Assessment of two medicinal plants, Psidium guajava L. and
Achillea millefolium L., in vitro and in vivo assays. Genet Mol
Biol 26: 551555.
Tozyo T, Yoshimura Y, Sakurai K, et al. 1994. Novel antitumor
sesquiterpenoids in Achillea millefolium.Chem Pharm Bull
42: 10961100.
Tunón H, Thorsell W, Bohlin L. 1994. Mosquito repelling activity of
compounds occurring in Achillea millefolium L. (Asteraceae).
Econ Bot 48: 111120.
Ugulu I, Baslar S, Yorek N, Dogan Y. 2009. The investigation and
quantitative ethnobotanical evaluation of medicinal plants
used around Izmir province, Turkey. J Med Plants Res 3:
345367.
Ulubelen A, Oksuz S, Schuster A. 1990. A sesquiterpene lactone
from Achillea millefolium subsp. millefolium.Phytochemistry
29: 39483949.
Vahid S, Dashti-Khavidaki S, Ahmadi F, Amini M, Salehi Surmaghi
MH. 2012. Effect of herbal medicine Achillea millefolium on
plasma nitrite and nitrate levels in patients with chronic
kidney disease: a preliminary study. Iran J Kidney Dis 6:
350354.
Verzar-Petri G, Tamas J, Radics L, Ujszaszi K. 1980. Separation
and identification of prochamazulenes of Achillea
millefolium L. sp. collina Becker. Acta Hortic (ISHS) 96:
105112 .
Vitalini S, Beretta G, Iriti M, et al. 2011. Phenolic compounds from
Achillea millefolium L. and their bioactivity. Acta Biochim Pol
58: 203209.
Wichtl M. 2004. Herbal Drugs and Phytopharmaceuticals: A
Handbook for Practice on a Scientific Basis, Third [English]
edn. Medpharm Scientific Publishers, Stuttgart: Germany.
Willuhn G. 2002. Millefolii herba. In Teedrogen und
Phytopharmaka, Wichtl M (ed), fouth edn. Wiss.
Verlagsgesellschaft: Stuttgart; 399403.
Wojdyło A, Oszmiańskia J, Czemerysb R. 2007. Antioxidant
activity and phenolic compounds in 32 selected herbs. Food
Chem 105: 940949.
Yaeesh S, Jamal Q, Khan AU, Gilani AH. 2006. Studies on
hepatoprotective, antispasmodic and calcium antagonist
activities of the aqueousmethanol extract of Achillea
millefolium.Phytother Res 20: 546551.
Yassa N, Saeidnia S, Pirouzi R, Akbaripour M, Shafiee A. 2007.
Three phenolic glycosides and immunological properties of
Achillea millefolium from Iran population of Golestan. DARU
J Pharma Sci 15:4952.
Yousefzadeh N, Zeinivand J. 2013. Essential oil composition of
Achillea millefolium growing in Darrehshahr township Iran.
Chem Commun 1:2534.
Zahara K, Tabassum S, Sabir S, et al. 2014. A review of
therapeutic potential of Saussurea lappaan endangered
plant from Himalaya. Asian Pac J Trop Med 7:6069.
Zolghadri Y, Fazeli M, Kooshki M, Shomali T, Karimaghayee N,
Dehghani M. 2014. Achillea millefolium L. hydro-alcoholic
extract protects pancreatic cells by down regulating IL-1β
and iNOS gene expression in diabetic rats. Int J Mol Cell Med
Autumn 3: 255262.
S.I. ALI ET AL.
Copyright © 2017 John Wiley & Sons, Ltd. Phytother. Res. (2017)
... Yarrow (Achillea millefolium L., AM) and stinging nettle (Urtica dioica L., UD) are highly bioactive traditional medicinal plants used to alleviate various symptoms, including gastric disorders [1][2][3][4]. Nowadays, their overground parts are approved for food supplement (AM) and food (UD) use in the European Union [5]. Bioactive plant extracts have multiple uses in the food and pharmaceutical industries, including functional foods or supplements, extending the shelf-life of foods, and contributing to the chemical and microbial safety of products at low cost and good consumer acceptance [6], even when proper hygiene and other safety actions cannot be completely replaced by bioactive plant compounds. ...
... The LPS is a cell wall structure typical of gram-negative bacteria and is a triggering ligand for the immune system via the Toll-Like Receptor 4 (TLR4), which ultimately leads to the activation of the transcription factor nuclear factor kappa B (NF-κB) and the production of pro-inflammatory cytokines [7]. The anti-inflammatory properties of AM and UD are mainly associated with their phenolic compounds [1,3,8]. ...
... The chemical compositions of AM and UD have been previously determined, with both plants containing different phenolic and other bioactive compounds [9,10]. In addition to anti-inflammatory effect, AM has demonstrated many bioactive properties, such as antioxidant, antimicrobial and antiproliferative [3,11,12] as well as modulating effects on the intestinal microbiota [1]. As for UD, it has shown antioxidant, antimicrobial and antitumour properties [4,9,12], and has also been shown to be a good source of bioactive chlorophylls and carotenoids, especially lutein and β-carotene [4,13]. ...
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Yarrow ( Achillea millefolium L., AM) and nettle ( Urtica dioica L., UD) are bioactive plants used commercially in functional food and supplement applications and traditionally to alleviate gastric disorders. In this work, the effects of food-grade optimized extracts of Finnish early-season AM and UD were tested on bacterial growth including potential beneficial and foodborne pathogens, as well as murine norovirus (MNV). The anti-inflammatory properties of the extracts were also tested in vitro by NF-κB reporter cells. The food-grade extraction was optimized with the response surface modelling in terms of total carotenoid, chlorophyll, and phenolic compounds contents and antioxidant capacities. The optimal food-grade extraction parameters were a 1-h extraction in 70% ethanol at 45 °C for AM, and at 49 °C for UD. There were no significant effects on the beneficial bacteria ( Lacticaseibacillus and Bifidobacterium strains), and the extracts were more effective against gram-positive than gram-negative foodborne bacteria and potential pathogens. Listeria innocua was the most susceptible strain in the optimized extracts with a growth rate of 0.059 ± 0.004 for AM and 0.067 ± 0.006 for UD, p < 0.05 compared to control. The optimized extracts showed a logarithmic growth reduction of 0.67 compared to MNV. The hydroethanolic extracts were cytotoxic to both cell lines, whereas aqueous AM and UD extracts induced and reduced TLR4 signalling in a reporter cell line, respectively. The results provide novel food-grade extraction parameters and support the bioactive effects of AM and UD in functional food applications, but more research is needed to elucidate the precise biological activity in vivo for gastric health.
... Antimalarial, antioxidant, antiulcer, Antispasmodic, antihypertensive, hepatoprotective, gastroprotective, antimicrobial, anticancer, anti-inflammatory, analgesic effect, skin rejuvenating activity [36] Aloe vera Anticancer, antimicrobial, cardioprotective effect, antidiabetic, digestive diseases protection, skin protection, prebiotic activity, bone protection, anti-inflammatory [116] Althaea officinalis Anti-inflammatory, anti-cough, anti-bacterial anti-fungal, immunostimulatory, antioxidant, wound healing [53] Calendula officinalis Anti-inflammatory, antioxidant, spasmogenic effects, neuropharmacological remedy [117] Matricaria chamomilla ...
... Bioactive phytochemicalcomponents ofAchillea millefolium L.[36]. ...
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The skin serves as the body’s first line of defense, guarding against mechanical, chemical, and thermal damage to the interior organs. It includes a highly developed immune response that serves as a barrier against pathogenic infections. Wound healing is a dynamic process underpinned by numerous cellular activities, including homeostasis, inflammation, proliferation, and remodeling, that require proper harmonious integration to effectively repair the damaged tissue. Following cutaneous damage, microorganisms can quickly enter the tissues beneath the skin, which can result in chronic wounds and fatal infections. Natural phytomedicines that possess considerable pharmacological properties have been widely and effectively employed forwound treatment and infection prevention. Since ancient times, phytotherapy has been able to efficiently treat cutaneous wounds, reduce the onset of infections, and minimize the usage of antibiotics that cause critical antibiotic resistance. There are a remarkable number of wound-healing botanicals that have been widely used in the Northern Hemisphere, including Achiella millefolium, Aloe vera, Althaea officinalis, Calendula officinalis, Matricaria chamomilla, Curcuma longa, Eucalyptus, Jojoba, plantain, pine, green tea, pomegranate, and Inula. This review addresses the most often used medicinal plants from the Northern Hemisphere that facilitate the treatment of wounds, and also suggests viable natural alternatives that can be used in the field of wound care.
... Among them, flavonoids containing baicalin have demonstrated anti-inflammatory, anti-oxidative, and anti-proliferative effects [14][15][16][17][18]. Baicalin (5,6-dihydroxy-2-phenyl-4H-1-benzopyran-4-one-7-O-D-b-glucuronic acid) is a plant-derived flavonoid isolated from Scutellaria baicalensis Georgi. Flavonoids have been used to treat pressure and diabetic ulcers [10,11,[19][20][21][22], but few studies have investigated the effect of the flavonoid baicalin on pressure ulcers, and its underlying molecular mechanisms remain to be clearly defined. Therefore, this study aimed to explore the effects of baicalin on wound healing in a mouse model of pressure ulcers. ...
... Among them, flavonoids containing baicalin have demonstrated anti-inflammatory, anti-oxidative, and anti-proliferative effects [14][15][16][17][18]. Baicalin (5,6-dihydroxy-2-phenyl-4H-1-benzopyran-4-one-7-O-Db-glucuronic acid) is a plant-derived flavonoid isolated from Scutellaria baicalensis Georgi. Flavonoids have been used to treat pressure and diabetic ulcers [10,11,[19][20][21][22], but few studies have investigated the effect of the flavonoid baicalin on pressure ulcers, and its underlying molecular mechanisms remain to be clearly defined. Therefore, this study aimed to explore the effects of baicalin on wound healing in a mouse model of pressure ulcers. ...
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One of the most frequent comorbidities that develop in chronically ill or immobilized patients is pressure ulcers, also known as bed sores. Despite ischemia-reperfusion (I/R)-induced skin lesion having been identified as a primary cause of pressure ulcers, wound management efforts have so far failed to significantly improve outcomes. Baicalin, or 5,6,7-trihydroxyflavone, is a type of flavonoid which has been shown to possess a variety of biological characteristics, including antioxidative and anti-inflammatory effects and protection of I/R injury. In vitro wound scratch assay was first used to assess the function of baicalin in wound healing. We established a mouse model of advanced stage pressure ulcers with repeated cycles of I/R pressure load. In this model, topically applied baicalin (100 mg/mL) induced a significant increase in the wound healing process measured by wound area. Histological examination of the pressure ulcer mouse model showed faster granulation tissue formation and re-epithelization in the baicalin-treated group. Next, baicalin downregulated pro-inflammatory cytokines (IL-6 and IL-1β), while upregulating the anti-inflammatory IL-10. Additionally, baicalin induced an increase in several growth factors (VEGF, FGF-2, PDGF-β, and CTGF), promoting the wound healing process. Our results suggest that baicalin could serve as a promising agent for the treatment of pressures ulcers.
... monoterpenes, sesquiterpenes, and sesquiterpenoids [5,8,9]. Studies on the chemical composition of A. millefolium date back to the early 1900s and more than 120 compounds have been identified [10]. ...
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Achillea millefolium L. is the most representative plant of the genus Achillea due to its long-standing use. Previous investigations have allowed for the identification of many chemical compounds including phenols, flavonoids, monoterpenes, sesquiterpenes, and their derivatives. However, only a few reports have considered flower color in relation to A. millefolium composition. In this work, the phytochemical analysis on the volatile content of fresh samples of three morphotypes—white, pink and deep pink—collected in different points of the Italian Alpine area, was performed by the SPME-GC-MS technique. The obtained data highlighted a high content of terpenic compounds in all of the investigated morphotypes with a general predominance of monoterpenes over sesquiterpenes with the exception of the white morphotype at collection point A (Saint Marcel, Valle d’Aosta). An in-depth statistical investigation was also carried out to better interpret the distribution of the various components both in relation to the morphotype and collection point.
... Yarrow plant (Achillea millefolium) belongs the Asteraceae family and it is found in Asia, European and America (Acar et al., 2020). It is mainly contained amazulene, α-pinene, βpinene, casticin, 1,8-cineole,cosmosiin and luteolin (Ali et al., 2017). It is known to have some properties such as anti-inflammatory, antipyretic, anthelmintic, antibacterial, antifungal, antitumor, antioxidant and anti-oedematous (Daniel et al., 2020). ...
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Medicinal plants and their derivations are used as safe agents for the treatment of parasitic diseases. This preliminary study investigates antileishmanial activities of Peganum harmala essential oil (PHEO), Achillea millefolium essential oils (AMEO) and their combinations against Leishmania infantum promastigotes. A standard strain of L. infantum promastigote was cultured in a 96-well Novy-MacNeal-Nicolle media culture and antileishmanial activities of glucantime, PHEO, AMEO, an equal ratio of both and 80% PHEO+20%AMEO were investigated in concentrations of 10, 100, 500 and 1000 mg/mL and interval times of 24h, 48h and 72h. The results showed that greatest inhibition was observed in 50PHEO+ AMEO and lowest inhibition was seen in control group. The increased time and increased concentration significantly increased their efficiencies. The analyses showed a significant interaction between time and agents [F (10, 360)=7.84, P=0.000]. The agents showed better effects with increased time. In sum, an equal combination of PHEO and AMEO showed its potential as an antileishmanial safe structure and must be considered for future studies.
... Recently, it has been established that medicinal plants are rich sources for new drug development, and traditional medicinal data has a quite good success rate in new therapeutics (Ochieng et al., 2022). Africa represents about a quarter of the world trade of biodiversity, and it is surprising that only a few drugs have been commercialized compared to other countries (Maroyi, 2016;Ali et al., 2017;Nabatanzi et al., 2020). The reason could be the lack of documentation, the secretive practices of local healers and folklore medicine practitioners, or lack of interest by first-world countries (Geethangili and Ding, 2018). ...
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Ethnopharmacological relevance: Alchornea laxiflora (Benth.) Pax & K. Hoffm. (Euphorbiaceae) is an important traditional medicinal plant grown in tropical Africa. The stem, leaves, and root have been widely used in the folk medicine systems in Nigeria, Cameroon, South Africa, and Ghana to treat various ailments, including inflammatory, infectious, and central nervous system disorders, such as anxiety and epilepsy. Material and methods: The scientific name of the plant was validated using the “The Plant List,” “Kew Royal Botanic Gardens,” and Tropicos Nomenclatural databases. The literature search on A. laxiflora was performed using electronic search engines and databases such as Google scholar, ScienceDirect, PubMed, AJOL, Scopus, and Mendeley. Results: To the best of our knowledge, no specific and detailed review has been reported on A. laxiflora . Consequently, this review provides an up-to-date systematic presentation on ethnobotany, phytoconstituents, pharmacological activities, and toxicity profiles of A. laxiflora. Phytochemical investigations disclosed the presence of important compounds, such as alkaloids, flavonoids, phenolics, terpenoids, and fatty acids. Furthermore, various pharmacological activities and traditional uses reported for this botanical drug were discussed comprehensively. Conclusion: This systemic review presents the current status and perspectives of A. laxiflora as a potential therapeutic modality that would assist future researchers in exploring this African botanical drug as a source of novel drug candidates for varied diseases.
... These species grow in the Mediterranean region and play an important role in traditional medicine and culinary purpose in some areas. Regarding phenol composition, Achillea millefolium L. (Asteraceae) is especially rich in phenolic substances, such as caffeic and salicylic acid, in addition to numerous avonoids [4]. Sideritis angustifolia Lag. ...
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Plant extracts can be an important adjuvant treatment in gastrointestinal diseases where intestinal transit is involved. Because transit disorders are often associated with infections and inflammation, in our investigation we have selected five aromatic Mediterranean plants with antimicrobial, antioxidant and anti-inflammatory activities which in certain areas are also used for culinary reasons. We evaluated the intestinal transit in mice after oral administration of hydro-alcoholic extracts of Achillea millefolium L. Sideritis angustifolia Lag., Rosmarinus officinalis L. Matricaria chamomile L., and Aloysia citriodora Palau. Total content of phenols and flavonoids and their antioxidant activity were previously determined. Rosmarinus officinalis showed the highest antioxidant capacity (p < 0.001) in the DPPH and ABTS methods with IC50 of 48.89 ± 2.98 and 27.28 ± 1.83 µg/mL respectively, in agreement with the highest phenol content. Oral administration of the extracts to mice and rats showed no signs or symptoms of toxicity in any case. The extracts of A. millefolium, R. officinalis, and M. chamomilla significantly inhibited intestinal transit (p < 0.01 and p < 0.05) when compared to the castor oil control group, with a percentage of intestinal transit similar to that of the reference antidiarrheal loperamide drug (47.8 ± 3.6%). These non-toxic plant extracts constitute a valuable basis to produce dietary supplements for intestinal motility disorders.