Methodology/Methods Search
All relevant information concerning the botanical description, traditional use, phytochemical
composition, pharmacological activities, and toxicological aspects of P. alba was collected from published literature, with no time restrictions. The electronic
databases used for the data collection included EBSCO, EMBASE, Google Scholar, PubMed,
REAXYS, ScienceDirect, Scopus, Springer Link, Taylor & Francis, and Web of Science
using the terms “Potentilla” and/or “Potentilla alba” and/or “white cinquefoil” and/or “Rosaceae” and/or “botanical description” and/or
“alba” and/or “herb extract” and/or “root extract” and/or “ethnopharmacology” and/or
“phytochemistry” and/or “antibacterial activity” and/or “antiviral activity” and/or
“antioxidant activity” and/or “adaptogenic activity” and/or “anti-neoplastic activity”
and/or “thyrotropic activity” and/or “thyroid treatment” and/or “toxicity”. Moreover,
books, conference papers, and PhD theses were studied for
relevant information.
Inclusion and exclusion criteria
Relevant articles in all languages were identified and independently evaluated for
their competence and inclusion by two different authors. After compliance with the
inclusion criteria, experimental research and clinical trials that assessed the target
plant composition and/or evaluated its effects were included in this research. Improper
studies (1), original papers considering only other species from the genus Potentilla (2), or articles with a lack of access to the abstract and/or main text (3) were
excluded.
Botanical Description and Distribution
P. alba, also known as white cinquefoil, is one of approximately 500 species of the genus
Potentilla belonging to the Rosaceae family. The valid taxonomic name of this species was first
described in 1753 by the Swedish botanist Carl von Linné in his work “Species Plantarum”
[8]. This Potentilla species is also known under the synonyms of Dasiphora alba (L.) Raf., Fragaria alba (L.) Crantz., Fragariastrum album (L.) Schur, P. alba f. obovata (Th.Wolf) Diklic, Potentilla nitida Scop., and Trichothalamus albus (L.) Fourr. [9].
P. alba is distributed in the central parts of Europe and West Asia in temperate and subarctic
climatic zones. Thus, this species is indigenous to France in the western part of
Europe to the central and southern parts of Russia in the east and from the Baltic
states, Poland, and Germany southwards to Italy, Albania, and Romania. This plant
has also been introduced to Great Britain [9]. P. alba is widely distributed in a variety of environments, including deciduous forests,
where it is a characteristic species for the plant community of the dry-mesic oak
forest Potentillo albae-Quercetum petraeae, as well as grasslands, heaths, and alpine slopes [10], [11]. However, the extensive demand of white cinquefoil rhizomes for medical purposes
threatens this species, causing it to be endangered or close to depleted in natural
habitats [12], [13].
The plant is a vigorous herbaceous perennial 8 – 25 cm high with a 35-cm long, oblique,
stout, and dun rootstock, i.e., roots and rhizomes. Rising stalks are often loosely
bent and surmounted by a rosette of leaves. Basal leaves are long stalked and palmate
with 5 leaflets, while stem leaves are alternate with 3 leaflets and short stalked
or stalkless. Leaflets have a lanceolate obovate shape, toothed at the apex, and silky
hair covering underneath. The stipules are usually smaller and red-yellow colored.
Notably, the plant creates 1 to 5 individual flowers occurring in spring, which, in
contrast to most Potentilla species, possess five obovate white-colored petals. Moreover, the stamens with white
filaments occur in the number of 20. There are 5 silvery hairy sepals and a 5-sectioned
epicalyx. The fruit takes the form of matt and lightly ridged achene [10], [14], [15].
Traditional Use
Potentilla species have been used in medicine since antiquity [5]. Before the introduction of the modern taxonomy by Linné in 1753, P. alba was known as Quinquefolium album and Pentaphyllum album
[8]. The first report treating P. alba use dates from 1543 in a New Kreüterbuch book by Leonhard Fuchs. One of the species
described and depicted in the chapter “Fünffingerkraut” was white cinquefoil (“Groß
Weiss Fünffingerkraut”), of which the underground parts were used externally to treat
inflammation of the mouth and throat and toothache. Internal use described for the
underground parts included the treatment of dysentery, ulcers, and jaundice. Aerial
part application included the treatment of fever, jaundice, fistula, and as an astringent
[16]. P. alba was also mentioned in the herbal book Tabernaemontanus dating from 1588, with similar
indications for
use [17]. Since the 18th century, in Eastern Europe and particularly in Belarusian Polesie,
there has been a common practice of using P. alba decoctions as a substitute for Camellia sinensis
[18].
White cinquefoil is traditionally used in Eastern Europe to treat diseases of the
liver, cardiovascular system, and gastrointestinal tract and as a wound healing agent
due to its antibacterial activity. Extracts from the aerial parts stimulate the central
nervous system, whereas the underground parts of this plant increase diuresis, enhance
bile secretion, and improve intestinal function. In folk medicine, an infusion of
P. alba roots is prepared for painful menstruation as an antispastic and analgesic agent.
A decoction of the roots with rhizomes is used for gout, rheumatism, jaundice, and
dysentery. In folk medicine of Belarus, it is recommended to drink a decoction of
the aerial parts of white cinquefoil when suffering from prolapse of the uterus [19], [20].
Currently, the use of an infusion of the underground parts to treat hypo- and hyperthyroidism
has been reported as a standard therapy, especially in Ukraine, Belarus, and the Federation
[13], [21]. Moreover, phytotherapists in post-Soviet states, especially Russia, recommend P. alba as an adaptogen, a treatment for heart diseases, or as a psychostimulant of the central
nervous system [22]. However, the only species from the genus Potentilla included in the latest Russian Pharmacopoeia is the Potentilla erecta rhizome [23].
Chemical Constituents of Potentilla alba
A number of studies have confirmed the occurrence of at least 47 compounds for the
rhizomes and/or aerial parts of P. alba that have been isolated or detected and completely identified with the use of chromatographic
and spectral methods.
A predominant group of constituents from the underground parts are condensed tannins,
with a total procyanidin content estimated to be 7.3% of the raw material dry mass.
However, the authors of this study did not detect hydrolysable tannins in P. alba rhizomes [24], [25]. Only ellagic acid, as a degradation product of ellagitannins, was identified, apart
from gallic acid, a precursor of hydrolysable tannins [26]. In addition to the precursors of condensed tannins (+)-catechin and (−)-epicatechin
and their 4-benzyl thioether derivatives, a series of oligomeric procyanidines have
been isolated and elucidated [27]. Additionally, two flavonoid aglycones and three flavonoid O-glucosides were identified [26]. Furthermore, from a chemophenetic point of view, the presence of tormentic acid
([Fig. 1]) in the subterranean parts of P. alba confirms the general chemical homogeneity in the genus Potentilla. Moreover, underground parts are rich in fatty acids, polysaccharides, amino acids,
and macro- and microelements such as calcium, magnesium, iron, phosphorus, potassium,
manganese, and iodine [28].
Fig. 1 Structure of tormentic acid.
Several phytochemical studies have been performed with the aerial parts of P. alba and at least 29 compounds were completely identified. The dominant group of compounds
were flavonoids, with five compounds identified as flavonoid aglycones and nine as
flavonoid O-glycosides, which are generally quercetin and kaempferol glycosides. Moreover, several
structures of O-glycosides have not been completely elucidated. Further ingredients include phenol
carboxylic acids, mainly structural isomers of caffeoylquinic and coumaroylquinic
acids. Additionally, the structures of dimeric and trimeric type B proanthocyanidins
were elucidated from the aerial parts of the plant, connected by 4,8-bonds, such as
procyanidin B1, procyanidin B2, and trimeric procyanidin C1. The structures of selected
procyanidins are presented in [Fig. 2]. More interestingly, in the leaves of P. alba, catechin, a precursor for proanthocyanidins, was not
detected [29], while in a recent work, catechin was present in whole aerial part preparations
[30]. Previously, (−)-epicatechin was isolated from the leaves of white cinquefoil [19]. The current status of the phytochemical constituents of P. alba is summarized in [Table 1].
Fig. 2 Structures of selected procyanidins, procyanidin B1 and procyanidin C1.
Table 1 Compounds and elements of the underground and aerial parts of P. alba L.
|
Compounds
|
Plant part
|
References
|
|
*Structure not fully elucidated; A = aerial part; R = root and/or rhizome
|
|
Flavonoids
|
|
Flavonoid aglycones
|
|
Apigenin
|
A, R
|
[31]
|
|
Cyanidin
|
A
|
[32]
|
|
Isorhamnetin
|
A
|
[30]
|
|
Kaempferol
|
A
|
[30], [32]
|
|
Quercetin
|
A, R
|
[30], [32], [33]
|
|
Flavonoid O-glycosides
|
|
Astragalin (kaempferol 3-O-β-glucoside)
|
A
|
[27], [30]
|
|
Avicularin (quercetin 3-O-α-arabinoside)
|
A
|
[19], [27], [29]
|
|
Cynaroside (luteolin 7-O-β-D-glucoside)
|
R
|
[26], [31], [33]
|
|
Hesperidin (hesperetin 7-O-rutoside)
|
R
|
[26], [33]
|
|
Isoquercitrin (quercetin 3-O-β-glucoside)
|
A
|
[19], [29]
|
|
Isorhamnetin O-pentoso-hexoside*
|
A
|
[30]
|
|
Juglain (kaempferol 3-O-α-arabinoside)
|
A
|
[34]
|
|
Kaempferol-O-hexoso-hexoside*
|
A
|
[30]
|
|
Kaempferol-O-pentoso-hexoside*
|
A
|
[30]
|
|
Quercetin 3,7-O-diglucoside
|
A
|
[30], [34]
|
|
Quercetin 3-O-β-D-glucosyl-O-β-D-rhamnoside
|
A
|
[27]
|
|
Quercetin O-hexoside*
|
A
|
[30]
|
|
Quercetin O-pentoso-hexoside* (2 isomers)
|
A
|
[30]
|
|
Quercitrin (quercetin 3-O-α-L-rhamnoside)
|
R
|
[26]
|
|
Rutin (quercetin 3-O-rutoside)
|
A
|
[19], [29], [30]
|
|
Tiliroside (kaempferol 3-O-β-D-(6″-O-trans-p-coumaroyl)-glucoside)
|
A
|
[30]
|
|
Trifolin (kaempferol 3-O-β-D-galactoside)
|
A
|
[30]
|
|
Organic acids and phenol carboxylic acids
|
|
Ascorbic acid
|
A
|
[35]
|
|
Caffeic acid
|
R
|
[26], [33]
|
|
Chlorogenic acid (3-O-caffeoylquinic acid)
|
A, R
|
[19], [26], [29]
|
|
Cryptochlorogenic acid (4-O-caffeoylquinic acid)
|
A
|
[30], [33]
|
|
Neochlorogenic acid (5-O-caffeoylquinic acid)
|
A
|
[19], [29]
|
|
Cinnamic acid
|
R
|
[26], [33]
|
|
p-Coumaric acid
|
A
|
[19], [32]
|
|
3-O-p-Coumaroylquinic acid
|
A
|
[30]
|
|
5-O-p-Coumaroylquinic acid
|
A
|
[30]
|
|
p-Coumaroyl tartaric acid* (2 isomers)
|
R
|
[27]
|
|
Ferulic acid
|
R
|
[26], [33]
|
|
3-O-Feruloylquinic acid
|
A
|
[30]
|
|
Gallic acid
|
A, R
|
[26], [29], [33]
|
|
Malic acid
|
R
|
[26]
|
|
Oxalic acid
|
R
|
[26]
|
|
Tannins
|
|
Condensed tannins (proanthocyanidins) and their precursors
|
|
(−)-Epicatechin
|
A, R
|
[19], [26], [27], [33], [36]
|
|
(+)-Epicatechin 4-benzylthioether
|
R
|
[36]
|
|
(+)-Epicatechin monoglucoside*
|
R
|
[27]
|
|
(+)-Catechin
|
A, R
|
[27], [30], [37], [38]
|
|
(+)-Catechin 4-benzylthioether
|
R
|
[36]
|
|
(+)-Catechin monoglucoside*
|
R
|
[27]
|
|
(+)-Catechin 3-O-β-D-glucopyranoside
|
R
|
[37]
|
|
(+)-Catechin 7-O-β-D-glucopyranoside
|
R
|
[37]
|
|
Epigallocatechin gallate
|
R
|
[26], [33]
|
|
Procyanidin B1 (epicatechin-(4β→8)-catechin)
|
A
|
[19], [29]
|
|
Procyanidin B2 (epicatechin-(4β→8)-epicatechin)
|
A
|
[19], [29]
|
|
Procyanidin type B dimer monoglucoside*
|
R
|
[27]
|
|
Procyanidin type B dimer* (5 isomers)
|
R
|
[27]
|
|
Procyanidin C1 (epicatechin-(4β→8)-epicatechin-(4β→8)-epicatechin)
|
A
|
[19], [29]
|
|
Procyanidin type B trimer* (2 isomers)
|
R
|
[27]
|
|
Procyanidin type B tetramer* (1 isomer)
|
R
|
[27]
|
|
Procyanidin type B pentamer* (3 isomers)
|
R
|
[27]
|
|
Procyanidin type A dimer* (3 isomers)
|
R
|
[27]
|
|
Procyanidin type A trimer* (4 isomers)
|
R
|
[27]
|
|
Procyanidin type A tetramer* (4 isomers)
|
R
|
[27]
|
|
Procyanidin type A pentamer* (2 isomers)
|
R
|
[27]
|
|
Procyanidin type A hexamer* (2 isomers)
|
R
|
[27]
|
|
Hydrolysable tannins and related compounds
|
|
Ellagic acid
|
A, R
|
[26], [32], [33]
|
|
Gallic acid monoglucoside
|
R
|
[27]
|
|
Triterpenes
|
|
Tormentic acid
|
R
|
[37]
|
|
Coumarins
|
|
Dihydrocoumarin
|
R
|
[33]
|
|
Others
|
|
Aminoacids
|
R
|
[28]
|
|
Fatty acids, e.g., palmic, stearic, linoleic, linolenic acid
|
A, R
|
[39], [40]
|
|
Polyprenols with 19 – 45 units
|
A
|
[41]
|
|
Polysaccharides
|
R
|
[28]
|
|
Sitosterol
|
R
|
[37], [80]
|
|
Sitosterol 3-O-β-D-glucoside (daucosterol)
|
R
|
[37], [80]
|
|
Micro- and macroelements, e.g., magnesium, calcium, potassium, iron, manganese, phosphorus,
iodine
|
R
|
[28]
|
Due to the limited natural reserves of P. alba, there have been attempts to develop a method allowing the production of the plant
using a hydroponics technique with clonal micropropagation. This method may lead to
the accumulation of elements from the nutrient media in plant organs similar to intact
plants. Although the obtained results are promising, there is still an advantage to
using intact plants when considering the content of secondary metabolites [31], [42]. Researchers in Pyatigorsk (Russia) in the Northern Caucasus worked on recommendations
for the conventional cultivation of P. alba. The most convenient method of white cinquefoil reproduction was the division of
the rhizomes into cuttings. Based on the observations of a 3-year project, the authors
concluded that during the first 5 years of life, active plant growth and an increase
in biomass are noted. By the 5th year of life, the rhizomes
are fully formed and suitable for pharmaceutical use [43]. In another approach, reported from a great P. alba plantation in the Bryansk region (Russia), shoot buds with a piece of the root and
two to four leaves were separated manually from the mother plant for plant propagation
[44].
Pharmacological Profile
Preparations based on the aerial part of P. alba have less pharmacological activity than the roots and rhizomes of this plant [19]. In addition to the in vitro and few in vivo studies, a number of publications address clinical studies of rhizome extracts for
the treatment of thyroid gland impairments. An overview of the current status of pharmacological
evaluations of P. alba is outlined in [Table 2].
Table 2 An overview on the current status of pharmacological evaluations of P. alba L.
|
Observed effects
|
Plant part
|
References
|
|
A = aerial part; R = root and/or rhizome
|
|
Effects in vitro
|
|
Antioxidative activity
|
A, R
|
[36], [45]
|
|
Antimicrobial activity against various bacterial and fungal strains
|
A, R
|
[32], [46], [47], [49]
|
|
Antiviral activity against herpes simplex virus type II
|
R
|
[50]
|
|
Antineoplastic activity against HT-29 human colon cancer
|
A
|
[30]
|
|
Effects in vivo
|
|
Adaptogenic activity
|
R
|
[22]
|
|
Anti-inflammatory activity
|
R
|
[51]
|
|
Thyrotropic activity
|
R
|
[63], [64], [65]
|
|
Clinical trials
|
|
Thyrotropic activity: efficacy in the treatment of hypo- and hyperthyroidism, hypothyroic
and toxic goiter, diffuse non-toxic goiter, nodular goiter, and autoimmune thyroiditis
|
R
|
[66], [67], [68], [69], [70], [71], [72], [73]
|
In vitro studies
Antioxidative activity
The radical scavenging properties were verified for the aerial and underground parts.
The abundance of polyphenols, such as flavonoids and procyanidins, present in the
species exerts a protective effect against oxidative damage. A few reports have uncovered
high antioxidant properties of various extracts from the herbal parts measured by
1,1-diphenyl-2-picrylhydrazyl (DPPH), ferric reducing antioxidant power (FRAP), and
ferrous ion chelating (FIP) assays [29], [30]. Similar significant antioxidant activity, with the assignment of additional assays,
such as N,N-dimethyl-p-phenylenediamine (DMPD+), superoxide radical, and hydroxyl radical assays, was reported for water and methanol
extracts obtained from rhizomes and roots of P. alba
[36], [45].
Antimicrobial activity
On several occasions, antimicrobial activities of rhizome extracts have been reported.
Bosnian authors investigated the antimicrobial potential of water, ethanol, acetone,
and ethyl acetate extracts against selected bacterial and fungal strains – Staphylococcus aureus ATCC 6538, Bacillus subtilis ATCC 6633, Escherichia coli ATCC 8739, and Candida albicans ATCC 10 231. Notably, only an acetone preparation at a 1 : 1 dilution and a water
preparation at a 1 : 10 dilution revealed moderate inhibitory activity against S. aureus, with zone of inhibition values peaking at 13.4 and 11.0 mm, respectively. Moreover,
acetone and alcohol samples inhibited the growth of the E. coli strain in a manner similar to the reference 2% tannic acid solution. However, the
growth of the B. subtilis and C. albicans strains was unaffected by the tested extracts [46]. Interestingly, in comparison to an earlier
study, recent results showed that the extracts from P. alba root exhibited more substantial antibacterial and antifungal activities against E. coli ATCC 25922, S. aureus ATCC 25923, and C. albicans EMTK 34 strains, with zone of inhibition values of 21.0 ± 1.1, 19.0 ± 1.0, and 22.0 ± 1.1 mm,
respectively. Additionally, strong antibacterial activity against Proteus vulgaris and Pseudomonas aeruginosa strains (zone of inhibition values of 20.0 ± 1.0 and 23.0 ± 1.2 mm, respectively)
was observed [47]. In another study, an aqueous extract of P. alba roots (1 : 10) was shown to be active against the test strains P. aeruginosa, C. albicans, and E. coli after 2- to 4-fold dilution, whereas this extract was even more active against S. aureus and Bacillus cereus, i.e., after 16- and 32-fold dilution [37]. However, the differences in the obtained
results may be explained by the variation in qualitative and quantitative secondary
metabolite composition in the plant tissue and in the type of obtained extracts [48] and perhaps also by the different test strains.
Chitosan is a polycationic polymer and one of the most widespread polysaccharides
in nature. It is a waste product from the marine food processing industry. Due to
its abundant availability, biocompatibility, biodegradability, and susceptibility
to chemical modification, a number of researchers are interested in the production
of chitosan-based products and their practical application inter alia in the food industry or medicine. In accordance with these advantages, the antimicrobial
effects of P. alba herbal decoction with a chitosan-based film-forming composition was investigated.
The tested sample revealed no toxicity or hemolytic activity and inhibited B. cereus growth, with a zone diameter of 34 mm. The authors concluded that the tested preparation
could serve as an excellent and safe remedy to increase the shelf life of plant-derived
products [49].
Antiviral activity
A recent study assessed the antiviral potential of P. alba ethanol and water extracts from both intact and regenerative plants against herpes
simplex virus type II. The study was carried out in the Vero cell line. It was demonstrated
that water extracts from intact and regenerative plants exhibited anti-herpes activity.
However, a weaker antiviral effect was observed for the ethanol extracts [50].
Antineoplastic activity
Patients diagnosed with cancer face a variety of problems connected with chemotherapy
treatment and with a decrease in quality of life. Thus, the scientific world has focused
on research for safer and more effective remedies to increase patient survivability
and comfort. Although digestive tract cancers are very common, they are still a significant
portion of the worldwide death toll. Recently, Polish authors assessed the cytotoxic
effects of selected extracts and fractions of P. alba aerial parts against HT-29 human colon cancer and the CCD 841 CoTr human noncancerous
colon epithelial cell line. The study showed that the tested samples affected the
integrity of the tumor cell membranes and decreased their proliferation. In particular,
extracts abundant in caffeoylquinic acids displayed the highest antineoplastic activity
due to their ability to modulate the cell cycle and thus increase apoptosis. Furthermore,
the proliferation of normal colon cells was highly
promoted, despite damage to cell membranes in the investigated samples, which
mildly affected mitochondrial metabolism [30].
In vivo studies
Adaptogenic activity
In the scientific literature, there have been only a few in vivo studies. Russian authors, based on the recommendations of phytotherapists [38], examined the adaptogenic influence of the P. alba rhizome water extract on mice. The experiment comprised swimming endurance, open-field,
and light/dark exploration tests. Interestingly, 1-week oral administration of the
investigated extract at doses of 36 and 72 mg/kg body weight (b. w.) revealed a significant
enhancement in the swimming time in a dose-dependent manner. Furthermore, the authors
found that high glycogen concentrations in the treated rodents correlated with prolonged
swimming time. However, the exact mechanism is unknown and should be investigated
in the future, but it may involve the antioxidant properties that can protect against
oxidative damage. Additionally, P. alba extracts attenuated anxiety symptoms in light/dark exploration and open-field tests.
Although the tested samples at a dose of 72 mg/kg b. w. increased the time spent
by mice in the light chamber, the effect was not significant. In a separate study,
animals treated at a dose of 12 mg/kg placed in a novel environment expressed a significant
increase in head dip frequency and the number of squares crossed in comparison to
the control group, as well as a reduction in grooming. These results indicate the
anxiolytic potential of P. alba rhizome preparations. Nonetheless, further phytochemical and pharmacological research
is needed to determine the exact mechanism of action and the main components responsible
for the observed effects [22].
Anti-inflammatory activity
It has been found that administration of the acetone and ethanol extracts from the
underground parts of white cinquefoil reduced the inflammation process in a mouse
ear test model. Inflammation was induced by administration of a 3% Crotonis oleum acetone solution to the mouse ear 2 hours after a single dose of the tested extracts.
The study indicated strong anti-inflammatory activity of the acetone extract in a
manner similar to the reference 1% hydrocortisone ointment. However, the activity
of the ethanolic extract was weaker than the reference [51].
Thyroid gland disorders
The thyroid gland is an essential part of the human endocrine system and directly
involved in proper organism development and growth, as well as adaptation to changing
environmental factors. Two thyroid hormones, triiodothyronine (T3) and thyroxine (T4),
are partially composed of iodine and are mainly responsible for the regulation of
cellular metabolism. Their narrow range of serum concentrations are controlled by
the thyrotropin-releasing hormone (TRH) released from the hypothalamus and thereafter
by the anterior pituitary hormone thyrotropin (TSH) [52].
Thyroid gland disorders can be classified by the characterization of thyroid tissue,
including euthyroidism, hyperthyroidism, hypothyroidism, thyroid-associated ophthalmopathy,
and abnormal thyroid parameters without thyroid diseases. Euthyroidism disorders are
characterized by the normal production of thyroid hormones and their normal levels
in the serum. This group includes euthyroid goiter, thyroid tumors, and thyroiditis.
However, the overproduction of thyroid hormones leads to primary hyperthyroidism,
which can be caused mainly by diffuse hyperthyroid goiter, Gravesʼ disease. However,
secondary hyperthyroidism occurs with elevated or inappropriately normal TSH levels
due to pituitary disorders and iodine-induced hyperthyroidism, among others. Similarly,
hypothyroidism can be divided into primary and secondary hypothyroidism with the manifestation
of decreased thyroid hormone production. Primary hypothyroidism includes adult iatrogenic
and iodine deficiency
hypothyroidism, diffuse and nodular goiter, and neonatal congenital hypothyroidism.
Secondary hypothyroidism occurs mainly due to disorders of the hypothalamic-pituitary
axis [53], [54].
Unfortunately, thyroid gland disorders are principally connected with an inadequate
intake of iodine from the diet, with approximately one-third of the worldʼs population
living in iodine deficient areas, which leads to cognitive impairment in infants and
children. The prevalence of overt hypothyroidism in Europe ranges from 0.2 to 5.3%
[55]. Therefore, the European Food Safety Authority (EFSA) and the WHO, together with
the United Nations Childrenʼs Fund (UNICEF) and International Council for the Control
of Iodine Deficiency Disorders (ICCIDD), derived values for adequate intake and the
recommended dietary allowance for iodine as 150 µg/day for adults, which increases
during pregnancy and lactation to a value of 200 – 250 µg/day [56], [57]. On the other hand, in areas with high iodine intake, a considerable number of thyroid
disorders are presumably due to hyperthyroidism and
autoimmune thyroiditis. A meta-analysis of European studies revealed a mean
prevalence rate of overt hyperthyroidism of 0.75% [58].
Despite the great advances in thyroid disorder therapy, the usage of phytomedicines
still offers fewer side effects than synthetic drugs. However, phytomedicines can
be considered a complementary part of comprehensive therapy to treat various thyroid
gland disorders. Several species have traditionally been used throughout Europe, Asia,
and North America to reduce hyperthyroidism symptoms. Particularly, herbal medicines
such as gypsywort, bugleweed, water horehound (Lycopus europaeus L., Lycopus virginicus L., Lycopus americanus Muhl. ex W. P. C. Barton, Lamiaceae, respectively), lemon balm (Melissa officinalis L., Lamiaceae), and western gromwell and European gromwell (Lithospermum ruderale Douglas ex. Lehm. and Lithospermum officinale L., Boraginaceae, respectively) exert beneficial effects to reduce hyperthyroid symptoms,
as found during in vitro and in vivo studies. The possible mechanism could be complex,
including processes such as reducing TSH formation and its binding to thyroid
follicles, decreasing peripheral deiodination of T4, and/or inhibiting the binding
of Gravesʼ disease antibodies to thyroid tissue [59], [60]. However, the herbal medicines administered to treat hypothyroidism mainly involve
the supplementation of iodine. The most widely used herbal medicine is bladderwrack
(Fucus vesiculosus L., Fucaceae), which is traditionally used in folk medicine and contains high quantities
of iodine, approximately 50 µg/g dried mass. Hence, bladderwrack has been evaluated
by the Committee on Herbal Medicinal Products (HMPC) of the European Medicines Agency
(EMA), which established that an upper daily limit of iodine intake for bladderwrack
should not exceed 400 µg/day [61]. Moreover, several other phytomedicines, such as ashwagandha (Withania somnifera (L.) Dunal,
Solanaceae), gotu kola (Centella asiatica (L.) Urb., Apiaceae), and guggul (Commiphora mukul (Hook. ex Stocks) Engl., Burseraceae), have been shown to efficiently treat hypothyroidism;
however, biological studies are very limited [62].
Thyrotropic activity of Potentilla alba extracts (roots and rhizomes) – in vivo studies
Recently, Abdreshov et al. (2021) reported the influence of Vozrozhdenie plus balm (a preparation containing iodine, starch, ascorbic acid, sodium chloride, glycerine,
and gelatine) and a P. alba root extract combination on the condition of adrenergic innervation of the thyroid
gland, thyroid blood vessels, lymph nodes, and lymphatic vessels in an induced hypothyroidism
rat model. The specific histochemical fluorescence microscopy method to visualize
catecholamines was used to observe changes in thyroid tissue. This analysis demonstrated
that the investigated mixture positively affected the restoration of nerve contours
and increased catecholamine concentrations in thyroid tissue and the surrounding lymphatic
vessels and nodes. However, the authors underlined that the histological changes after
treatment were more marked for the lymphatic system than for the thyroid gland tissue
[63]. Moreover, the CCl4 extract
rich in triterpenes from P. alba whole root segments transformed by Agrobacterium rhizogenes exhibited a reduction in thyroxine levels in the rat thyroid gland, thus protecting
the gland from the damage induced by γ-ray irradiation [64]. Additionally, an extract prepared from the root and rhizomes of P. alba was tested in rats with experimental hypothyroidism. Application of the extract raised
the levels of the thyroid hormones (T3 and T4 by 34 and 30%, respectively) [65].
Thyrotropic activity of Potentilla alba extracts (roots and rhizomes) – studies in humans
The first publication on the thyrotropic activity of white cinquefoil dates from 1975
[13]. White cinquefoil (roots and rhizomes) is currently used in traditional medicine
throughout Eastern Europe either alone or as a part of comprehensive therapy against
thyroid gland impairments [6]. Based on those reports, several clinical trials have been performed to evaluate
the validity and clinical efficacy of the P. alba rhizome extracts. In 2012, three independent clinical trials were performed with
the same preparation. During the first trial, 55 patients with diagnosed hyperthyroidism,
chronic thyroiditis, and diffuse nontoxic goiter during the 6-month trial were treated
with a P. alba preparation containing 300 mg of an extract twice a day. It was found that this treatment
reduced thyroid size and normalized thyroid function, decreased serum antibody levels
against thyrotropin receptor (AB-r TSH), and
shortened the time needed to stabilize TSH serum levels [66]. In the second study, 77 patients with mixed diffuse and benign goiter divided into
a control group and an herbal treatment group were enrolled. The patients in the control
group received levothyroxine or thyrostatic therapy, while the treatment group also
received a P. alba dry rhizome extract twice a day containing 300 mg per capsule for 2 consecutive months.
Compared to control therapy, the extract significantly decreased somatic symptoms
of hypo- and hyperthyroidism. Significant changes in nodule volume were also observed
[67]. Additionally, in another study, the clinical efficacy of a P. alba rhizome extract (300 mg, 2 capsules per day) added to the basic treatment was evaluated
according to international guidelines in 46 patients with toxic goiter. Three months
of treatment improved the structure of the thyroid gland, significantly
increased thyroid-stimulating hormone, and reduced AB-r TSH levels [68]. A further multicenter clinical study conducted in Ukraine assessed the influence
of P. alba rhizome extract on thyroid gland volumes. In brief, 1107 patients with autoimmune
thyroiditis, nodular goiter, or diffuse nontoxic goiter were enrolled. Monotherapy
with a dry rhizome extract at a dose of 300 mg was applied twice a day for 6 months.
Notably, the preparation decreased the volume of the thyroid gland by a minimum of
15% in patients with all investigated impairments. These results showed a significant
increase with a higher initial gland volume [69]. Moreover, oral administration of the P. alba dry rhizome extract to pediatric patients resulted in a decrease in thyroid size
and a normalization of thyroid function [70]. In another clinical trial, the efficacy of a P. alba extract (roots
and rhizomes) was investigated in 100 patients with subclinical autoimmune thyroiditis,
i.e., 74 patients (group 1) had subclinical hypothyroidism (characterized by an elevated
TSH level with a normal free thyroxine level), and 26 patients (group 2) had subclinical
hyperthyroidism (characterized by a low or undetectable TSH level with a normal serum
free thyroxine level). All patients received 300 mg of the extract twice a day for
6 months. At the end of the study, there was a normalization of TSH levels in both
group 1 and group 2 accompanied by an improvement in general well-being. In both study
groups, a significant decrease in the volume of the thyroid gland and improvement
in the morphological structure of the thyroid tissue were observed [71].
Recently, one study described the efficiency and safety of the complex herbal formula
Tireoclean, containing P. alba rhizome extract, black chokeberry fruit, redhaw hawthorn, and sodium selenite. A
total of 60 patients with chronic autoimmune thyroiditis were enrolled equally in
the control and treatment groups. The authors found that a 3-month treatment with
the addition of the abovementioned preparation to a complex therapy had a significant
influence on the TSH and free thyroxine levels in only the subgroup with subcompensated
hypothyroidism, with values of 5.88 ± 0.56 µU/mL and 1.09 ± 0.11 pg/mL before treatment
and 4.49 ± 0.38 µU/mL and 1.21 ± 0.11 pg/mL after treatment for TSH and free thyroxine,
respectively. However, the tested preparation had no influence on the thyroid gland
volume [72]. More interestingly, in another study, a multicomponent phytopreparation (containing
80 mg of an extract of P. alba underground
parts and other extracts from underground parts of species such as Filipendula vulgaris, Genista tinctoria, and Paeonia anomala, as well as Gemmae betulae extract, Arthrospira, and a leaf extract from Corulus sp.) was administered to elderly women working in chemical factories suffering from
cardiovascular and hypothyroidism disorders. This extract combination improved the
cardiological, endocrinological, and gastroenterological symptoms of the patients
[73].
Toxicity
Despite the wide usage of white cinquefoil preparations in medicine, the full toxicological
profile has not been fully explored through studies in humans due to ethical reasons
and economic costs. However, animal rodent models are an acceptable alternative to
assess the toxicological potential of herbal formulas. Therefore, there is a need
to investigate the safety profile of P. alba due to its widespread usage. For the aerial parts of P. alba, an LD50 value of 2359.9 mg/kg b. w. was deduced based on acute toxicity testing with mice
in the dose range of 1000 – 4000 mg/kg b. w. Administration of 239 mg/kg b. w. (i.e.,
1/10 of the LD50) in a chronic 3-month toxicity study in rats showed no negative impact on the laboratory
animals, i.e., no deaths, no changes in consumption and intake of water, and no changes
to the hair. Based on these results, the authors classified the aerial part of P. alba as virtually nontoxic according to the
Organisation for Economic Co-operation and Development (OECD) classification [74]. Acute and chronic toxicity of a rhizome extract of P. alba was evaluated in mice and rats. It was found that single intraperitoneal and 3-month
chronic administration did not cause toxicity or mortality in the tested rodents [75], [76]. For an extract prepared from the underground parts of P. alba with a mixture of ethanol and water, an LD50 value of 6500 mg/kg b. w. was determined in male and female rats [33].
Immunotoxicity studies revealed that the dry rhizome extract from white cinquefoil
at a dose of 50 mg/kg b. w. had no negative impact on humoral, cellular, or macrophage
immunity in the two mouse breeds. Furthermore, a study revealed that P. alba rhizome extract at a dose of 3 mg/kg b. w. administered to albino guinea pigs stimulated
the primary humoral response. Moreover, the tested sample had no sensitizing effect
in either systemic or active skin anaphylaxis or delayed hypersensitivity [77]. Moreover, the application of an extract of white cinquefoil (underground parts)
to mice treated with the cytostatic agent azathioprine led to a decrease in the suppressive
action of the cytostatic agent on antibody formation and the indirect cellular immune
reaction, thus demonstrating the immunomodulatory effects of the extract [78]. Unfortunately, white cinquefoil preparations administered orally have a negative
impact on the ante- and postnatal rat offspring periods of development, resulting
in retardment of the ossification process occurring in the cartilaginous part of bones
of 20-day-old fetuses [79]. Furthermore, the same extract had an impact on the male rat reproductive system,
resulting in a decrease in sperm motility and Leydig cell nucleus diameters and an
increase in pyknotic nuclei and a higher number of pathological spermatozoa. Despite
these observations, the authors concluded that the extract did not significantly affect
rodent fertility or offspring development after healthy female impregnation [80].
