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Acute and chronic antiinflammatory profile of the ivy plant, Hedera helix, in rats

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Hedera helix is a plant well-known as ivy or English ivy, and a member of the Araliaceae family. In the present study, we tested the possible antiinflammatory effects of a crude saponin extract (CSE) and a saponin's purified extracts (SPE) of Hedera helix in carrageenan- and cotton-pellet-induced acute and chronic inflammation models in rats. Both the CSE and SPE of Hedera helix were found to have antiinflammatory effects. The most potent drug screened was indomethacin (89.2% acute antiinflammatory effect), while the most potent extract screened was the CSE of Hedera helix at 100 and 200 mg/kg body wt. doses with 77% acute antiinflammatory effects. For testing chronic antiinflammatory (antiproliferative) effects, the cotton-pellet-granuloma test was conducted. Indomethacin was found to be the most potent drug in the chronic phase of inflammation, with 66% effect. The SPE of Hedera helix was more potent than the CSE in its chronic antiinflammatory effect (60% and 49%, respectively).
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Phytomedicine
Acute and chronic antiinflammatory profile
of the ivy plant, Hedera helix, in rats
H. Süleyman1, V. Mshvildadze2, A. Gepdiremen1, and R. Elias3
1Atatürk University, Medical Faculty, Department of Pharmacology, Erzurum, Turkey
2Institute of Pharmacochemistry, Tbilisi, Georgia
3Laboratory of Pharmacognosy and Homeopathy, Pharmacy Faculty of Mediterranean University, Marseille, 13385 Marseille,
France
Summary
Hedera helix is a plant well-known as ivy or English ivy, and a member of the Araliaceae family. In
the present study, we tested the possible antiinflammatory effects of a crude saponin extract (CSE)
and a saponin’s purified extracts (SPE) of Hedera helix in carrageenan- and cotton-pellet-induced
acute and chronic inflammation models in rats. Both the CSE and SPE of Hedera helix were found
to have antiinflammatory effects. The most potent drug screened was indomethacin (89.2% acute
antiinflammatory effect), while the most potent extract screened was the CSE of Hedera helix at
100 and 200 mg/kg body wt. doses with 77% acute antiinflammatory effects. For testing chronic
antiinflammatory (antiproliferative) effects, the cotton-pellet-granuloma test was conducted.
Indomethacin was found to be the most potent drug in the chronic phase of inflammation, with
66% effect. The SPE of Hedera helix was more potent than the CSE in its chronic antiinflammato-
ry effect (60% and 49%, respectively).
Key words: Inflammation, antiinflammatory, Hedera helix, ivy plant, carrageenan, cotton pellet, rats
0944-7113/03/10/05-370 $ 15.00/0
Introduction
Inflammatory diseases are treated currently with
steroidal and nonsteroidal antiinflammatory drugs
(NSAIDs). NSAIDs exert their effects by inhibiting the
metabolism of arachidonic acid by both cyclooxyge-
nase and lipoxygenase enzyme pathways (Insel, 1996).
Despite their widespread use, NSAIDs are often asso-
ciated with severe adverse effects, the most common
being gastrointestinal bleeding (Fung and Kirschen-
baum, 1999). Because of these effects, safer com-
pounds are needed.
Hedera helix is well-known as ivy or English ivy,
and is a member of the Araliaceae family. The fresh
leaves and fruits are toxic, causing gastrointestinal irri-
tation, bloody diarrhea and death (Baytop, 1984). Its
best-known effect is to cause contact dermatitis, and
several cases have been reported (Garcia et al. 1995,
Massmanian et al. 1988, Hausen et al. 1987). Addition-
ally, antibacterial (Cioaca et al. 1978), antihelmintic
(Julien et al. 1985), leishmanicidic (Majester-Savornin
et al. 1991), in-vitro antispazmodic (Trute et al. 1997)
and antifungal (Moulin-Traffort et al. 1998) effects of
Hedera helix extracts have been reported.
To investigate the effects of drugs on the acute phase
of inflammation, models induced by pro-inflammatory
agents such as carrageenan, dextrane, formaldehyde,
serotonin histamine and bradykinin in rat paws are em-
ployed (Campos et al. 1995). Chronic inflammation
models produced by implanting a foreign body under
the skin are used to study the effects of a drug on the
proliferation phase of inflammation (Gilman et al.
1985, Süleyman et al. 1999). Carrageenan, a mu-
copolysaccaride, is perhaps the most commonly-used
Phytomedicine 10: 370–374, 2003
©Urban & Fischer Verlag
http://www.urbanfischer.de/journals/phytomed
Antiinflammatory effects of Hedera helix 371
and well-studied of these phlogistics (Leme et al.
1973), producing a maximal edematous in 3 h. While
the carrageenan model is typically associated with acti-
vation of the cyclo-oxygenase pathway and is sensitive
to glucocorticoids and prostaglandin synthesis antago-
nists, the early phase of the carrageenan response is due
to the release of serotonin and histamine (DiRosa et al.
1971).
In the present study, we tested the possible antiin-
flammatory effects of the crude saponin extract (CSE)
and the saponin’s purified extracts (SPE) of Hedera
helix in the carrageenan- and cotton-pellet-induced
acute and chronic inflammation models in rats.
Materials and Methods
Hedera helix
The leaves of Hedera helix were collected in Marseille,
France, in September 1999. The material was identified
by Riad Elias, a staff member of Laboratory of Phar-
macognosy and Homeopathy, Pharmacy Faculty of the
Mediterranean University, Marseille, France.
Hedera helix extract
The materials were shade-dried. One kg of crushed
plant leaves were extracted three times with seven
liters of 80% EtOH. After evaporation of the organic
solvent, the aqueuos phase was treated with one liter of
CHCl3four times, and then with one liter of BuOH
three times. The BuOH was evaporated and the residue
was dried in a vacuum oven at 50 °C. The yield of CSE
was 100 g for Hedera helix. The obtained CSE was dis-
solved in 400 ml of MeOH and precipitated in 2 liters
of acetone. After filtration, the residue was dried in a
vacuum oven at 50 °C. The yield of SPE was 80 g for
Hedera helix. Both extracts contain mono- and bi-
desmoside triterpene glycoside derivatives of oleanolic
acid and hederagenin, as described previously (Elias
et al. 1991).
Animals
In this study, 66 adult male Wistar albino rats weighing
180–210 g each, obtained from Atatürk University,
Faculty of Medicine, Department of Pharmacology Ex-
perimental Animal Laboratory, were used. The rats
were fed standard laboratory chow and tap water be-
fore the experiment. The animal laboratory was
equipped with automatic temperature (22 ± 1 ºC) and
lighting controls (14 hours light/10 hours dark). Rats
were divided into groups, each containing 6 individuals
and each of the groups were kept in different cages.
The ethical guidelines for investigations using con-
scious animals were obeyed and the procedures were
approved by the University ethics committee.
Antiinflammatory Studies
Antiinflammatory effects of CSE and SPE of Hedera
helix were investigated in an aseptic arthritis model,
which was induced by carrageenan and cotton-pellet-
granuloma tests in subsequent doses. The ratio of the
antiinflammatory effects of Hedera helix extracts were
calculated using the following equation: Antiinflam-
matory activity (%) = (1 – D/C) · 100 where D repre-
sents the percentage difference in paw volume after the
compounds were administered to the rats, and C repre-
sents the percentage volume difference in the control
group (Süleyman et al. 1999).
Carrageenan-induced paw edema in rats
Hedera helix CSE and SPE in 50, 100 and 200 mg/kg
body wt. doses, and indomethacin 20 mg/kg body wt.
doses were given to rats orally by feeding tube once
daily for 4 days. Two h after final administration of the
compounds, 0.1 ml (1%, w/v) carrageenan solution in
distilled water was injected subcutaneously into the
plantar surface of the right hind paw. The paw volume
was measured using a plethysmometer: before injec-
tion and 5 times at 1-h intervals (Birch et al. 1992). The
antiinflammatory activity in animals receiving Hedera
helix extracts was compared with that in indomethacin
and control groups.
Cotton-pellet-granuloma test
In this series, the effects of Hedera helix extracts and
indomethacin on the proliferation phase of inflamma-
tion were studied using a cotton-pellet-granuloma test.
Doses of 100 mg/kg body wt. CSE; and 100 mg/kg
b
ody wt. SPE of Hedera helix, and of 20 mg/kg body wt.
indomethacin were administered orally to 3 groups
separately. The same volume of distilled water (1 ml)
was administered to the control group. After 30 min,
the animals were anesthetized with 25 mg/kg thio-
penthal sodium, intraperitoneally. Under sterile condi-
tions, cotton pellets, weighing 7 mg each, were im-
planted an interscapular distance under the skin. The
same doses of Hedera helix extracts and indomethacin
were administered once a day for a period of 7 days.
The rats were killed by a higher dose of thiopenthal
sodium on the eighth day, and the pellets surrounded by
granuloma tissues were dissected out. The moist pellets
were weighed and then dried at 70 ºC, after which, they
were weighed again and the antiproliferative effect of
Hedera helix extracts compared with the control and
indomethacin groups.
Statistical analysis
Values are presented as mean ± SEM. Independent
samples-t test and analysis of variance (ANOVA, Dun-
net method) were used for the evaluation of data and
p < 0.05 was accepted as statistically significant.
372 H. Süleyman et al.
Results
Despite the fact that they have weaker antiinflammato-
ry effects than indomethacin, both CSE and SPE of
Hedera helix were found to have antiinflammatory ef-
fects. For the acute phase of inflammation, car-
rageenan-induced paw-volume increase, and the ef-
fects of the indomethacin and Hedera helix extracts
were evaluated. Because of the most potent effect was
seen in the fourth hour, prior to others, statistical data
for that period was regarded to evaluate acute antiin-
flammatory effect. The most potent drug was found to
be indomethacin (89.2% acute antiinflammatory ef-
fect) while the most potent extract was found to be
CSE of Hedera helix at doses of 100 and 200 mg/kg
body wt., with 77% acute antiinflammatory effects.
The same drug in a dose of 50 mg/kg body wt. exerted
a 51% antiinflammatory effect. For the SPE of Hedera
helix, acute antiinflammatory effects of 41.5% for 50,
60% for 100 mg/kg doses and 67.7% for 200 mg/kg
doses were found. For further information, please refer
to Table 1.
For testing chronic antiinflammatory (antiprolifera-
tive) effects, the cotton-pellet-granuloma test was con-
ducted. Indomethacin was found to be the most potent
drug in the chronic phase of inflammation, with 66%
effect. The SPE of Hedera helix was found to be more
potent than the CSE in terms of chronic antiinflamma-
tory effect, at 60% and 49%, respectively. For further
information, please refer to Fig. 1.
Discussion
Triterpene saponins of Hedera helix have already been
tested in several applications. Buddlejasaponin’s and
saikosaponin’s in-vivo antiinflammatory effects on
mouse ear edema (Bermejo-Benito et al. 1998) and
zanhasaponin’s acute and chronic antiinflammatory ef-
fects in different models (Cuellar et al. 1997) have been
reported. For the first time in the literature, we have
demonstrated the antiinflammatory effects of Hedera
Table 1. The effects of CSE (Crude saponin extract) and SPE (Saponin’s Purified Extract) of Hedera helix in subsequent
doses and indomethacin (Indomet.) in carrageenan-induced acute paw edema.
Drugs Dose n Right paw volume (ml ×100)
mg/kg
body wt. Before 1 h 2 h 3 h 4 h 5 h
Vehicle 6 77 ± 2.5 104 ± 6.4* 134 ± 2.1**** 139 ± 2.7**** 142 ± 1.7**** 140 ± 1.6****
Indomet. 20 6 101 ± 2.9 112 ± 3* 110 ± 2.4* 109 ± 2.1 108 ± 4.1 105 ± 3.7
CSE 50 6 112 ± 1.6 113 ± 1.4 129 ± 4.5* 142 ± 3.1**** 145 ± 3.2**** 156 ± 5.1****
CSE 100 6 117 ± 3.2 128 ± 3.2* 130 ± 4.5* 131 ± 4.4* 132 ± 5.1* 129 ± 5.1
CSE 200 6 113 ± 3.1 113 ± 3.6 119 ± 4.4 126 ± 4* 128 ± 3.3** 124 ± 3.4*
SPE 50 6 110 ± 1.3 115 ± 2.5 150 ± 3.2**** 149 ± 4.4**** 149 ± 6.5* 146 ± 5.7****
SPE 100 6 115 ± 4 123 ± 3 137 ± 3.3*** 139 ± 3**** 141 ± 4.2**** 138 ± 4***
SPE 200 6 113 ± 1.3 130 ± 3.6*** 147 ± 4.8**** 136 ± 2.4**** 134 ± 1.7**** 130 ± 2****
*p < 0.05, **p < 0.01, *** p < 0.005 and ****p < 0.001 in respect to the values “before injection” for each group.
Fig. 1. The effects of indomethacin (20 mg/kg body wt.),
Hedera helix CSE (Crude saponin extract) and SPE (Sapon-
in’s Purified Extact, 100 mg/kg body wt. for both) on granu-
loma tissue formation induced by the cotton-pellet-granulo-
ma test. *p < 0.001.
Antiinflammatory effects of Hedera helix 373
helix due to mono and bidesmoside triterpene glyco-
sides. Despite the fact that they have weaker antiin-
flammatory potential than indomethacin, in all of the
groups tested, we found quite effective antiinflamma-
tory action. The CSE of Hedera helix was more potent
than the SPE form in the acute phase, while the SPE
form showed better results than the CSE form of Hed-
era helix in the chronic phase of inflammation.
It was reported that the antiinflammatory effects of
several agents result in the partial inhibition of inflam-
mation-mediator release (Amadio et al. 1993). Subcu-
taneous injection of carrageenan into the rat paw pro-
duces plasma extravazation (Szolcsanyi et al. 1998),
and inflammation characterized by increased tissue
water and plasma protein exudation with neutrophil ex-
travazation and metabolism of arachidonic acid by
both cyclooxygenase and lipoxygenase enzyme path-
ways (Gamache et al. 1986). There are biphasic effects
in carrageenan-induced edema. The first phase begins
immediately after injection and diminishes in 1 h. The
second phase begins at 1 h and remains through 3 h
(Garcia-Pastor et al. 1999). It is suggested that the early
hyperemia of carrageenan-induced edema results from
the release of histamine and serotonin (Kulkarni et al.
1986). Both Hedera helix extracts and indomethacin
started to block inflammation in the first measurement.
So it seems possible that Hedera helix blocks histamine
and/or serotonin release in the first phase of acute in-
flammation. On the other hand, the delayed phase of
carrageenan-induced edema results mainly from the
potentiating effect of prostaglandins on mediator re-
lease, especially of bradykinin. Hydrocortisone and
some NSAIDs inhibit strongly the second phase of car-
rageenan-induced edema, but some others are effective
against both phases (Kulkarni et al. 1986). In the light
of these data and Table 1, Hedera helix extracts seem
more effective in the first phase of acute inflammation
than in the second phase. Therefore, Hedera helix ex-
tracts may block histamin and/or serotonin release bet-
ter than the prostaglandin and/or bradykinin.
It was also observed that both extracts of Hedera helix
are effective in chronic inflammation, despite the fact
that the effect was not strong as indomethacin. Chronic
inflammation is a reaction arising when the acute re-
sponse is insufficent to eliminate proinflammatory
agents, and induces a proliferation of fibroblasts and the
infiltration of neutrophils and exudation (Dunne, 1990).
Chronic inflammation occurs by means of the develop-
ment of proliferative cells. NSAIDs cause a decrease in
granuloma tissue arising as a result of cellular reaction,
released by inhibiting granulocyte infiltration to the for-
eign body implanted (Ionac et al. 1996). According to
the chronic inflammation model of the cotton pellet, the
Hedera helix SPE and CSE may exert their effects by in-
hibiting the functions of macrophages and fibrosis.
The results of the present study show that Hedera
helix CSE and SPE are potent inhibitors of acute and
chronic inflammation. The mechanism of the effect
may depend on inhibition of the formation of several
inflammation mediators. Detailed studies are needed to
clarify the mechanism(s) of the antiinflammatory ef-
fects of Hedera helix triterpene saponins.
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Address
H. Süleyman, Atatürk University, Medical Faculty, De-
partment of Pharmacology, TR-25240 Erzurum, Turkey
Tel.: ++90-442-2361212/2423; Fax: ++90-442-2360968;
e-mail: suleyman@atauni.edu.tr
... It has been reported that H. colchica has similar chemical content in terms of secondary metabolite groups and contains high levels of hederacholchiside F (Mshvildadze et al. 2000;Gepdiremen et al. 2004;Getia et al. 2015). The acute anti-inflammatory effects of the extract of H. helix leaves prepared with 80% ethanol and the saponin fraction prepared from these extracts were demonstrated with different test models (Süleyman et al. 2003;Rauf et al. 2014). The acute anti-inflammatory effects of saponins obtained from H. helix leaves were examined in a carrageenan-induced claw edoema test, and it was observed that both compounds were ineffective in the first phase of acute inflammation. ...
... Previous studies have reported that extracts from H. helix showed stronger anti-inflammatory activity compared to compounds isolated from the plant. Products standardised according to the saponin content of the plant are used in treatment (Süleyman et al. 2003;Şöhretoğlu 2017;Barnes et al. 2020). ...
... In previous studies, the anti-inflammatory activity of H. helix extracts, fractions, and isolated secondary metabolites has been noted in different experimental models (Süleyman et al. 2003;Park et al. 2009;Shan et al. 2009;Rai 2013;Rauf et al. 2014). The leaf ethanol extract of H. helix, phenolic-rich fraction, and saponin-rich fraction of the same extract inhibited COX-1 with IC 50 values of 301.1 ± 2.2, 273.5 ± 2.9, and 500 ± 3.3 µg/mL, and COX-2 enzyme with IC 50 values of 3.36 ± 0.8, 1.5 ± 0.09, and 7.4 ± 0.3 µg/mL, respectively, whereas the IC 50 values for COX-1 and COX-2 enzymes for celecoxib were 248.9 and 0.26 µg/mL, respectively. ...
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This study aimed to evaluate the potential of Hedera colchica as an alternative to Hedera helix species for the treatment of mild inflammatory conditions of the upper respiratory tract and chronic inflammatory bronchial diseases. The H. colchica extract with the highest saponin content (C3S; 468.19 ± 16.01 mg HE/g dry weight) and the extract with the highest total phenol content (C1F; 108.60 ± 5.61 mg GAE/g dry weight). Chemical analysis and standardisation of the extract with the highest selective COX-2 inhibitory effect was performed using the LC-MS/MS technique. It was determined that the substances found in the highest ratio in the C1F extract were quinic acid (45.909 µg/g extract) and hesperidin (37.077 µg/g extract). As a result, secondary metabolites, in addition to saponins, found in Hedera species may also contribute to the extract's effectiveness, more potent extracts can be obtained compared to the total extract-containing preparations available in the market.
... Le second composé d'intérêt dans la racine de la griffe du diable est le verbascoside ( Figure 9) qui possède des propriétés antioxydantes [91] [87]. contre, il a été rapporté que le lierre a des propriétés antispasmodiques [92], anti-inflammatoires [93], antiallergiques [94] et des effets antiarthritiques [95]. ...
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Cette étude se déroule en deux parties, la première partie est consacrée à la mise en place d’une méthodologie dans le but d’isoler les métabolites secondaires. La seconde partie décrit les propriétés phytochimiques de poudres issues de matrices végétales en fonction de leur granulométrie. Dans la première partie, qui est consacrée à l’isolement de métabolites secondaires par HPLC semi-préparative, la mise en place du processus d’isolement de l’hédéracoside C et l’α-hédérine, a été effectuée à partir d’extraits de parties aériennes du lierre (Hedera helix L.). La généralisation de ce processus d’isolement appliqué aux extraits de parties aériennes du millepertuis (Hypericum perforatum L.) a permis d’isoler avec succès un hypéroside qui est un des flavonoïdes marqueur du millepertuis. Le but de cette deuxième partie est dans un premier temps, de valider le procédé de broyage et de tamisage du matériel végétal : PTC « Pulvérisation & Tamisage différentiel Contrôlés » à l’échelle industrielle pour la production de différentes classes granulométriques des poudres. A cet effet, les résultats d’analyses phytochimiques de classes granulométriques de neuf plantes de la Région Lorraine obtenues par PTC à l'aide d’un pilote industriel sont comparés à ceux obtenus à l’échelle du laboratoire. Les plantes sélectionnées snot : le fenouil (Foeniculum vulgare Mill.), le saule blanc (Salix alba L.), le millepertuis (Hypericum perforatum L.), l’ortie (Urtica dioica L.), la solidage (Solidago virgaurea L.), la piloselle (Hieracium pilosella Vaill.), le rosier des chiens (Rosa canina L.), la griffe du diable (Harpagophytum DC.) et le lierre (Hedera helix L.). L’évaluation de l’activité antioxydante ainsi que les analyses effectuées par LC-MS indiquent que la production des poudres à l’échelle du laboratoire est généralisable à l’échelle industrielle.Par ailleurs, pour la première fois, l’application à quatre fruits : la cerise (Prunus avium L.), la pêche (Prunus persica L.), la quetsche (Prunus domestica subsp. Insititia L.) et la mirabelle (Prunus domestica subsp. Syriaca) de la Région Lorraine du procédé PTC à l’échelle du laboratoire montre que l’extraction par voie sèche est une nouvelle méthode pour enrichir certaines classes granulométriques en composés bioactifs.
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Hedera helix L. (family Araliaceae) is classified as a conventional plant used as a medicinal product in the cure and prevention of upper respiratory tract inflammation and infection due to its secretolytic and broncholytic effects. Our research was conducted to authenticate the anti-inflammatory effect of ivy leaves extract in the prevention of acute lung injury (ALI) caused by intranasal administration of lipopolysaccharides (LPS). In-vitro antimicrobial, anti-inflammatory, and anti-oxidant were evaluated, in addition to the in-vivo acute lung inflammation model induced by LPS in mice. The animals were divided into seven groups randomly (each group containing 10 mice): control negative (saline only), control positive (LPS group), standard (Dexamethasone 2 mg/kg), ethanolic ivy leaves extract (EIE, 100 mg/kg), ethanolic ivy leaves extract (EIE, 200 mg/kg), saponin rich fraction (SRF, 100 mg/kg) and phenolic rich fraction (PRF,100 mg/kg). Right lungs were homogenized to determine the levels of SOD, MDA, catalase, IL-10, TNF-α, NO, IL-1β, IL-6, PGE2, and MPO. Left lungs were excised for histopathology and histomorphometry. Immunohistochemistry of Cox-2 and TNF-α levels were measured. Additionally, Western blotting was used to determine the levels of phosphorylated MAPK. The data showed that the oral supplementation with EIE, 200 mg/kg significantly (P<0.05) decreased the pro-inflammatory mediators, and oxidative stress biomarkers induced by LPS. Interestingly, the phenolics showed promising activity, therefore they are responsible for the action. The ethanolic extract was also standardized through HPLC analysis for its content of rutin. In conclusion, the standardized ivy leaf extract could be advised for acute lung injury for its antimicrobial, anti-oxidant, and anti-inflammatory activities.
... This model causes an inflammatory response which occurs in two phases: the first phase occurs within the first hour post carrageenan-injection followed by the second phase which lasts beyond three hours post injection (Garcia-Pastor et al., 1999). The first phase involves the release of histamine and 5HT while the second phase is dependent on the release of proinflammatory mediators such as prostaglandin E2 (Kulkarni et al., 1986;Suleyman et al., 2003). Like celecoxib, the extract of UG was effective against both phases of carrageenan-induced inflammation. ...
... Furthermore, its leaves are also widely used to relieve neuralgic pain, heal ulcers and burns (Chiummariello et al., 2009). It is reported that both the crude extract and the purified extract of saponins of Hera leaves have antiinflammatory effects (Gepdiremen et al., 2005;Suleyman et al., 2003). The compounds having biological activity, responsible for the medicinal use of hera, as saponins (2.5 -6%), glycosides (0.1-4.8%), the hederin (0.1 -0.3%), and phenolic compounds (phenolic acids, flavonoids, anthocyanins, coumarins), amino acids, steroids and lectins (Gepdiremen et al., 2005) are described. ...
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28-29 октомври 2021 г. Медицински колеж към Медицински университет-Плевен Българска Първо издание Издание в електронен вид на CD © Издателски център на МУ-Плевен ISBN 978-954-756-266-0
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