333
dressing,
histological,
electron
microscopic,
morphometric research methods.In the postnatal period,
there is a structural restructuring of the sinus system of
the deep cervical lymph nodes. The first is
В статье приведены данные изучения динамику
структурно - клеточных преобразований глубоких
шейныхлимфатических
узлов
у
крыс
в
неонатальном периоде (2-е, 10 суток).Материалом
исследования,
являются
экспериментальныеживотные
(крысы)
постнатального периода развития (2-х, 10-ти
дневные
крысы.
Авторами
использована
анатомическая
приправка,
гистологические,
электронно-микроскопические,
The aim of study was to evaluate the anti-
inflammatory effect of dry extract of medicinal plants
(DEMP)-Glycirrhiza glabra L., Hypericum scabrum L.,
Mediazia
macrophylla
and
ZiziphorapedicellataPazijVvedin complete Freund’s
adjuvant-induced arthritis in rats.
The preventative anti-inflammatory activity of
dry extract of medicinal plants (50 mg/kg, 100 mg/kg)
was studiedin complete Freund's adjuvant induced
arthritis model in albino rats in comparison with sodium
diclofenac (10 mg/kg) and Articure (100 mg/kg). The
induction of adjuvant induced arthritis (AIA) was
carried out by subplanetary injection of 0.1 ml complete
Freund's adjuvant.
It has been shown that DEMP had a significant
anti-inflammatory effect on the development of
adjuvant-induced arthritis in its preventive using. The
right paw increased by 161,5 and 148,0% at the 3
rd
day
of observationin animals treated with DEMP in doses
50 and 100 mg/kg,,respectively. The percentage of
inhibition in groups were 38,2% and 45,6%. At 14
th
day
of formed under the capsular sinus, then the cerebral
sinuses and, last of all, the intermediate ones, which
reflects the dynamics of changes in the transport
function of the lymph nodes.
морфометрические методы исследования. В
постнатальном периоде происходит структурная
перестройка синусной системы глубоких шейных
лимфатических узлов. Первым формируется под
капсульный синус, затем мозговые синусы и в
последнюю очередь - промежуточные, что
отражает динамику изменения транспортной
функции лимфатических узлов.
experiment, the right paw increased by 197,4% and
169,3% in comparison with initial volume of paw,
respectively. The percentage of inhibition were
27,5%and 39,8%, respectively.In its effectiveness in
the prevention of the development of adjuvant- induced
arthritis, DEMP is clearly superior to Articure and not
inferior to sodium diclofenac.
Inflammation, arthritis,
dry extract, Freund's adjuvant
Rheumatic diseases aroused the interest of the
medical community from ancient times and continue to
occupy a significant place in modern medicine.
Rheumatoid arthritis (RA) is an autoimmune diseases
characterized
by
the
systemic
inflammation
accompanied
by
synovial
tissue
hyperplasia
(proliferation and fibrosis of synovial cells), structural
destruction of cartilage, bones and ligaments. It is
considered that the main mediators of RA formation are
pro-inflammatory cytokines, such as TNF-a IL-1b and
there is no complete clarity on the aetiology and
pathogenesis of this disease. It has not been discovered
an effective therapeutic medicines with
Ахадова 3.A., Акрамова М.Ю.
СТРУКТУРНОЕ СТРОЕНИЕ ГЛУБОКИХ ШЕЙНЫХ ЛИМФАТИЧЕСКИХ УЗЛОВ В РАННЕМ
ПОСЛЕНАТАЛЬНОМ ПЕРИОДЕ КРЫС, РОЖДЕННЫХ ОТ МАТЕРИ, НАХОДЯЩИХСЯ НА
НОРМАЛЬНОМ ПИТАНИИ
Ключевые слова:
морфология шейных лимфатических узлов, экспериментальные работы,
экспериментальные животные, крысы.
Khakimov Z.Z., Rakhmanov A.Kh.,Mavlanov Sh. R., Sharipov A.M., Mamatkulov B.B., Akhmatalieva M.A.,
Mamatkulov I.B.
ANTI-INFLAMMATORY ACTION OF DRY EXTRACT OF MEDICINAL PLANTS IN ADJUVANT
INDUCED ARTHRITIS IN RATS
Inter-institutional Research Laboratory, Tashkent medical academy;
Department of pharmacology and clinical pharmacy, Tashkent medical pharmaceutical institute;
Tashkent Pediatric Medical Institute
П
ос
вя
щ
ае
тс
я
к
1
00
-л
ет
и
ю
с
о
дн
я
р
ож
де
н
и
я
п
ро
ф
ес
со
р
а
К
ар
и
м
а
С
ул
ей
м
ан
ов
и
ч
а
С
ул
ей
м
ан
ов
а
ПЕДИАТРИЯ
low toxicity [1]. The clinical course of the experimental
model of RA in rats is similar to chronic autoimmune
inflammation of human joints [2]. This model is
characterized by reliable, rapid onset of arthritis and
progression with persistent manifestations of
polyarthritis, bone resorption and increasing of
proliferation of the periosteal zone [1]. Earlier, we
found that dry extract of medicinal plants (DEMP)
consisting mix of Hypericum scabrum L., Mediazia
macrophylla,
Glycyrrhiza
glabra
L.
and
ZiziphorapedicellataPazijVved had a high anti-
inflammatory effect and its efficacy was not inferior
comparing with diclofenac sodium which is a typical
representative of the group of non-steroidal anti-
inflammatory drugs [3,4,5]. However, studies on the
effectiveness of DEMP in RA have not been
investigated, which served as the basis for the present
experimental study.
Materials and methods Plant
Dry extract of medicinal plants was obtained
from plants: Hypericum scabrum L., Mediazia
macrophylla,
Glycyrrhiza
glabra
L
and
ZiziphorapedicellataPazijVved.
Aerial
parts
of
Hypericum perforatum L., ZiziphorapedicellataPazij et
Vved. and Mediazia macrophylla as well as root and
rhizome parts of Glycyrrhiza glabra L. were collected in
summer of 2018 from foothills to medium zones of
mountains of Tashkent region, Fergana, Samarkand and
Surkhandaryo regions of Uzbekistan by researchers
Institute of Botany of Science Academy of Uzbekistan.
Preparation of extract
Plant material was dried under dark conditions
at room temperature for 10 days. Taking into account
that the soil is contained various bacterial spores, raw
material of plants were treated with special methods.
The dry material was milled, obtaining 4-6 mm particles
and mixed in proportion 1,25:1,0:1,25:1,5 (productivity
of dried extract was higher than other proportions) then
extracted by water at 93-95 °С temperature for 3 hours.
The extract was then separated from the sample residue
by filtration through filter paper. The resulting extracts
were concentrated in vacuum until remaining a crude
solid extract, which was then dried in a thermostat at
temperature of 60 ° C.
Animals
mature albino rats - males with an
initial weight of 140-160 g which were obtained from
the animal organization. Animals were housedin
standard vivarium conditions, quarantined for at least
12-14
days.
Each experimental group consisted of 6-7 animals. The
rats were maintained on standard pelleted diet and
water. Approval for the research was obtained from the
Ethics Committee of Health Ministry of the Republic of
Uzbekistan for experimental studies. All experiments
were carried out in compliance with the requirements of
the European Convention "On Protection of vertebrate
animals used for experimental and other scientific
purposes" (Strasbourg 1986).
Experiment
The induction of adjuvant induced arthritis
(AIA) was carried out by subplanetaryinjection of 0.1
ml complete Freund's adjuvant (CAF) (Chondrex, Inc.,
USA), which contains killed mycobacteria H37RA at a
concentration of 2 mg/ml suspended in oil designed to
reproduce AIA in rats [6]. It is known that an adjuvant
can be introduced into the base of the tail or into one of
the paw pads [7], which makes possible to study the
acute inflammatory reaction at the injection site, as well
as the immunological reaction, which develops after
about 9 days in the contralateral paw and various
organs. The developed oedema in hind paw was
monitored from the very first day to 15 days. In order to
study the preventative effect of DEMP in AIA, the
animals were divided into several groups and DEMP
were administered orally once a day in doses of 50 and
100 mg/kg, diclofenac sodium -10 mg/kg and Articure
-100 mg/kg for 14 days. Next day after the last
administration, blood samples were taken for
hematological studies.
Measurement of the volume of the hind paw of
the animals was carried out by the oncometric method
with plethysmometer (ugo basile, Italy) before and 3, 7,
10, 14 days after the injection of PAF. The percentage
of inhibition of inflammation was calculated by formula
as follows:
Percentage of inhibition=(V
0
-V
t
)
control
- (V
0
-V
t
)
treated
/
(V
0
-V
t
)
control
Х 100 = %.
Where, V
0
is initial volume of paw and V
t
volume of paw
after injection CAF.
Along with this, the preventive effect of the studied
medicines was evaluated in points at the indicated terms
of study.
Statistical analysis
The results were expressed as mean± standard
error of the mean (M±m). Statistical processing
performed by using standard software package Biostat
2009. Differences between means were assessedby the
Student’s t-test. P<0.05 was considered significant.
Results
The results of experimental studies showed that
the injection of Freund's adjuvant provoked an
expressed inflammatory process in rats. Already on the
3rd day after immunization, the rats became lethargic,
aggressive, inactive, the hair of animals became dull,
disheveled, and feed intake decreased. A significant
increase of the volume of rat’s paw was observed. So,
the volume of the right paw, into which
П
ос
вя
щ
ае
тс
я
к
1
00
-л
ет
и
ю
с
о
дн
я
р
ож
де
н
и
я
п
ро
ф
ес
со
р
а
К
ар
и
м
а
С
ул
ей
м
ан
ов
и
ч
а
С
ул
ей
м
ан
ов
а
The experiments were carried out on sexually
house of Republican sanitary and epidemiology
335
CAF was injected, increased by 268% on the 3rd day of
the experiment, and the left paw increased only by
19.0%. The increase of observation days did not lead to
a significant difference in the volume of the left paw
compared with the 3rd day’s observation period.
However, the volume of the CAF injected paw
increased by 276% by the end of the 14th day of
observation (table 1).
So, in rats treated with diclofenac sodium, the
right paw increased by 117.0% after 3 days from the
start of the experiment and the percentage of inhibition
was 55,4%.At the end of the 14th day, it increased by
132.0% and the percentage of inhibition was 51.7%.
The volume of the left paw (control) and intervertebral
joints remained unchanged.
Table 1
Effect of DEMP on paw arthritis induced by complete Freund’s adjuvant
Values expressed as mean ± SEM, n= 6 in each group*P<0.05compared with control.
Groups
leukocytes,
10
9
/l
lymphocytes,
10
9
/l
Absolute count
of mix of
monocytes,
basophiles,
eosinophiles
10
9
/l
Granulocytes,
10
9
/l
Hemoglobin,
г/л
Erythrocytes,
10
12
/l
Platelets, 10
9
/l,
PLT
Trombokrites %,
PCT
Intact
16,17±0,78
8,09±1,08
1,43±0,36
5,71±0,16
141,3±2,1
7,21±0,09
419,7±60,2
0,337±0.04
Control
28,71±1,85
15,61±1,40
2,20±0,63
6,06±1,0
138,3±4,1
6,72±0,17
542,7±25,2
0,387±0,034
Diclofenac
10 mg/kg
21,91±1,02* 11,82±0,87*
2,01±0,37
5,95±2,2
142,8±4,5
6,08±0,2
449,2±14,7*
0,361±0,033
DEMP
50 mg/kg
22,81±0,89*
13,35±0,47
2,13±0,16
6,1±1,2
139,3±2,5
6,45±0,12
472,7±15,5*
0,377±0,02
DEMP 100
mg/kg
21,61±0,89* 12,15±0,47*
2,01±0,16
5,99 ±1,2
149,3±2,5
6,05±0,12
492,5±15,5*
0,347±0,02
Articure 100
mg/kg
24,61±1,14
13,97±0,37
2,04±0,37
6,75±1,2
147,7±4,6
6,91±0,45
435,9±82,4*
0,348±0,06
Table 2
Effect of DEMP on hemogram in rats with the Freund’s adjuvantinduced arthritis
Values expressed as mean ± SEM, n= 6 in each group*P<0.05compared with control.
Groups
Volume of paw, sm
3
Absolute volume of paw/inflammation
Initial
3
rd
day
7
th
day
10
th
day
14
th
day
Right
Left
Right
Left
Right
Left
Right
Left
Right
Left
Control
0,76±0,0
2
0,75±0,0
2
2,8±0,36
2,04±0,35
0,89±0,05
0,15±0,04
2,45±0,19
1,68±0,18
0,88±0,03
0,13±0,03
2,61±0,1 3
1,84±0,1
1
0,83±0, 03
0,08±0, 03
2,86±0,11
2,11±0,10
0,98±0,04
0,23±0,04
Diclofenac Sodium
10 mg/kg
0,78±0,0
1
0,79±0,0
1
1,69±0,09*
0,91±0,10*
1,55±0,07
*
0,78±0,07
*
1,55±0,07*
0,77±0,07
0,81±0,02
0,02±0,02
1,81±0,0 2
1,02±0,0 2
0,87±0, 03
0,09±0, 03
1,81±0,07
*
1,02±0,07
0,79±0,01
0,01±0,01
*
DEMP, 50 mg/kg 0,78±0,0
1
0,79±0,0
1
2,04±0,06*
1,26±0,06
0,81±0,01 0
0,01±0,00
5
2,13±0,10*
1,35±0,09
0,87±0,04
0,07±0,04
1,96±0,1 6*
1,18±0,1 5*
0,78±0, 02
0,02±0,
02*
2,32±0,16
*
1,53±0,15
*
1,10±0,21
0,30±0,21
DEMP, 100 mg/kg 0,75±0,0
3
0,77±0,0
1
1,86±0,11*
1,11±0,09*
0,82±0,02
0,05±0,02
*
2,08±0,11*
1,33±0,12
0,79±0,02 0
0,03±0,00
7
1,92±0,2
1*
1,17±0,2
2*
0,79±0,
003
0,03±0,
010
2,02±0,19
*
1,27±0,20
*
1,01±0,14
0,24±0,13
Articure,
100 mg/kg
0,73±0,0
1
0,75±0,0
1
2,01±0,07*
1,28±0,07
1,02±0,03
*
0,27±0,04
2,01±0,11*
1,28±0,11
0,92±0,05
*
0,17±0,06
2,0±0,14
*
1,27±0,1
4*
0,95±0,
04*
0,19±0, 04
2,15±0,15
* 1,43±0,15
0,86±0,04
*
0,10±0,03
П
ос
вя
щ
ае
тс
я
к
1
00
-л
ет
и
ю
с
о
дн
я
р
ож
де
н
и
я
п
ро
ф
ес
со
р
а
К
ар
и
м
а
С
ул
ей
м
ан
ов
и
ч
а
С
ул
ей
м
ан
ов
а
We noted a similar direction of changes in animals
treated with DEMP in doses 50 and 100 mg/kg, in which
the right paw increased by 161,5 and 148,0% at the 3rd
day of observation,respectively. The percentage of
inhibition in groups were 38,2% and 45,6%. At 14th day
of experiment, the right paw increased by 197,4% and
169,3% in comparison with initial volume of paw,
respectively. The percentage of
inhibition were 27,5%and 39,8%, respectively. There
were minor changes in the left paw of rats. Unlike other
preparations, in the group of rats treated with Articure,
the increase of paw volume was preserved in a degree
similar to animals of control group. It should be noted
that effectiveness of DEMP was superior to Articure,
especially at a dose of 100 mg/kg.
ПЕДИАТРИЯ
336
Itis known thatthe presence of a chronic
inflammatory process in animals is evidenced by the
corresponding changes in hematological parameters.
Indeed, it can be seen from the table 2 that there were
marked leukocytosis with an increase of the absolute
content of lymphocytes by 93.0%, a mixture of
macrophages, eosinophils and basophils by 54.0% on
14thday of observation of the development of AIA. It is
characteristic that the number of granulocytes did not
undergo significant changes. However, the absolute
platelet count increased by 30.0%. It is seen that with
RA, the immune system undergoes significant changes,
as indicated by lymphocytosis. In contrast, in animals
preventively receiving diclofenac sodium, the number
of leukocytes decreased by 24.0%, but remained high
by 35.4% compared with intact animals. We noted
similar changes in animals treated with DEMP,
especially at a dose of 100 mg/kg.It should be noted that
under the influence of Articure, a decrease of
leukocytosis
in treated animals was accompanied by a decrease of the
absolute content of lymphocytes and a decrease of the
mixture of macrophages, basophils and eosinophils.
The data in the table 2 indicate that the effectiveness of
DEMP and diclofenac sodium are not significantly
different and their effect significantly exceed Articure.
It was characteristic that the elimination of leukocytosis
and lymphocytosis was accompanied by a decrease of
the absolute number of platelets and thrombocritin
treated rats in contrast to untreated animals. Given that
leukocytosis, and with autoimmune diseases and
lymphocytosis, are objective indicators of the
inflammatory process, the results indicate a high
efficiency of the studied drugs in preventing the
development of AI.
Discussion
Rheumatoid arthritis is very common (about
1% of the population suffers) chronic autoimmune,
systemic disease with an unfavorable outcome. It is
characterized by lesions of the synovial membranes of
the joints, its hyperplasia and a rapid increase of the
volume of synovial tissue with progressive destruction
of cartilage and bone tissue. Adjuvant- induced arthritis
(AIA) is one of the main experimental models used to
test substances for the treatment of rheumatoid arthritis
(RA). The similarities between AIA and human RA are
the presence of edema on the joints, cartilage
degradation, lymphocytic infiltration of the inflamed
tissue of the joints, the loss of their function, in addition,
bone and periosteum resorption is observed [8]. The
AIA model is T-cell dependent and complement
independent [9,10,11,12]. The increased content of
TNF, INFc, and interleukins such as IL-1, IL-6, and IL-
17A were found in the lymphatic nodes and (or)
inflamed joints of rats with AIA [13,14]. The inhibition
of TNF, IL-1, IL-21, and IL-17A in rats with AIA
improves the course of the disease, which indicates the
role of these cytokines in the pathogenesis of
experimental arthritis [15,16,17]. Experimental models
induced in laboratory animals are widely used to study
new substances which is a valuable tool for studying
potential medicines for treatment of this pathalogy
[18,19,20].
Consequently, subplantary injection of CAF
led to the development of a chronic inflammatory
process of the joints, which manifested by the expressed
increase of the volume of the injected paw, as well as
other joints.The expressed oedema of the soft tissues of
the paw were noted as well as there were swelling of the
affected joints areas, such as interphalangeal,
metatarsophalangeal,
ankle
and
knee.
Local
temperature increased. A significant decrease of active
and passive movements of knee was observed in
experimental rats and there was severe pain on palpation
(the animal was aggressive and pulled its paw).
The preventative administration of DEMP as
well as diclofenac sodium had a noticeable effect on the
course of arthritis. So, lesion of joints developed later in
the experimental group of animals and the severity of
the joint syndrome decreased. In this case, the increase
of dose of the preparations led to the increase of the
noted positive effect. Therefore, the preventive use of
studied preparations have the same focus of effect- they
prevent the development of autoimmune arthritis.
It should be noted that the anti-edematous effects of
DEMP are comparable with the corresponding effect of
diclofenac sodium.
From the above data, it is clear that there is a
direct dependence of the severity of the joint syndrome
on time of the onset of the disease. The preventative
introduction of DEMP, as well as diclofenac sodiumhad
a noticeable effect on the course of arthritis. So, arthritis
in the treated group’s animals started later, the severity
of the articular syndrome was less, which was clearly
noticeable with an increase of the dose of preparations.
To conclude, the presented data allow us to
assume that DEMP has aexpressed positive effect on the
course of AIA, especially at a dose of 100 mg/kg, while
it was not inferior to the reference non-steroidal anti-
inflammatory drug diclofenac sodium.
П
ос
вя
щ
ае
тс
я
к
1
00
-л
ет
и
ю
с
о
дн
я
р
ож
де
н
и
я
п
ро
ф
ес
со
р
а
К
ар
и
м
а
С
ул
ей
м
ан
ов
и
ч
а
С
ул
ей
м
ан
ов
а
Acknowledgement
The work was supported by National grant PZ -20170926458
337
References
1.
Orlovskaya IA, Tsyrendorzhiev DD, Schelkunov SN. Rheumatoid arthritis: laboratory models of the
disease. Medical Immunology. 2015;(17)3:203-210.
2.
Valeeva IKh, Titarenko AF, Khaziakhmetova VN, Ziganshina KT. Xymedon antioxidant activity in a
model of chronic autoimmune inflammation. Experimental and Clinical Pharmacology. 2016;(79)1:33-37.
3.
Khakimov ZZ, Rakhmanov AKh, Mavlanov ShR. Study of the Influence of Dry Extract of Medicinal
Plants on the Course of Carrageenan-Induced. Inflammation. American Journal of Medicine and Medical Sciences.
209;(9)8:307-310.
4.
Khakimov ZZ, Rakhmanov AKh, Mavlanov Sh R et al. Influence of flavonoids containing extract from
medicinal plants to the course os aseptic inflammation. American Journal of Medicine and Medical Sciences.
2018;(8)11:291-294.
5.
Khakimov ZZ, Rakhmanov AKh, Mavlanov ShR. A comparative study of the effect of diclofenac sodium,
LIV-52 and dry extract of medicinal plants on the proliferative phase of inflammation. Medical Journal of
Uzbekistan. 2018;5:64-66.
6.
Allison A, Byars A. An adjuvant formulation that selectively elicits the formation of antibodies of
protective isotypes and of cell-mediated immunity. J. Immunol. Methods. 1986;95:157-168.
7.
Kopieva T.N. Pathology of rheumatoid arthritis. M.: Medicine. 1980:208.
8.
Bendele A. Sustained blood levels of interleukin-1 receptor antagonist in animal models of ar thritis.
Arthritis Rheum. 1999;42:498-506.
9.
Issekutz T, Miyasaka M, Issekutz A. Rat blood neutrophils express very late antigen 4 and it mediates
migration to arthritic joint and dermal inflammation. J Exp Med. 1996;183:2175-2184.
10.
Linton S, Morgan B. Complement activation and inhibition in experimental models of arthritis. Mol
Immunology. 1999;36:905-914.
11.
Santos L.Anti-neutrophil monoclonal antidiv therapy inhibits the development of adjuvant arthritis. Clin
Exp Immunology. 1997;107:248-253.
12.
Yoshino S. Suppression and prevention of ad juvant arthritis in rats by a monoclonal antidiv to the a / b
T cell receptor. Eur. J. Immunology. 1990;20:2805-2808.
13.
Ayer L. Cytokine mRNA in the joints and draining lymph nodes of rats with adjuvant arthritis and eff ects
of cyclosporine A. Inflammation. 2000;24:447-461.
14.
Bush K. Cytokine expression on and synovial pathology in the initiation and spontaneous resolution phas
es of adjuvant arthritis: inter-leukin-17 expression is upregulated in early disease. Clin. Exp. Immunol.
2001;123:487-495.
15.
Bush K. Reduction of joint inflammation and bone erosion in rat ad-juvant arthritis by treatment with
interleukin-17 receptor IgG1 Fc fu-sion protein. Arthritis Rheum. 2002;46:802-805.
16.
Feige U. Anti-interleukin-1 and anti-tumor necrosis factor-a synergistically inhibit adjuvant arthritis in
Lewis rats. Cell. Mol. Life Sci. 2000;57:1457-1470.
17.
Young D. Blockade of the interleukin-21 interleukin-21 receptor pathway ameliorates disease in animal
models of rheumatoid arthritis. Arthritis Rheum. 2007;56:1152-1163.
18.
Voleeva IKh, Titarenko A F, Khaziakhmetova VN, Ziganshina LE. Xymedon antioxidant activity in a
model of chronic autoimmune inflammation. Experimental and Clinical Pharmacology. 2016;(79)1:33-37.
19.
Ivanova E A, Matyushkin AI, Voronina TA. The effect of hemanthan in a dosage form for external use on
the inflammatory process caused by Freund's complete adjuvant in rats. Experimental and Clinical Pharmacology.
2019;(82)4:23-27.
20.
Gromyko M V, Gritsuk AI. Experimental models of rheumatoid arthritis. Problems of Health and Ecology
(Gomery State Medical University). 2012;(2)32:115-118.
21.
Икрамов, А. И., et al. "Методическое руководство «Медицинские основы физического воспитания
и спорта в формировании гармонично-развитого поколения»." Ташкент,«Узбекистон (2011).
22.
Акрамова, Х. А., and Д. И. Ахмедова. "Характерные особенности плацентарного фактора роста при
задержке внутриутробного развития плода." Педиатрия 3-4 (2014): 29-31.
23.
Ahmedova, D. I., and Rahimjanov Sh A. Growth. "development of children. Methodical recommendation."
(2006): 3-82.
24.
Хакимова, Г. Г., А. А. Трякин, and Г. А. Хакимов. "Применение ниволумаба при раке толстой кишки
с синдромом Линча. Клиническое наблюдение." Злокачественные опухоли 10.1 (2020): 41-48.
П
ос
вя
щ
ае
тс
я
к
1
00
-л
ет
и
ю
с
о
дн
я
ро
ж
де
н
и
я
п
ро
ф
ес
со
р
а
К
ар
и
м
а
С
ул
ей
м
ан
ов
и
ч
а
С
ул
ей
м
ан
ов
а
