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STUDYING THE MECHANISM OF ACTION OF SOME CHEMICAL
COMPOUNDS WITH ANTI-INFLAMMATORY PROPERTIES
Sh.М.Маkhsumov
1
, О.А. Zaytseva
2
,
G.Yu. Djanaev
3
1
Associate professor, Pharmacology department, Tashkent Medical Academy,
Email:
, Uzbekistan.
2
Associate professor, Pharmacology department, Tashkent Medical Academy,
Email:
, Uzbekistan.
3
Senior Lecturer, Department of Pharmacology, Tashkent Medical Academy, Tashkent,
Uzbekistan
,
Email:
, Uzbekistan.
Abstract.
Nonsteroidal anti-inflammatory drugs belong to the most widely used medications.
This work is devoted to studying the effect of benzoic acid derivatives diphenyl-/bis-
(benzoyloxy)/-silone and 1,4-bis-(bromobenzoyloxy)-butyne-2 on the exudative and
proliferative phases of inflammation. Experiments conducted on animals showed that the
mechanism of the anti-inflammatory action of the studied chemical compounds is associated
with inhibition of the exudative and proliferative phases of the inflammatory process.
Key words:
inflammation, anti-inflammatory effect, analgesic effect, antipyretic effect,
benzoic acid derivative, mechanism of anti-inflammatory action, antiexudative effect,
antiproliferative effect, antiallergic effect.
Introduction.
The process of inflammation, being one of the central links in the
pathogenesis of many diseases, is protective in nature, however, in some cases the
inflammatory reaction has a negative effect on the div, which requires
pharmacotherapeutic intervention. Increasing the effectiveness of pharmacotherapy for
diseases whose pathogenesis involves an inflammatory process is one of the most important
problems of modern medicine. Currently, clinical medicine has a large range of anti-
inflammatory drugs belonging to various classes of compounds. However, many of these
drugs do not meet the requirements of clinicians due to the insufficient therapeutic effect
they cause, frequent adverse events and serious complications. Analysis of literature data
shows that undesirable side effects of non-steroidal anti-inflammatory drugs are less
pronounced and occur more favorably than those of steroidal anti-inflammatory drugs.
Nonsteroidal anti-inflammatory drugs have a universal and unique combination of analgesic
and anti-inflammatory effects for this class of drugs, which explains their leading place in
modern medicine. The role of drugs of this pharmacological group in the practice of a doctor
of any specialty is difficult to overestimate, however, this is what creates the main difficulty
in choosing an adequate drug in each specific case. Nonsteroidal anti-inflammatory drugs
are a class of pharmacological agents whose therapeutic activity is associated with
preventing the development or reducing the intensity of inflammation. Currently, there are
more than fifty dosage forms differing in chemical structure, classified as non-steroidal anti-
inflammatory drugs, which in turn are divided into several main subclasses. Despite the
huge variety of non-steroidal anti-inflammatory drugs, they remain one of the most popular
drug groups. For this reason, the search and study of new highly active and low-toxic anti-
inflammatory drugs among various classes of chemical compounds of non-steroidal
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structure is more appropriate and remains a very pressing problem in practical medicine
[1,2,3,4,5,6].
Objectives of the work.
Studying the anti-inflammatory activity of diphenyl-(bis-
(benzoyloxy))-silane in various models of aseptic arthritis, as well as studying the effect of
this compound on the exudative and proliferative phases of inflammation in comparison
with known anti-inflammatory drugs, such as voltaren, indomethacin and butadione. Study
of the anti-inflammatory, analgesic, antipyretic, antiallergic effects of 1,4-bis-
(bromobenzoyloxy)-butine-2.
Material and research methods.
A study of the anti-inflammatory effect of benzoic acid
derivatives - diphenyl-(bis-(benzoyloxy))-silane and 1,4-bis-(bromobenzoyloxy)-butyne-2 -
was carried out on white rats weighing 150-200 g. For comparison, well-known anti-
inflammatory drugs were used - voltaren (10 mg/kg), indomethacin (15 mg/kg) and
butadione (100 mg/kg). The anti-inflammatory effect of the studied chemical compounds
was studied in well-known models of arthritis caused by formaldehyde, carrageenan,
serotonin, histamine and dextran. Phlogogenic agents were injected in an amount of 0.1 ml
into the dorsal surface of the aponeurosis of the rat ankle joint [7,8,9,10].
The anti-inflammatory activity of the drugs was determined by the difference in the
volume of the paws of control and experimental animals. The test compounds were
administered orally in the form of suspensions in 3% starch paste 48, 24 and 2 hours before
the administration of phlogogenic agents at doses of 50, 100 and 150 mg/kg. Control
animals received an equal volume of starch paste. The volume of the paws was measured at
different time intervals depending on the nature of the phlogogenic agent.
The effect of the compounds on the exudative phase of inflammation was studied in a
model of aseptic peritonitis caused by the introduction of a silver nitrate solution into the
abdominal cavity. The drugs were administered orally 48, 24 and 2 hours before the
administration of silver nitrate. The anti-inflammatory activity of the drug was assessed by
the difference in the amount of exudate in control and experimental animals.
The effect of drugs on the exudative-proliferative phase of inflammation was studied
using the “cotton ball” method. The drugs were administered before implantation and once
within 7 days after implantation of cotton balls. On the eighth day, the animals were killed,
cotton balls were removed and their wet weight was determined, then dried at a temperature
of 70
o
C to constant weight and weighed again in dry form.
When studying diphenyl-(bis-(benzoyloxy))-silane, the technique proposed by Selye was
also used: after introducing an irritant into the cavity of the air sac under the skin of the rat’s
back, a pocket granuloma appears. The study drug was administered orally in doses of 50,
100 and 150 mg/kg for 7 days, once a day. On the eighth day, the pocket granuloma was
separated, the exudate was sucked out with a syringe, it was weighed to a constant weight
and weighed in dry form, the volume of exudate in the bag and the total protein content in it
were determined.
The effect of 1,4-bis-(bromobenzoyloxy)-butine-2 on pain sensitivity was studied in rats
using the method of A.K.Sangailo. The antipyretic effect of the drug was studied on white
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laboratory mice against the background of preliminary administration of a standard solution
of pyrogenal. The antiallergic effect of this chemical compound was studied in guinea pigs
using the generally accepted method [11,12,13,14,15,16,17,18].
The resulting digital material was subjected to statistical processing using the standard
software package using the well-known method of variation statistics with assessment of the
significance of indicators and differences in the samples under consideration using the
Student’s t-test.
Research results and discussion.
A study of the anti-inflammatory effect of diphenyl-(bis-(benzoyloxy))-silane showed its
high activity in various aseptic arthritis. Thus, this chemical compound had a pronounced
inhibitory effect on the course of formaldehyde arthritis, starting with small doses. The drug
at a dose of 50 mg/kg suppressed the development of the inflammatory process by 40.3%;
with an increase in dose to 100 and 150 mg/kg, a significant increase in the effect was noted
by 47.3% and 52.8%, respectively. Whereas, in the formaldehyde edema model, comparison
drugs reduced edema as follows: voltaren by 38.4%, indomethacin by 36.1% and butadione
by 27.3%. Consequently, the drug under study turned out to be more active and superior to
voltaren, indomethacin, and butadione.
A comparison of the data presented in Table 1 shows that the drug under study is
noticeably superior to the comparison drugs in its ability to suppress inflammation caused by
various phlogogenic agents.
Table 1
Effect of diphenyl-(bis-(benzoyloxy))-silane, voltaren, indomethacin and butadione on
inflammation caused by various phlogogenic agents
(at P<0.05)
A drug
Dose,
mg/kg
Numbe
r
of
animals
in the
group
Inhibition of inflammation (%) caused
Formalin Corragenine Seroton
in
Histami
ne
Dextra
n
Diphenyl-(bis-
(benzoyloxy))-
silane
50
10
40,9
39,1
38,0
37,3
36,2
Diphenyl-(bis-
(benzoyloxy))-
silane
100
10
47,9
46,3
46,1
45,4
44,1
Diphenyl-(bis- 150
10
52,8
51,9
50,3
50,8
49,8
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(benzoyloxy))-
silane
Voltaren
10
10
38,4
40,9
38,2
39,4
38,2
Indomethacin
15
10
36,1
35,3
33,4
35,8
35,6
Butadion
100
10
27,3
28,1
25,0
26,9
26,1
A study of the anti-inflammatory effect of 1,4-bis-(bromobenzoyloxy)-butine-2 revealed
its high activity in various types of aseptic arthritis. The drug had a pronounced inhibitory
effect on the course of formaldehyde arthritis, starting with small doses: at a dose of 50
mg/kg it suppressed the development of the inflammatory process by 48.1%. With an
increase in dose to 100 and 150 mg/kg, an increase in effect was observed by 53.5% and
59.8%, respectively. Whereas in this model, voltaren at a dose of 10 mg/kg suppressed the
development of the inflammatory process by 40.1%, indomethacin at a dose of 15 mg/kg -
by 40.1%, and butadione at a dose of 100 mg/kg - by 28.4%. Consequently, the drug under
study is more active and exceeds voltaren and indomethacin by 1.5 times, butadione by 2.5
times.
To fully characterize the anti-exudative effect of the first test drug, experiments were
conducted to study its effect on the amount of exudative fluid in the abdominal cavity of rats
with intraperitoneal administration of 1 ml of 0.2% silver nitrate solution.
It was noted that in animals of the control group after administration of silver nitrate, the
amount of exudative fluid averaged 2.3 ± 0.04 ml, and in rats that had previously received
the drug, it was less. Thus, when the drug was administered at a dose of 50 mg/kg, the
amount of peritoneal fluid averaged 1.4±0.02 ml, and at doses of 100 and 150 mg/kg -
1.31±0.03 ml and 1.25±0 .04 ml respectively. This means that the drug reduced the
formation of exudative fluid at a dose of 50 mg/kg by 39.2%, at a dose of 100 mg/kg by
43.1%, and at a dose of 150 mg/kg by 45.7%. The formation of peritoneal fluid was also
suppressed under the influence of known anti-inflammatory drugs. Thus, with the
introduction of butadione, the amount of peritoneal fluid decreased compared to the control
by 26.1%, and with indomethacin and voltaren by an average of 32.2% and 34.8% (Table 2).
Table 2
Effect of diphenyl-(bis-(benzoyloxy))-silane, voltaren, indomethacin and butadione on
aseptic peritonitis caused by silver nitrate in rats (at P<0.05)
A drug
Number
of
animals in the
group
Dose, mg/kg Amount
of
exudate in the
abdominal
cavity in ml
Antiexudative
effect in %
Control
10
-
2,3 ±0,04
0
Diphenyl-(bis-
(benzoyloxy))-
10
50
1,4 ±0,02
39,2
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silane
Diphenyl-(bis-
(benzoyloxy))-
silane
10
100
1,31 ±0,03
43,1
Diphenyl-(bis-
(benzoyloxy))-
silane
10
150
1,25 ±0,04
45,7
Voltaren
10
10
1,5 ±0,04
34,8
Indomethacin
10
15
1,56 ±0,03
32,2
Butadion
10
100
1,7 ±0,04
26,1
These data indicate that the drug has a fairly pronounced anti-exudative activity and in
this ratio is approximately 1.7 times higher than butadione, 1.4 and 1.3 times higher than
indomethacin and voltaren, respectively.
When studying the effect of the second drug under study on the exudative phase of
inflammation, a decrease in the amount of fluid in the abdominal cavity was noted compared
to the control; in this indicator, 1,4-bis-(bromobenzoyloxy)-butyne-2 is 2 times superior to
the comparison drugs.
Thus, analysis of the data obtained allows us to conclude that benzoic acid derivatives:
diphenyl-/bis-(benzoyloxy)/-silone and 1,4-bis-(bromobenzoyloxy)-butyne-2 are quite active
in terms of anti-exudative effect, and in this significantly superior to comparison drugs:
voltaren, indomethacin and butadione.
In the next series of experiments, we studied the ability of 1,4-bis-(bromobenzoyloxy)-
butine-2 to have an inhibitory effect on the formation of granulomas during subcutaneous
implantation of “cotton balls” in rats. As can be seen from the data presented in Table 3, on
the eighth day of the experiment, the weight of wet balls in control animals was 233.9 ± 4.42
mg. This indicator in experimental rats who were orally administered the drug for seven
days was equal to: at a dose of 50 mg/kg - 179.17 ± 3.11 mg, at a dose of 100 mg/kg 139.64
± 3.01 mg and at dose of 150 mg/kg – 127.7±2.88 mg. Consequently, the activity of
diphenyl-(bis-(benzoyloxy))-silane was 23.4% at a dose of 50 mg/kg, and 40.3% and 45.4%
at doses of 100 mg/kg and 150 mg/kg, respectively. Under similar conditions, voltaren,
indomethacin and butadione inhibited exudative impregnation of granulation tissue around
cotton balls by 24.9%, 22.4% and 16.5%, respectively. Consequently, the drug under study
has a more pronounced anti-exudative effect than voltaren, indomethacin and butadione.
Table 3
The influence of diphenyl-(bis-(benzoyloxy))-silane, voltaren, indomethacin and
butadione on the weight gain of wet and dry cotton swabs after
7 day subcutaneous implantation
A drug
Dose Numb Wet
Reductio Р
Weight
Reductio Р
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,
mg/k
g
er of
animal
s
in
the
group
weight of
granulatio
n tissue,
mg
n in the
weight of
wet
granulati
on tissue
compare
d
to
control
in %
of
granulati
on tissue
after
drying
n in the
weight of
dry
granulati
on tissue
compare
d
to
control
in %
Контроль
-
10
233,9±4,4
2
0
-
33,9±3,1
8
0
-
Diphenyl-
(bis-
(benzoyloxy
))-silane
50
10
179,17±3,
11
23,4
<0,0
5
25,12±2,
06
25,9
<0,0
5
Diphenyl-
(bis-
(benzoyloxy
))-silane
100
10
139,64±3,
01
40,3
<0,0
5
19,63±2,
01
42,1
<0,0
5
Diphenyl-
(bis-
(benzoyloxy
))-silane
150
10
127,7±2,8
8
45,4
<0,0
5
17,83±1,
65
47,4
<0,0
5
Voltaren
10
10
175,66±3,
09
24,9
<0,0
5
25,15±2,
68
25,8
<0,0
5
Indomethaci
n
15
10
181,5±3,1
8
22,4
<0,0
5
26,01±2,
74
23,2
<0,0
5
Butadion
100
10
195,3±3,9
1
16,5
<0,0
5
28,0±2,9
1
17,4
<0,0
5
This drug had a clear inhibitory effect on the development of granulomas according to the
Selye method. This effect of the drug at doses of 50, 100 and 150 mg/kg was expressed by a
decrease in the weight of the wet granuloma sac by 60.1%, 50.3%, 47.5%, respectively, and
the dried one - by 48.1%, 40.8%, 39 .0%. The effectiveness of voltaren, indomethacin and
butadione was slightly lower. At the same time, voltaren reduced the weight of the wet
granuloma sac by 61.4% and dry by 53.5%, and indomethacin and butadione, respectively,
by 64.8% and 56.4%, by 74.3% and 65.4% (Table 4).
Table 4
Effect of diphenyl-(bis-(benzoyloxy))-silane, voltaren, indomethacin and butadione on
the weight of the granuloma sac in exudative inflammation
according to Selye (P<0.05)
A drug
Dose,
mg/kg
Number of
animals in
the group
Wet sac weight
Dry sac weight
г
%
г
%
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Control
-
10
3,142±0,11 100
2,12±0,09
150
Diphenyl-(bis-
(benzoyloxy))-
silane
50
10
1,911±0,08 60,8
1,02±0,04
48,1
Diphenyl-(bis-
(benzoyloxy))-
silane
100
10
1,580±0,06 50,3
0,865±0,04 40,8
Diphenyl-(bis-
(benzoyloxy))-
silane
150
10
1,486±0,05 47,3
0,827±0,03 39,0
Voltaren
10
10
1,929±0,08 61,4
1,134±0,07 53,5
Indomethacin
15
10
2,036±0,08 64,8
1,196±0,06 56,4
Butadion
100
10
2,334±0,09 74,3
1,386±0,07 65,4
The drug under study reduces the intensity of the development of exudative phenomena.
This is evidenced by a decrease in the volume of exudate in the granuloma sac. If the
volume of exudate in the granuloma sac in animals of the control group averaged 6.3 ± 0.3
ml, then in experimental animals that were administered the first test drug, the amount of
exudate in the granuloma sac was 4.4 ± 0.15 ml, 3. 9±0.1 ml and 3.1±0.12 ml according to
the administered doses. At the same time, the effectiveness of voltaren, indomethacin and
butadione was slightly lower: the volume of exudate in the granuloma sac upon
administration of voltaren was 4.4±0.21 ml, and for indomethacin and butadione 4.6±0.22
and 4.9±0.24 ml respectively.
Thus, the studies have convincingly shown that the studied chemical compound diphenyl-
(bis-(benzoyloxy))-silane exhibits a pronounced anti-inflammatory effect, which is
expressed by a significant decrease in the mass of the granuloma sac (wet and dry) and the
amount of exudate in it. According to these indicators, it is superior to Voltaren,
indomethacin and butadione.
In the next series of experiments, the effect of 1,4-bis-(bromobenzoyloxy)-butine-2 on the
pain sensitivity threshold of animals was studied. First, the pain sensitivity threshold was
determined in all male rats, then the animals were divided into four groups. The first group
is the control group. Animals in this group were administered a suspension of 3% starch
paste. Rats of the second group were administered the study drug at a dose of 50 mg/kg, the
third - at a dose of 100 mg/kg, and the fourth - at a dose of 150 mg/kg. Pain sensitivity was
measured every 30 minutes for 5 hours. During the experiments, it was found that the
threshold of pain sensitivity in animals in the control group remained the same as before the
introduction of a suspension of 3% paste, while the drug at a dose of 50 mg/kg increased the
threshold of pain sensitivity by 42.3% compared to the initial level. As the dose of the drug
increased, an increase in the threshold of pain sensitivity was observed.
Consequently, the drug under study quite significantly increases the threshold of pain
sensitivity in rats.
An increase in div temperature is one of the main components of the inflammatory
process and occurs as a result of destructive changes in tissue, which leads to the formation
and entry into the general bloodstream of protein breakdown products, polysaccharides, etc.
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In this regard, studying the effect of the drug on the div temperature of animals is of
particular interest. In the first series of experiments, the effect of the drug on the temperature
of intact animals was studied. Analysis of the results showed that the div temperature of
animals in the control group, which were administered a starch suspension, fluctuated during
the observed period by only 0.1-0.2 degrees. In experimental mice, after administration of
the drug, a tendency to a decrease in div temperature was observed within 30 minutes.
Thus, the drug at a dose of 50 mg/kg caused a decrease in div temperature by 0.5 degrees,
at a dose of 100 mg/kg - by 0.6 degrees, and at a dose of 150 mg/kg - by 0.7 degrees Celsius.
The duration of action of the drug was 3-4 hours.
In the second series of experiments, the effect of the drug on the div temperature of
animals that had previously received pyrogenal was studied. In all experimental animals,
approximately 2 hours after the administration of pyrogenal, an increase in div temperature
of 2.3-2.5 degrees Celsius was noted. Subsequent administration of the drug after 30
minutes caused a decrease in div temperature. This effect gradually increased and reached
its maximum 2-3 hours after administration of the drug.
Thus, in animals, 3 hours after administration of the drug at a dose of 50 mg/kg of
weight, a decrease in div temperature was observed, at a dose of 100 mg/kg - by 1.6-1.7
degrees, and at a dose of 150 mg/kg - by 1. 9-2.0 degrees. Then a gradual decrease in the
div temperature of the animals was observed almost to normal.
Therefore, based on the data obtained, we can conclude that the drug, under
conditions of a febrile reaction caused by the administration of pyrogenal, clearly lowers the
div temperature of animals, that is, it has a pronounced antipyretic effect.
A study of the antiallergic effect of the drug under study showed that 1,4-bis-
(bromobenzoyloxy)-butine-2 exhibits an antiallergic effect, which is manifested by a mild
course of anaphylactic shock and a decrease in the number of dead animals. Thus, if in the
control group, after the introduction of a permissive dose of horse serum, 10 (100%) out of
10 guinea pigs died, then when the drug was administered at a dose of 50 mg/kg, 8 (80%)
out of 10 died, and at doses of 100 and 150 mg/kg kg - 7 (70%) out of 10 and 6 (60%) out of
10, respectively.
Thus, the successful combination of anti-inflammatory, analgesic, antipyretic and
antiallergic properties of the drug makes it promising in the treatment of various
inflammatory diseases, including those with an allergic component.
Conclusions:
1. Diphenyl-/bis-(benzoyloxy)/-silone and 1,4-bis-(bromobenzoyloxy)-butyne-2 are highly
active anti-inflammatory drugs and are superior in their activity to comparison drugs.
2. The drug under study, 1,4-bis-(bromobenzoyloxy)-butine-2, exhibits analgesic, antipyretic
and antiallergic effects.
3. Diphenyl-[bis-(benzoyloxy)]-silone and 1,4-bis-(bromobenzoyloxy)-butyne-2 are of some
theoretical and practical interest as potential anti-inflammatory drugs.
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