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MINISTRY OF EDUCATION AND TRAINING

MINISTRY OF

DEFENCE

MILITARY INSITUTE OF TRADITIONAL MEDICINE

LE THI MINH PHUONG

Antioxidant and anti-atherosclerTiC effects
of Ich tri vuong soft capsule in experimental
and clinical trial
Speciallized: Traditional Medicine
Code: 62720201

DOCTORS OF PHILOSOPHY DISSERTATION SUMMARY


HANOI – 2019
The Work has been successfully completed at:

MILITARY INSITUTE OF TRADITIONAL MEDICINE
Suppervisers:
1. Assoc. Prof, Ph.D. DO THI PHUONG
2. Assoc.Prof, Ph.D. NGUYEN TRAN THI GIANG HUONG
Opponent1: Assoc. Prof, Ph.D. Pham Quoc Binh
Opponent 2: Prof, Ph.D. Do Doan Loi
Opponent 2: Assoc. Prof, Ph.D. Vu Thi Ngoc Thanh

The Dissertation defend is scheduled to examine by Dissertation
Defense Committee of Insitute
At , ...... ...... (hour), ...../...../2019

This thesis may be found in:
1. The National Library of Vietnam
2. The Library of Military Insitute Of Traditional Medicine
3. The Library of Hanoi Medical University


DISSERTATION INCLUDING PUBLICATION

1.

Le Thi Minh Phuong, Nguyen Tran Thi Giang Huong, Do Thi
Phuong, Nguyen Thi Tuyet Nga (2018). Effect of Ichtrivuong
capsule on plasma lipid level and degree of atherosclerosis in
cholesterol - fed rabbits. Jounal of Medical Research, 111 E2 (2),
28 - 37.

2.

Le Thi Minh Phuong, Do Thi Phuong, Nguyen Tran Thi Giang
Huong (2019). Effect of Ich tri vuong capsule on carotid
atherosclerosis patients with early-onset of chronic cerebral
circulation insufficiency, Journal of Traditional Vietnamese
Medicine and Pharmacy,

3.

Le Thi Minh Phuong, Do Thi Phuong, Nguyen Tran Thi Giang
Huong (2019). Oxidative stress makers in carotid atherosclerosis
patients

with

early

onset

chronic

cerebral

circulation

insufficiency. Journal of Military Traditional Medicine and
Pharmacy, 9 (2)



INTRODUCTION
Ich Tri Vuong capsule is composed of Ginkgo biloba, Radix
Salviae miltiorrhizae, Radix Astragali membranacei and Radix
Angelicae sinensis. In recent studies, those components have effect on
atherosclerotic progression. The median lethal dose (LD50) of Ich tri
vuong had not been yet identified, and it also did not cause subchronic
toxicity in experimental animals. Ich tri vuong soft capsule increased
cerebrovascular circulation in experiment and antioxidant in invitro. In
traditional medicine (TM) theory, Ich Tri Vuong capsule is composed of
have effects of qi-promoting and phlegm-resolving, nourishing blood
and activate blood to expel wind. Those effects were used on treatment
vertigo, a common symptom of cerebrovascular flow disorder due to
carotid atherosclerosis. The research “Antioxidant and antiatherosclerotic effects of Ich tri vuong capsule in experimental and
clinical trial” was conducted with arms:
(1) To evaluate antioxidant and anti-atherosclerotic effects
on the experimental animal of Ich tri vuong soft capsule.
(2) To evaluate the effects of Ich tri vuong soft capsule on
carotid atherosclerosis patients.
The urgency of the dissertation: Carotid atherosclerosis has many
serious complications with a high rate of disability and death. Recently
there has been a rapid increse in research related to slowing the
progression of atherosclerotic cerebrovascular disease and the
treatment of the early symptoms of cerebrovascular disease. The
research has shown that these herbal medicines in the component of
Ich tri vương had many effects on the pathogenesis of atherosclerosis.
So that, Ich tri vương has a potential to use in the treatment early
symptoms and prevent progression of atherosclerosis.
New contributes of dissertation:
- The research assessing effects of Ich tri vương soft capsule, an
traditional medicine agent, that component base on traditional
medicine theory and the results of pharmacology researchs.
- The research result demonstrations the treatment effect and the
safety of Ich tri vuong on the patient and contributes knowledge of


its mechanism on antioxidant and anti-atherosclerosis.
- The research result contribute demonstrations to develop Ich tri
vuong soft capsule to use on treatment early symptoms and prevent
progression of atherosclerosis
CHAPTER 1: LITERATURE OVERVIEW
1.1.
WESTERN
MEDICINE
CONCEPTION
OF
ANTIOXIDANT AND ATHEROSCLEROSIS, DIAGNOSIS,
TREATMENT CAROTID ATHEROSCLEROSIS.
An excess of free radicals can lead to oxidative stress, cause
peroxidation of lipids, which promotes the formation of atherosclerosis.
The process of atherosclerosis involves deposition of low-density
lipoproteins (LDL) and its oxidation products, infiltrating chronic
inflammatory cells in tunica intima and media, and lesion calcification.
The progression of carotid atherosclerosis can lead to narrowing and
embolims of arteries, which reduce cerebrovascular blood flow, causing
symptoms of chronic cerebral circulation insufficiency and stroke.
Treatment of atherosclerosis includes cholesterol-lowering agents, antianti-platelet agents to prevent agglutination and plaque rupture,
vasodilators. Also agents with antioxidant capabilities are used for
prevention and treatment of atherosclerosis
1.2. TRADITIONAL MEDICINE CONCEPTION OF DIAGNOSIS,
TREATMENT CAROTID ATHEROSCLEROSIS
1.2.1. Traditional medicine conception of diagnosis, treatment
atherosclerosis
In TM theory, the mechanism of atherosclerosis was seen
related to the deficiency of organs in the body. That cause stagnation of
qi and blood stasis leads to stagnation of fluid and transforming fluids
into the retention of phlegm can cause blood stasis. Depending on the
main clinical symptoms, the early manifestations of carotid
atherosclerosis attributed to vertigo, headaches, and insomnia. In TM,
atherosclerosis is classified to 4 syndromes: qi and yin deficiency,
phlegm stagnation and blood stasis, qi stagnation and blood stasis and qi
deficiency and blood stasis syndrome.


1.2.2. Overview of traditional medicinal research
for antioxidant and anti-atherosclerosis in
Vietnam and other countries
The TM research into the treatment of atherosclerosis is
focused upon the seach for herbal medicines and prescriptions that affect
on the mechanisms of atherosclerosis such as: protecting blood vessels,
reducing LDL, preventing peroxide LDL, preventing infiltrating chronic
inflammatory cells in tunica intima and media. and in preventing
thrombosis.
1.3. OVERVIEW OF ICH TRI VUONG SOFT CAPSULE
1.3.1. The source and formulas of Ich tri vuong soft capsule
Ich tri vuong soft capsule formulas base on “Angelica
Decoction for Enriching Blood” (a traditional formula includes
Radix Astragali and Radix Angelicae sinensis) combined with
Radix Salviae multiorrhizae, and Ginkgo biloba. Components of Ich
tri vuong include 40 mg Ginkgo biloba extract, 150 mg extracts of
Radix Salviae miltiorrhizae, Radix Astragali membranacei, Radix
Angelicae sinensis.
1.3.2. Study components of Ich tri vuong soft capsule
- Radix Angelicae sinensis: the dry rhizome and root of Angelica
sinensis (Oliv.) Diels. Constituents: alkyl phthalides, terpenes, phenyl
propanoids, benzenoid, and coumarins. . Cardiovascular activity on the
experiment: increased coronary blood flow improving microcirculation,
inhibited platelet aggression, decreased endothelial damage, decreased
total cholesterol, triglyceride, LDL, and increased HDL blood level
- Radix Astragali: the dry rhizome and root of Astragalus
membranaceous Fish. Major chemical constituents: saponins and
polysaccharides. Cardiovascular activity on the experiment: protecting
myocardial cells, improving cardiac function, antioxidant effects,
protecting neurons, and suppressing atherosclerosis.
- Radix Salviae multiorrhizae: the dry rhizome and root of Salvia
miltiorrhiza
Bunge..
Constituents:
hydrophilic,
hipophilic.
Cardiovascular activity on the experiment: antioxidant effects, coronary
vasodilation, reduction of LDL peroxidation, and suppression of


atherosclerosis.
- Ginkgo biloba: Synonyms: the dry leaves of Ginkgo biloba Lin.
Constituents: alkane, phenylpropanoid, carbohydrate, flavonoids.
Cardiovascular activity on the experiment: vasomotor regulation,
antiplatelet aggregatoin, antioxidant effects, improvement in cerebral
blood flow, and protection of the endothelial cell.
1.3.3. The available research of Ich tri vuong soft capsule
The median lethal dose (LD50) of Ich tri vuong had not been
yet identified. It has not been known to cause subchronic toxicity on
the liver, kidney or the hematopoietic system in experimental
animals. In the experimental study, Ich tri vuong slightly increased
arterial blood pressure, cardiac contractility, peripheral
vasoconstriction, and cerebral vasodilation. It resulted in the release
of sympathetic nerve agents, increased the activated clotting time,
and protected nerve cells.
Clinical trials in healthy volunteers, revealed no adverse side
effects. In lipidemia disorder patients, Ich tri vuong had the effect on
decreasing of total cholesterol, triglyceride, LDL blood level.
1.3.4. Theory and evidence base of using Ich tri vuong on
treatment carotid atherosclerosis
Ich Tri Vuong capsule is composed of Ginkgo biloba, Radix
Salviae miltiorrhizae, Radix Astragali membranacei, and Radix
Angelicae sinensis. Recent studies shown that Ich Tri Vuong capsule
is composed of agents that have an effect on the pathology of
atherosclerosis. The effect of Ich tri vuong in the experimental study
was accordant on treatment cerebral funtion disorder related to
atherosclerosis, which is common in chronic cerebral circulation
insufficiency (CCCI) on carotid atherosclerosis patients.
CHAPTER 2: SUBJECTS AND METHODS
2.1. SUBJECTS AND METHODS OF EXPERIMENTAL
STUDY
2.1.1. Animal: New Zealand and White rabbits (both gender,
bodyweight 1.8 – 2.5 kg).
2.1.2. Material




Ich tri vuong soft capsule
Ich Tri Vuong capsule is composed of 40 mg Folium Ginkgo
biloba extract, 150 mg extract of Radix Salviae miltiorrhi zae, Radix
Astragali membranacei, Radix Angelicae sinensis, supplied by National
Institute of Drug Quality Control, stored at room temperature.
Dose 1 in rabbit: 60 mg/kg/day, dose 2 in rabbit 180 mg/kg/day
• Atorvastatin
Atorvastatin 20 mg tablet, a product of Standa Vietnam, stored
at room temperature. Dose in rabbit was 5mg/kg/day.
2.1.3. Study lab: Department of Experiment research, Military
Insitute Of Traditional Medicine
2.1.4. Method: Model of atherosclerosis in cholesterol-fed rabbits
response to OECD direction.
Rabbits were divided into 5 groups of 10. Normal group: fed
water 2 ml/kg/day. Control group: fed cholesterol oil 0.5 g/kg/day,
1ml/kg, 2 hours later fed water 2 ml/kg/day. Atorvastatin group: fed
cholesterol oil 0.5 g/kg/day, 1ml/kg, 2 hours later fed Atorvastatin
5mg/kg/day. Ich tri vuong dose 1 (60 mg/kg/day): fed cholesterol oil
0.5 g/kg/day, 1ml/kg, 2 hours later fed Ich Tri Vuong 60 mg/kg/day
(equivalent to clinical dose). Ich tri vuong dose 2 (180 mg/kg/day): fed
cholesterol oil 0.5 g/kg/day, 1ml/kg, 2 hours later fed Ich Tri Vuong
180 mg/kg/day (three time higher than clinical dose).
Weight, the plasma triglyceride, total cholesterol, highdensity lipoprotein cholesterol (HDL) and LDL were determined at
baseline (T0), after 4 weeks (T4) and 8 weeks (T8). The plasma total
antioxidant status (TAS), Malondialdehyde(MDA) and superoxide
dismustase (SOD) in red blood cell at were determined at T0 and T8.
At the end of the experiment, 30% of rabbit aorta was subsequently
collected for analysis of the aortic lesions.
2.1.5. Statistical analysis: Biomedical statistics, SPSS 16.0 software.
2.2. SUBJECTS AND METHODS OF CLINICAL TRIAL
2.2.1. Subject
Carotid atherosclerosis patients with symptom of CCCI,
voluntary participation.


2.2.1.1. Inclusion Criteria: Patients must fulfill the following
inclusion criteria to be eligible for enrolment in the study: (1) Male
or female patients, the age ≥ 45 years. (2) Presence of CCCI such as
headache, dizziness, memory loss, loss of concentration, emotional
disturbance, insomnia lasted for at least 2 months. (3) Presence of
carotid intima-media thickness (IMT) on Doppler ultrasound by IMT
≥ 0.8 mm. (4) The degree of carotid artery stenosis <50%. (5) LDL
blood ≥ 1.8 mmol / L. (6) voluntary participation.
2.2.1.2. Exclusion Criteria: Patients with signs and symptoms of
neurological degeneration, cerebral infarction, peripheral vestibular
syndrome, chronic anemia; heart valve and myocardial disease that
affected hemodynamics; cancer; fever or suffering from infectious and
infectious diseases; have acute medical conditions requiring
hospitalization/specialized treatment; surgery/injury in the previous
month; chronic liver and kidney disease; pregnant or lactating; use of
antiplatelet agents, anticoagulants, neuronal metabolism, brain
vasodilators within 4 weeks prior to starting of the study; do not taken
study medications for 3 day; do not cooperate in the research process.
2.2.2. Material
• Ich tri vuong soft capsule
Ich Tri Vuong capsule is composed of 40 mg Folium Ginkgo
biloba extract, 150 mg extract of Radix Salviae miltiorrhizae, Radix
Astragali membranacei, Radix Angelicae sinensis, supplied by National
Institute of Drug Quality Control, stored at room temperature. Dose in
the clinical trial: take 4 capsules per day, 2 at a time, after the meal.
• Atorvastatin
Atorvastatin 10 mg tablet, a product of Standa Vietnam, stored at
room temperature. Dose in clinical trial: take 1 pill daily, in the evening.
2.2.3. Time and study site: 6/2016 - 12/2016. at Traditional
Medical Hospital of Ministry of Public Security.
2.2.4. Method
2.2.4.1. Study Design: randomized clinical trial, comparative study
- Sample size: 60 patients will be randomly assigned in 1:1
- Groups:


+ Group 1: 30 patients take Ich tri vuong, 4 capsules per day, 2 at a
time, 8 am and 6 pm, for 56 days (8 weeks).
+ Group 2: 30 patients take Atorvastatin 10 mg, 1 pill daily, 8 pm,
for 56 days (8 weeks).
Patients adherence diet and exercise for cardiovascular disease.
2.2.4.2. Assessments
- Demographic data and risk: percentage of age, gender, and risk of
atherosclerosis.
- Characteristis of carotid atherosclerosis: percentage of complication,
LDL blood level, degree of carotid atherosclerosis, HIT-6 score, DHI score.
- Characteristis of traditional medicine clinical: percentage of
traditional medicine syndromes.
- Assessing antioxidant effects: compare the mean of TAS, MDA
serum, SOD red blood cell two groups at T0. T8.
- Assessing anti-atherosclerotic effects: comparing the mean of HIT6. DHI score, internal carotid artery peak systolic velocity (ICAPSV), internal carotid artery end-diastolic velocity (ICA-EDV),
internal carotid artery resistant index (ICA-RI), the serum level of
total cholesterol, trigliceride, LDL, HDL of two groups at T0. T8.
- Assessing treatment effect on TM clinical syndromes: compared the
degree improving of TM symptoms. Logistic regression of TM
syndromes and treatment results of Ich tri vuong group.
- Safety assessment: percentage of patients have adverse side effects,
comparing the mean number of blood cells. Comparing the mean of the
serum level of AST, ALT, GGT, creatinine, thrombin time at T0. T4. T8.
2.2.5. Ethic: Research protocol had approved by Research Ethics
Committee of at Traditional Medical Hospital of Ministry of Public
Sercurity, 12 december 2015.
2.2.6. Statistical analysis: Biomedical statistics, SPSS 16.0 software.
CHAPTER 3: RESULTS
3.1. ANTIOXIDANT AND ANTI-ATHEROSCLEROSIS OF
ICH TRI VUONG SOFT CAPSULE ON THE
EXPERIMENTAL STUDY
3.1.1. Antioxidant effect of Ich tri vuong soft capsule


Table 3.1: Plasma level of TAS
T0
T8
Δ (T8-T0)
Groups
n
p
± SD (mmol/L)
1 (Normal)
10 1.14 ± 0.11 1.25 ± 0.12 0.11 ± 0.10
< 0.05
2 (control)
10 1.25 ± 0.09 1.05 ± 0.10 - 0.20 ± 0.07 < 0.05
3 (atorvastatin)
10 1.12 ± 0.09 1.41 ± 0.18 0.29 ± 0.19
< 0.05
4 (Ich tri vuong dose 1) 10 1.19 ± 0.10 1.29 ± 0.04 0.11 ± 0.12
< 0.05
5 (Ich tri vuong dose 2) 10 1.14 ± 0.11 1.33 ± 0.14 0.17 ± 0.06
<0.05
p
> 0.05
< 0.05
< 0.05
p1-2 <0.05; p2-3 <0.05; p2-4<0.05; p2-5 <0.05;p3-4<0.05
p Δ (T8-T0)
p3-5 > 0.05; p4-5 >0.05
After 8 weeks, TAS of group 2 was significantly lowest (p < 0.05),
TAS increased highest in group 3, 5, 1 and 4.
Table 3.2: Red blood cell SOD activity
Δ T8-T0
T0
T8
Groups
n
p
± SD (U/gHb)
1 (Normal)
10 1268.3 ± 248 1537.4 ± 206.8 269.1 ± 364.1
<
2 (control)
10
1002.3 ±
1978.4 ± 465.7 976.1 ± 556.1
<
3 (atorvastatin )
10
1268.6 ±
1325.9 ± 190.6
57.3 ± 225.9
> 0.05
4 (Ich tri vuong dose 1) 10 1106.7 ± 153.4
1531.5 ±
424.7 ± 217.6
<
5 (Ich tri vuong dose 2) 10 1117.2 ± 116.3
1458.3 ±
341.5 ± 283.2
<
p
> 0.05
> 0.05
< 0.05
p1-2 <0.05; p2-3<0.05; p2-4<0.05; p2-5 <0.05; p3-4 <0.05;
p Δ (T8-T0)
p3-5 >0.05; p4-5 > 0.05
After 8 weeks, SOD groups 2 was significantly highest (p < 0.05), SOD
increasing level was lower in groups 4, 5, 1,3. (p < 0.05).
Table 3.3: Plasma level of MDA
Groups
n
T0
T8
Δ T8-T0
p
± SD (nmol/L)
1 (Normal)
10
0.13 ± 0.08 0.26 ± 0.07
0.13 ± 0.1
< 0.05
2 (control)
10
0.16 ± 0.08 0.25 ± 0.07 0.09 ± 0.11 < 0.05
3 (atorvastatin )
10
0.31 ± 0.11 0.25 ± 0.12 0.04 ± 0.18 > 0.05
4 (Ich tri vuong dose 10
0.2 ± 0.09
0.29 ± 0.49 0.09 ± 0.13 < 0.05
5 (Ich tri vuong dose 10
0.29 ± 0.12
0.3 ± 0.08
0.01 ± 0.13 > 0.05
p
< 0.05
> 0.05
> 0.05
After 8 weeks, MDA level of groups 1, 2, 4 was significantly increased (p <
0.05), MDA of group 3, 5 had no difference between baseline (p > 0.05).


3.1.2. Anti-atherosclerotic effect
Table 3.4: Bodyweight of rabbit
T0
T8
Groups
n
p
± SD (gr)
1 (Normal)
10
2.66 ± 0.25
2.80 ± 1.98
> 0.05
2 (control)
10
2.62 ± 0.22
2.92 ± 0.06
< 0.05
3 (atorvastatin)
10
2.85 ± 0.21
2.27 ± 0.10
< 0.05
4 (Ich tri vuong dose 1)
10
2.73 ± 0.24
2.31 ± 0.12
< 0.05
5 (Ich tri vuong dose 2)
10
2.57 ± 0.20
2.45 ± 0.16
> 0.05
p
> 0.05
< 0.05
After 8 weeks, body weight of group 2 was significantly higher than
baseline (p < 0.05), no difference in group 1 and 5 (p > 0.05),
significantly decreased in groups 3 and 4 (p < 0.05).
Table 3.5: Plasma level of total cholesterol
T0
T4
T8
Groups
n
pT0-T8
± SD (mmol/L)
1 (Normal)
1 2.73 ± 1.01 4.29 ± 5.00
3.06 ± 1.39
> 0.05
2 (control)
10 2.78 ± 1.81 21.13 ± 9.98
22.35 ± 10.31 < 0.05
3 (atorvastatin )
10 2.88 ± 1.51 10.74 ± 8.18
10.71 ± 6.17
< 0.05
0
4 (Ich tri vuong dose 1) 1 3.51 ± 1.76 23.97 ± 14.28 17.31 ± 9.56
< 0.05
5 (Ich tri vuong dose 2) 10 2.04 ± 0.68 13.91 ± 9.36
12.76 ± 7.13
< 0.05
0
p
> 0.05
< 0.05
< 0.05
After 4 and 8 weeks, total cholesterol of groups 1 had no difference (p > 0.05),
significantly increased in other groups, highest in group 2, then 4, 5, 3 (p < 0.05).
Table 3.6: Difference in total cholesterol plasma
level over 8 weeks
Δ T8-T0
Groups
n
p
X

±0.33
SD ±(mmol/L)
1 (Normal)
10
1.28
p < 0.05; p1-2 < 0.05; p22 (control)
10
19.57 ± 9.34
3 < 0.05; p2-4 > 0.05; p2-5
3 (atorvastatin )
10
7.74 ± 5.84
< 0.05; p3-4 < 0.05; p3-5 >
4 (Ich tri vuong dose 1) 10
13.81 ± 9.17
0.05; p4-5 > 0.05
5 (Ich tri vuong dose 2) 10
10.72 ± 6.77
After 8 weeks, the increasing level of total cholesterol of group 3 and 5
were equivalent and significantly lower than group 2 (p < 0.05), the
increasing level of groups 4 was equivalent to group 2 (p > 0.05).


Table 3.7: Plasma level of triglyceride
n
T0
T4
T8
Groups
pT0-T8
± SD (mmol/L)
1 (Normal)
10 0.99 ± 0.40 1.22 ± 0.46 1.06 ± 0.74 > 0.05
2 (control)
10 0.76 ± 0.34 1.81 ± 1.62 1.47 ± 0.75 < 0.05
3 (atorvastatin)
10 0.89 ± 0.49 2.01 ± 1.21 1.09 ± 0.53 > 0.05
4 (Ich tri vuong dose 1) 10 0.98 ± 0.40 2.43 ± 1.07 1.86 ± 1.03 > 0.05
5 (Ich tri vuong dose 2) 10 0.89 ± 0.26 1.90 ± 0.60 1.17 ± 0.31 < 0.05
p
> 0.05
> 0.05
> 0.05
After 8 weeks, triglyceride had no difference in group 1. 3. 5 (p > 0.05),
increased in group 2. 4 (p < 0.05)
Table 3.8: Difference in triglyceride plasma level over 8
weeks
Δ T8-T0
p
Groups
n
± SD (mmol/L)
p > 0.05; p1-2<0.05;
2 (control)
10
0.71 ± 0.77
p2-3 > 0.05; p2-4 > 0.05;
3 (atorvastatin)
10
0.23 ± 0.61
p2-5 > 0.05; p3-4 > 0.05;
4 (Ich tri vuong dose 1)
10
0.87 ± 1.25
p3-5 > 0.05; p4-5 > 0.05
5 (Ich tri vuong dose 2)
10
0.28 ± 0.47
After 8 weeks, triglyceride increased in 5 groups, but the increasing level
had no significant difference between 5 groups (p > 0.05).
Table 3.9: Plasma level of LDL
T0
T4
T8
Groups
n
pT0-T8
± SD (mmol/L)
1 (Normal)
10
2.24 ± 1.01
3.69 ± 4.40
2.35 ± 1.13 > 0.05
2 (control)
10
2.20 ± 1.60 18.55 ± 9.18 19.51 ± 9.66 < 0.05
3 (atorvastatin)
10
2.26 ± 1.31
9.35 ± 7.31
8.98 ± 5.35 < 0.05
4 (Ich tri vuong dose 1) 10
2.83 ± 1.55 21.30 ± 3.12 14.96 ± 8.58 < 0.05
5 (Ich tri vuong dose 2) 10
1.49 ± 0.51 11.96 ± 8.18 10.59 ± 6.23 < 0.05
p
> 0.05
< 0.05
< 0.05
After 8 weeks, LDL had no difference in groups 1 (p > 0.05), and
significantly increased in other groups (p < 0.05).
Table 3.10: Difference in LDL plasma level over 8 weeks
Groups
n
p
± SD (mmol/L)
1 (Normal)
10
0.12 ± 1.09
p < 0.05; p1-2<0.05; p23 < 0.05; p2-4 > 0.05; p2-5
2 (control)
10
17.31 ± 8.82


< 0.05; p3-4 > 0.05; p3-5
3 (atorvastatin )
10
6.64 ± 5.13
> 0.05; p4-5 > 0.05
4 (Ich tri vuong dose 1) 10
12.13 ± 8.27
5 (Ich tri vuong dose 2) 10
9.11 ± 6.01
After 8 weeks, LDL was significantly increased highest in group 2
and lower in group 4, group 5 and group 3 (p < 0.05).
Table 3.11: Plasma level of HDL
T0
T4
T8
Groups
n
pT0-T8
± SD (mmol/L)
1 (Normal)
10 0.49 ± 0.16 0.61 ± 0.62 0.71 ± 0.28 > 0.05
2 (control)
10 0.59 ± 0.28 2.59 ± 0.91 2.84 ± 0.69 < 0.05
3 (atorvastatin)
10 0.61 ± 0.29 1.39 ± 0.89 1.73 ± 0.83 < 0.05
4 (Ich tri vuong dose 1) 10 0.68 ± 0.26 2.68 ± 1.26 2.35 ± 1.01 < 0.05
5 (Ich tri vuong dose 2) 10 0.56 ± 0.19 1.94 ± 1.20 2.17 ± 0.94 < 0.05
p
> 0.05
< 0.05
< 0.05
After 8 weeks, HDL had no difference in groups 1(p > 0.05), and
significantly increased in other groups (p < 0.05).
Table 3.12: Difference in HDL plasma level over 8 weeks
Δ T8-T0
Groups
n
p
± SD (mmol/L)
1 (Normal)
10
0.21 ± 0.23
p < 0.05; p1-2< 0.05; p22 (control)
10
2.26 ± 0.67
3 < 0.05; p2-4 > 0.05; p2-5
3 (atorvastatin)
10
1.10 ± 0.74
> 0.05; p3-4 > 0.05; p3-5
4 (Ich tri vuong dose 1) 10
1.67 ± 0.97
> 0.05; p4-5 > 0.05
5 (Ich tri vuong dose 2) 10
1.61 ± 0.83
After 8 weeks, HDL was significantly increased highest in group 2,
the increasing level was lower in group 4, 5 and 3 (p < 0.05).
3.1.2.3. Pathological Anatomy of aortic atherosclerosis lesion
• Macros examination
After 8 weeks, all samples of group 1 and 1/3 sample of group 3 and
2/3 sample of group 5 had atherosclerotic gross lesions grade 0. 1/3
sample of group 2, group 4 and group 5 had atherosclerotic gross
lesions grade I. All sample of group 2, 2/3 sample of group 4 and 1/3
sample of group 3 had gross lesion of aortic atherosclerosis grade II.
• Histological examination
Group 1: all samples were normal. Group 2: 2/3 sample had type 5. 1/3
sample had type 4 . Group 3: 1/3 sample was normal, 1/3 sample had type 1. 1/3
sample had type 3. Groups 4: 2/3 sample had type 4. 1/3 sample had type 5.
Groups 5: 1/3 sample was normal, 1/3 sample had type 2. 1/3 sample had type


3.
3.2. EFFECT OF ICH TRI VUONG SOFT CAPSULE IN
CAROTID ATHEROSCLEROSIS PATIENTS
3.2.1. Patients characteristic
3.2.1.1. Demographic and atherosclerosis risk of patient
- Mean of age: 62.57 ± 7.69 years; female: 40%, male: 60%
- Atherosclerosis risk: dyslipidemia: 100%, overweight and obesity: 63.33%,
hypertension: 50%, diabetes typ2: 26.67%, smocking: 21.67%.
- No significant difference of age, gender, and risk of atherosclerosis
between two groups (p > 0.05).
3.2.1.2. Carotid atherosclerosis characteristics of patients
- The score of headache HIT-6: 85% little impact,15% some and substantial impact
- The score of vertigo DHI: 95% little impact, 5 % some impact.
- Had no complication of carotid atherosclerosis: 95%, TIA: 5%
- 85% LDL optimal/nearly optimal, 15% borderline high to very high
- Increasing common carotid IMT in the right and left sides were 75%
and 73.33%. Level stenosis of under 30% luminal narrowing in the right
and left sides were 90% and 98.33%.
- No significant difference in carotid atherosclerosis characteristics between
two groups (p > 0.05).
3.2.1.3. Traditional medicine clinical characteristics of patients
Qi and yin deficiency: 75%, phlegm stagnation and blood stasis:
33.33%, qi stagnation and blood stasis: 38.33% and qi deficiency and
blood stasis: 15%. No significant difference in atherosclerosis classified
between two groups (p > 0.05).
3.2.2. Clinical effect of Ich tri vuong
3.2.2.1. Antioxidant effect
Table 3.20: Plasma level of TAS
TAS (mmol/L)
T0
T8
p
Δ T8 - T0

Ich tri vuong
n
± SD
30
1.51 ± 0.16
30
1.66 ± 0.17
< 0.05
30
0.15 ± 0.23

Atorvastatin
n
± SD
30 1.65 ± 0.16
30 1.66 ± 0.20
> 0.05
30 0.01 ± 0.16

p
< 0.05
> 0.05
< 0.05


After 8 weeks, TAS of Ich tri vuong group was significantly increased
(p < 0.05), there was no difference in the atorvastatin group (p > 0.05).
Table 3.21: Red blood cell SOD activity
SOD (U/gHb)
T0
T8
p
Δ T 8 - T0

Ich tri vuong
± SD
966 ± 270.4
832.4 ± 179.4
< 0.05
30 - 133.6 ± 251.2
n
30
30

Atorvastatin
± SD
1125.3 ± 376.6
873.9 ± 175.3
< 0.05
30 -251.6 ± 311.5
n
30
30

p
< 0.05
> 0.05
< 0.05

After 8 weeks, SOD was significantly decreased in two groups (p < 0.05).
Decrease level of Ich tri vuong was significantly lower than the atorvastatin group
(p < 0.05).
Table 3.22: Plasma level of MDA
MDA
(nmol/L)
T0
T8
p
Δ T 8 - T0

Ich tri vuong
± SD
0.21 ± 0.09
0.22 ± 0.14
> 0.05
30
0.01 ± 0.19
n
30
30

Atorvastatin
± SD
0.17 ± 0.07
0.22 ± 0.09
< 0.05
30 0.05 ± 0.09
n
30
30

p
> 0.05
> 0.05
> 0.05

After 8 weeks, MDA of Ich tri vuong group had no difference with baseline
(p > 0.05), MDA of atorvastatin was significantly decreasing (p < 0.05).
3.2.2.2. Anti-atherosclerotic effect
p0 >0.05; p4<0.05; p8<0.05

Figure 3.1: HIT-6 score of patients
After 4 and 8 weeks, HIT-6 score of Ich tri vuong group was lower than
the atorvastatin group (p < 0.05).
Table 3.23: Difference in HIT-6 score after 4 and 8 weeks
Atorvastatin
Ich tri vuong
p
HIT-6 (score)
n
± SD
n
± SD
Δ T4 - T0
30
- 4.07 ± 3.13
30
- 0.73 ± 2.55
< 0.05
< 0.05
Δ T8 - T0
30
- 5.67 ± 3.97
30
- 2 ± 3.86
After 4 and 8 weeks, the decrease level of HIT-6 score of Ich tri vuong


group was better than atorvastatin group (p < 0.05).
p0 >0.05; p4 <0.05; p8<0.05

Figure 3.2: DHI score of patients
After 8 weeks, the mean of DHI score of Ich tri vuong group was lower
than the atorvastatin group (p < 0.05).
Table 3.24: Difference in DHI score after 4 and 8 weeks
Ich tri vuong
Atorvastatin
p
DHI (score)
n
± SD
n
± SD
Δ T4 - T0
30
-3.53 ± 2.01
30
-0.47 ± 1.87
< 0.05
Δ T8 - T0
30 -4.73 ± 3.34
30 -1.07 ± 1.36
< 0.05
After 4 and 8 weeks, the decrease level of DHI score of Ich tri vuong
group was significantly better than atorvastatin group (p < 0.05).

Figure 3.3: ICA-PSV of patients
After 8 weeks, ICA-PSV both side of Ich tri vuong group was
significantly lower than baseline, the right side of Ich tri vuong group was
lower than that of atorvastatin group (p < 0.05).
p0 >0.05; p4 <0.05; p8<0.05
Table 3.25: Difference in ICA-PSV over 8 weeks
Δ ICA-PSV
Ich tri vuong
Atorvastatin
p
T8 - T0 (cm/s)
n
± SD
n
± SD
Right
30
-11.90 ± 14.73
30 - 3.70 ± 17.28
> 0.05
Left
30 -16.60 ± 20.21
30 - 5.07 ± 22.85
< 0.05
After 8 weeks, the decrease level of ICA-PSV on the left side of Ich tri
vuong group was significantly better than atorvastatin group (p < 0.05).
Thời gian


Figure 3.4: ICA-EDV of patients
After 8 weeks, ICA-EDV both side of Ich tri vuong group was
significantly lower than baseline (p < 0.05).
Table 3.26: Difference in ICA-EDV over 8 weeks
Δ ICA-EDV T8 - T0
Ich tri vuong
Atorvastatin
n
± SD
n
± SD
(cm/s)
Right
30
-2.67 ± 6.04
30
0.95± 6.18
Left
30
-3.87 ± 8.16
30
-0.63 ± 8.84
After 8 weeks, the decrease level of ICA-EDV right side Ich tri
vuong group was lower than the atorvastatin group (p< 0.05).

p

< 0.0
> 0.0

Figure 3.5: ICA-RI of patients
After 8 weeks, ICA-RI in the right side of Ich tri vuong group was
significantly lower than that of atorvastatin group (p < 0.05).
Table 3.27: Difference in ICA-RI after 8 weeks
Atorvastatin
p
Δ RI ICA
Ich tri vuong
T8 - T0
n
± SD
n
± SD
Right
30 - 0.04 ± 0.07
30
- 0.03 ± 0.07
> 0.05
30
- 0.02 ± 0.07
Left
30 - 0.04 ± 0.1
> 0.05
After 8 weeks, the decrease level of ICA-RI of Ich tri vuong group
had no difference compare with of atorvastatin group (p > 0.05).
p0 >0.05; p4>0.05; p8>0.05

Thời gian
Figure 3.6: Plasma level of total cholesterol


After 4, and 8 weeks, total cholesterol of the two groups had no difference (p
> 0.05).
Table 3.28: Difference in total cholesterol over 8 weeks
Ich tri vuong
Atorvastatin
Cholesterol
p
(mmol/L)
n
± SD
n
± SD
Δ T4 - T0
30 0.38 ± 1.05 30 - 0.23 ± 0.98 > 0.05
Δ T8 - T0
30 0.19 ± 0.69 30 - 0.38 ± 0.88 < 0.05
After 8 weeks, the decrease level of total cholesterol of atorvastatin
group was better than Ich tri vuong group (p < 0.05).
p0 >0,05; p4>0,05; p8>0,05

Figure 3.7: Plasma level of triglyceride
After 4 and 8 weeks, triglyceride of two groups had no difference
with baseline, and had no difference between two groups (p>0.05).
Table 3.29: Difference in triglyceride over 8 weeks
Triglyceride
Ich tri vuong
Atorvastatin
p
(mmol/L)
n
± SD
n
± SD
Δ T4 - T0
30 0.25 ± 2.49
30 - 0.51 ± 1.27
> 0.05
Δ T8 - T0
30 0.38 ± 1.98
30 - 0.08 ± 1.34
> 0.05
After 4 and 8 weeks, the decrease level of triglyceride of the two
groups had no difference (p > 0.05).
p0 >0,05; p4 <0,05; p8 >0,05

Figure 3.8: Plasma level of LDL
After 4 weeks, LDL of atorvastatin group was significantly lower
than Ich tri vuong group and baseline (p < 0.05). After 8 weeks, LDL
of the two groups had no difference with baseline (p > 0.05).
Table 3.30: Difference in LDL over 8 weeks
Atorvastatin
LDL (mmol/L)
Ich tri vuong


n
± SD
n
± SD
0.32 ± 0.75 30
- 0.24 ± 0.97 < 0.05
30
Δ T4 - T0
0.23 ± 0.67 30
- 0.26 ± 0.80 < 0.05
30
Δ T8 - T0
After 4 and 8 weeks, the decrease level of LDL of atorvastatin group
was significantly better than Ich tri vuong group (p < 0.05).
p0 >0,05; p4 >0,05; p8 >0,05

Figure 3.9: Plasma level of HDL
After 4 and 8 weeks, HDL of two groups had no difference with
baseline. HDL had no difference bettween two groups (p > 0.05).
Table 3.31: Difference in HDL over 8 weeks
Ich tri vuong
Atorvastatin
HDL (mmol/L)
p
n
± SD
n
± SD
30
0.10 ± 0.37
30
0.02 ± 0.17
> 0.05
Δ T4 - T0
30
- 0.001 ± 0.24
30
- 0.06 ± 0.18
> 0.05
Δ T8 - T0
After 4 and 8 weeks, the decreased level of HDL of two groups had
no significant difference (p > 0.05).
3.2.2.3. Treatment effect on TM clinical syndromes

Figure 3.10: TM symptom score of patients
After 4 and 8 weeks, TM symptom score of Ich tri vuong group was
significantly lower than the atorvastatin group (p < 0.05).
Table 3.33: Classified the decrease level of TM symptom score
over 4 and 8 weeks
Classifield the decrease
Ich tri vuong
Atorvastatin
p
level
n
%
n
%
No change
2
6.67
15
50
T4
Little change
24
80
15
50
< 0.05
Moderate change
4
13.33
0
0


No change
1
3.33
8
26.76
Little
change
8
26.67
21
70
T8
< 0.05
Moderate change
19
63.33
1
3.33
Good change
2
6.67
0
0
After 4 and 8 weeks, the decrease level of TM symptom score of Ich tri
vuong group was significantly better than atorvastatin group (p < 0.05).
Table 3.34: TM symptom score of atherosclerosis syndromes of
Ich tri vuong group after 8 weeks
n
T8
Δ T8 - T0
T0
Syndrome
± SD
± SD
± SD
26 ± 4.19
17 ± 4.62
-9 ± 2.40
Phlegm stagnation and blood stasis 1
0
2
24.72
±
4.85
16.96
±
3.80
-7.76
± 2.61
Qi and yin deficiency
5
3
25 ± 5.20
16.67 ± 2.52 -8.33 ± 3.51
Qi deficiency and blood stasis
1
25.60 ± 5.44 17.20 ± 4.24 -8.40 ± 1.78
Qi stagnation and blood stasis
0
> 0.05
> 0.05
> 0.05
p

p
<
0.05
<
0.05
<
0.05
<
0.05

After 8 weeks, TM symptom score of all syndromes was significantly decreased
with baseline (p < 0.05), no difference between syndromes (p > 0.05).
Table 3.35: Logistic regression of TM syndromes
and treatment results of Ich tri vuong group after 8
weeks
Qi
Qi
Phlegm stagnation
Qi and yin
stagnation
TM
deficiency
and blood stasis
deficiency
and blood
syndromes
and blood
(n = 10)
(n = 24)
stasis
(n= 3)
(n = 9)
-2log likelihood
27.61
16.54
28.19
The treatment result was most agreeably with qi and yin deficiency
syndrome, then phlegm stagnation and blood stasis and qi stagnation
and blood stasis with - 2log likelihoods were 16.54; 27.61 and 28.19.
Qi deficiency and blood syndrome had the number of the patient not
enought to calculate -2log likelihood value.
3.2.2.4. Safety assessment of Ich tri vuong


- There were 2 patients (6.67%) of Ich tri vuong group had the symptom of
heartburn when taking the capsule before the meal. There was no significant
difference in percentage of adverse side effect symptom between two groups (p
> 0.05).
- After 8 weeks, mean counts of blood cells, and the plasma level AST, ALT,
GGT, creatinin of two groups were on the normal range, there was no difference
with baseline either between two groups (p > 0.05).
Table 3.40: Thrombin time at baseline and over 8 weeks
Thời gian
Atorvastatin
Ich tri vuong
p
thrombin
n
± SD
n
± SD
(giây)
T0
30
17.79 ± 0.87
30 17.13 ± 1.65
> 0.05
T4
30
18.05 ± 1.31
30 17.11 ± 1.88
> 0.05
T8
30
15.41 ± 2.96
30 15.57 ± 2.84
> 0.05
p0-4 > 0,05, p0-8 > 0.05
p0-4 > 0,05, p0-8 > 0.05
After 4 weeks, thrombin time of two groups was on the normal
range, there was no significant difference between two groups (p >
0.05). After 8 weeks, thrombin time of two groups was lower than
baseline but still on the normal range (p > 0.05).
CHAPTER 4: DISCUSSION
4.1. DISCUSSION OF ANTIOXIDANT AND ANTIATHEROSCLEROTIC EFFECT OF ICH TRI VUONG SOFT
CAPSULE ON THE EXPERIMENTAL STUDY
*Antioxidant effect of Ich tri vuong soft capsule on the
experiment
Ich tri vuong had an antioxidant effect by increasing plasma
level of TAS, decreasing the level of SOD in the red blood cell, and
decreasing the plasma level of MDA. The antioxidant effect of Ich tri
vuong 180 mg/kg/day was equivalent to atorvastatin 5 mg/kg/day
and better than Ich tri vuong 60mg/kg/day.
* Anti-atherosclerosis of Ich tri vuong soft capsule on the
experiment
Ich tri vuong with a dose of 180 mg/kg/day and 60
mg/kg/day had effect on reducing atherosclerosis in comparison with


the control group in the rabbit. The anti-atherosclerosis of Ich tri
vuong with a dose of 180 mg/kg/day equivalent to atorvastatin 5
mg/kg/day and better than Ich tri vuong 60mg/kg/day on decreased
plasma total cholesterol TP, LDL, increased plasma HDL and
reduced atherosclerosis lesion in histological examination aortic arch
of the rabbit.
4.2. DISCUSSION OF ANTIOXIDANT AND ANTIATHEROSCLEROTIC EFFECTS OF ICH TRI VUONG SOFT
CAPSULE ON CLINICAL TRIAL
The randomized clinical trial comparing the effect of Ich tri
vuong soft capsule with atorvastatin conducted on 60 carotid
atherosclerosis patients with chronic cerebral circulation
insufficiency (CCCI). Two groups had the same distribution of age,
gender, risk factors, target organ complication, level of CCCI by
HIT-6 score and DHI score, level of plasma LDL, the proportion of
carotid atherosclerosis, degree of diameter reduction in the internal
carotid artery and traditional medical clinical characteristics.
* Antioxidant of ich tri vuong soft capsule on clinical trial
The results of assessing effect of Ich tri vuong soft capsule
on plasma level of TAS, activity of SOD in red blood cell, and
plasma level of MDA shown that Ich tri vuong had the antioxidant
effect by increasing the level of plasma TAS, decreasing the activity
of SOD in red blood cell, and decreasing the level of plasma MDA.
These outcomes corresponded to the results of experimental study.
The antioxidant effect of Ich tri vuong may due to in Ich tri vuong
have Ginkgo biloba, Radix Salviae miltiorrhizae, Radix Astragali
membranacei, and Radix Angelicae sinensis, these components had
antioxidant effect. The research result contributed demonstrations to
clarification mechanism of Ich tri vuong on treatment
atherosclerosis.
* Anti-atherosclerotic effects of ich tri vuong soft capsule on
clinical trial
The results of improving the symptom of headache and vertigo
by reduced HIT-6 and DHI score shown that Ich tri vuong had the


effect on improving the symptom of CCCI after 4 weeks, and more
clearly after 8 weeks of treatment. These outcomes corresponded to
the result of improving cerebral circulation by decreasing PSV, EDV,
and RI of ICA in carotid atherosclerosis patients. These outcomes
also corresponded to the results of the experimental study shown that
after 8 weeks, the rabbits of Ich tri vuong groups had been reduced
the degree of atherosclerosis lesion compared with the control group.
There was no effect of Ich tri vuong with a dose of 4
capsules/day on plasma level of lipids in atherosclerosis patients.
That may be due to atherosclerosis patients less responsive to
treatment than patients that were only with the lipid disorder.
* Effect of Ich tri vương on traditional medical syndrome
The improvement of traditional medical symptoms of
patients treated with Ich tri vương corresponded to the outcomes of
improving symptom headache and vertigo of CCCI after 4 weeks and
8 weeks. The component of Ich tri vuong base on a prescription
namely “Angelica decoction for enriching blood”, that has the effect
of supplementing qi to promote the production of blood. So that Ich
tri vương has the effect of supplementing qi removing phlegm,
nourishing liver blood and subduing wind. That effect would help
reducing symptoms of CCCI. The research interpreted the
concordance statistic of the outcome of treatment and traditional
medicinal syndromes in a logistic regression model. The logistic
regression models of 4 traditional medical syndromes shown that the
effect of Ich tri vuong in qi and yin deficiency syndromes was better
than that of phlegm stagnation and blood stasis syndrome and qi
stagnation and blood stasis syndromes with -2 log-likelihoods were
16.54; 27.61 and 28.19. The qi deficiency and blood syndrome could
not be calculated 2log likelihood because there were only 3 patients.
This result conformity to traditional medical theory, Ich tri vuong
components have the herbal that had the effect of supplementing qi
removing phlegm, nourishing blood, activate blood. So that Ich tri
vuong had a better effect on qi and yin deficiency syndrome and
phlegm stagnation and blood stasis syndrome.


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