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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: Assoc Prof, Ph.D DO THI PHUONG 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: The National Library of Vietnam The Library of Military Insitute Of Traditional Medicine The Library of Hanoi Medical University DISSERTATION INCLUDING PUBLICATION 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 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, 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, (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 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 in rabbit: 60 mg/kg/day, dose 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 groups of 10 Normal group: fed water ml/kg/day Control group: fed cholesterol oil 0.5 g/kg/day, 1ml/kg, hours later fed water ml/kg/day Atorvastatin group: fed cholesterol oil 0.5 g/kg/day, 1ml/kg, hours later fed Atorvastatin 5mg/kg/day Ich tri vuong dose (60 mg/kg/day): fed cholesterol oil 0.5 g/kg/day, 1ml/kg, hours later fed Ich Tri Vuong 60 mg/kg/day (equivalent to clinical dose) Ich tri vuong dose (180 mg/kg/day): fed cholesterol oil 0.5 g/kg/day, 1ml/kg, 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 weeks (T4) and 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 months (3) Presence of carotid intima-media thickness (IMT) on Doppler ultrasound by IMT ≥ 0.8 mm (4) The degree of carotid artery stenosis 0.05 (control) 10 2.62 ± 0.22 2.92 ± 0.06 < 0.05 (atorvastatin) 10 2.85 ± 0.21 2.27 ± 0.10 < 0.05 (Ich tri vuong dose 1) 10 2.73 ± 0.24 2.31 ± 0.12 < 0.05 (Ich tri vuong dose 2) 10 2.57 ± 0.20 2.45 ± 0.16 > 0.05 p > 0.05 < 0.05 After weeks, body weight of group was significantly higher than baseline (p < 0.05), no difference in group and (p > 0.05), significantly decreased in groups and (p < 0.05) Table 3.5: Plasma level of total cholesterol T0 T4 T8 Groups n pT0-T8 ± SD (mmol/L) (Normal) 2.73 ± 1.01 4.29 ± 5.00 3.06 ± 1.39 > 0.05 (control) 10 2.78 ± 1.81 21.13 ± 9.98 22.35 ± 10.31 < 0.05 (atorvastatin ) 10 2.88 ± 1.51 10.74 ± 8.18 10.71 ± 6.17 < 0.05 (Ich tri vuong dose 1) 3.51 ± 1.76 23.97 ± 14.28 17.31 ± 9.56 < 0.05 (Ich tri vuong dose 2) 10 2.04 ± 0.68 13.91 ± 9.36 12.76 ± 7.13 < 0.05 p > 0.05 < 0.05 < 0.05 After and weeks, total cholesterol of groups had no difference (p > 0.05), significantly increased in other groups, highest in group 2, then 4, 5, (p < 0.05) Table 3.6: Difference in total cholesterol plasma level over weeks Δ T8-T0 Groups n p X ±0.33 SD ±(mmol/L) (Normal) 10 1.28 p < 0.05; p1-2 < 0.05; p22 (control) 10 19.57 ± 9.34 < 0.05; p2-4 > 0.05; p2-5 (atorvastatin ) 10 7.74 ± 5.84 < 0.05; p3-4 < 0.05; p3-5 > (Ich tri vuong dose 1) 10 13.81 ± 9.17 0.05; p4-5 > 0.05 (Ich tri vuong dose 2) 10 10.72 ± 6.77 After weeks, the increasing level of total cholesterol of group and were equivalent and significantly lower than group (p < 0.05), the increasing level of groups was equivalent to group (p > 0.05) Table 3.7: Plasma level of triglyceride n T0 T4 T8 Groups pT0-T8 ± SD (mmol/L) (Normal) 10 0.99 ± 0.40 1.22 ± 0.46 1.06 ± 0.74 > 0.05 (control) 10 0.76 ± 0.34 1.81 ± 1.62 1.47 ± 0.75 < 0.05 (atorvastatin) 10 0.89 ± 0.49 2.01 ± 1.21 1.09 ± 0.53 > 0.05 (Ich tri vuong dose 1) 10 0.98 ± 0.40 2.43 ± 1.07 1.86 ± 1.03 > 0.05 (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 weeks, triglyceride had no difference in group (p > 0.05), increased in group (p < 0.05) Table 3.8: Difference in triglyceride plasma level over weeks Δ T8-T0 p Groups n ± SD (mmol/L) p > 0.05; p1-2 0.05; p2-4 > 0.05; (atorvastatin) 10 0.23 ± 0.61 p2-5 > 0.05; p3-4 > 0.05; (Ich tri vuong dose 1) 10 0.87 ± 1.25 p3-5 > 0.05; p4-5 > 0.05 (Ich tri vuong dose 2) 10 0.28 ± 0.47 After weeks, triglyceride increased in groups, but the increasing level had no significant difference between groups (p > 0.05) Table 3.9: Plasma level of LDL T0 T4 T8 Groups n pT0-T8 ± SD (mmol/L) (Normal) 10 2.24 ± 1.01 3.69 ± 4.40 2.35 ± 1.13 > 0.05 (control) 10 2.20 ± 1.60 18.55 ± 9.18 19.51 ± 9.66 < 0.05 (atorvastatin) 10 2.26 ± 1.31 9.35 ± 7.31 8.98 ± 5.35 < 0.05 (Ich tri vuong dose 1) 10 2.83 ± 1.55 21.30 ± 3.12 14.96 ± 8.58 < 0.05 (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 weeks, LDL had no difference in groups (p > 0.05), and significantly increased in other groups (p < 0.05) Table 3.10: Difference in LDL plasma level over weeks Groups n p ± SD (mmol/L) (Normal) 10 0.12 ± 1.09 p < 0.05; p1-2 0.05; p2-5 (control) 10 17.31 ± 8.82 < 0.05; p3-4 > 0.05; p3-5 (atorvastatin ) 10 6.64 ± 5.13 > 0.05; p4-5 > 0.05 (Ich tri vuong dose 1) 10 12.13 ± 8.27 (Ich tri vuong dose 2) 10 9.11 ± 6.01 After weeks, LDL was significantly increased highest in group and lower in group 4, group and group (p < 0.05) Table 3.11: Plasma level of HDL T0 T4 T8 Groups n pT0-T8 ± SD (mmol/L) (Normal) 10 0.49 ± 0.16 0.61 ± 0.62 0.71 ± 0.28 > 0.05 (control) 10 0.59 ± 0.28 2.59 ± 0.91 2.84 ± 0.69 < 0.05 (atorvastatin) 10 0.61 ± 0.29 1.39 ± 0.89 1.73 ± 0.83 < 0.05 (Ich tri vuong dose 1) 10 0.68 ± 0.26 2.68 ± 1.26 2.35 ± 1.01 < 0.05 (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 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 weeks Δ T8-T0 Groups n p ± SD (mmol/L) (Normal) 10 0.21 ± 0.23 p < 0.05; p1-2< 0.05; p22 (control) 10 2.26 ± 0.67 < 0.05; p2-4 > 0.05; p2-5 (atorvastatin) 10 1.10 ± 0.74 > 0.05; p3-4 > 0.05; p3-5 (Ich tri vuong dose 1) 10 1.67 ± 0.97 > 0.05; p4-5 > 0.05 (Ich tri vuong dose 2) 10 1.61 ± 0.83 After weeks, HDL was significantly increased highest in group 2, the increasing level was lower in group 4, and (p < 0.05) 3.1.2.3 Pathological Anatomy of aortic atherosclerosis lesion • Macros examination After weeks, all samples of group and 1/3 sample of group and 2/3 sample of group had atherosclerotic gross lesions grade 1/3 sample of group 2, group and group had atherosclerotic gross lesions grade I All sample of group 2, 2/3 sample of group and 1/3 sample of group had gross lesion of aortic atherosclerosis grade II • Histological examination Group 1: all samples were normal Group 2: 2/3 sample had type 1/3 sample had type Group 3: 1/3 sample was normal, 1/3 sample had type 1/3 sample had type Groups 4: 2/3 sample had type 1/3 sample had type Groups 5: 1/3 sample was normal, 1/3 sample had type 1/3 sample had type 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, % 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 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 - 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 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 - 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 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 After 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 weeks, total cholesterol of the two groups had no difference (p > 0.05) Table 3.28: Difference in total cholesterol over 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 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 and 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 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 and weeks, the decrease level of triglyceride of the two groups had no difference (p > 0.05) p0 >0,05; p4 0,05 Figure 3.8: Plasma level of LDL After weeks, LDL of atorvastatin group was significantly lower than Ich tri vuong group and baseline (p < 0.05) After weeks, LDL of the two groups had no difference with baseline (p > 0.05) Table 3.30: Difference in LDL over 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 and 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 and 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 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 and 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 and 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 and weeks Classifield the decrease Ich tri vuong Atorvastatin p level n % n % No change 6.67 15 50 T4 Little change 24 80 15 50 < 0.05 Moderate change 13.33 0 No change 3.33 26.76 Little change 26.67 21 70 T8 < 0.05 Moderate change 19 63.33 3.33 Good change 6.67 0 After and 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 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 24.72 ± 4.85 16.96 ± 3.80 -7.76 ± 2.61 Qi and yin deficiency 25 ± 5.20 16.67 ± 2.52 -8.33 ± 3.51 Qi deficiency and blood stasis 25.60 ± 5.44 17.20 ± 4.24 -8.40 ± 1.78 Qi stagnation and blood stasis > 0.05 > 0.05 > 0.05 p p < 0.05 < 0.05 < 0.05 < 0.05 After 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 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 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 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 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 weeks, thrombin time of two groups was on the normal range, there was no significant difference between two groups (p > 0.05) After 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 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 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 weeks, and more clearly after 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 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 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 weeks and 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 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 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 * Safety assessment The results of safety assessment of Ich tri vuong in clinical and laboratory tests shown that Ich tri vuong was safety when used for atherosclerosis patients, there was no abnormal of hematopoiesis, liver, kidney, and coagulation functions during weeks of treatment There were patients (6.67%) of Ich tri vuong group had the symptom of heartburn when taking Ich tri vuong before meal That symptom appeared when medication was initiated and resolved spontaneously after eating There was no need for any intervention No adverse side effects were observed 4.2.6 Discussion about the potential of using Ich tri vuong soft capsule for early atherosclerosis stage patients The prevention and early treatment of atherosclerosis includes lifestyle modification, management of risk factors, and medication that has effects on the mechanism of atherosclerosis, such as lipid level modification and platelet aggregation in conjunction with vasodilators and antioxidant agents The research has shown that Ich tri vuong soft capsule had the effect of antioxidant and antiatherosclerosis in the experimental model, and improve symptoms of CCCI in carotid atherosclerosis patients No adverse side effects of Ich tri vuong were observed there was no abnormality of the hematopoietsis or liver, kidney, or coagulation function during weeks of treatment In the traditional medicine aspects, Ich tri vuong components have the herbal that had the effect of supplementing qi removing phlegm, nourishing blood, activate blood subduing wind, that appropriated in treatment common symptom of CCCI in carotid atherosclerosis patients CONCLUSIONS The research evaluated the antioxidant and anti-atherosclerotic effect of Ich tri vuong soft capsule on rabbits induced atherosclerosis by cholesterol-fed with doses of 180 mg/kg/day and 60 mg/kg/day for weeks and on 60 carotid atherosclerosis patients with a dose of capsules/day for weeks in compared with atorvastatin The results suggested that: Ich tri vuong has effects of antioxidant an antiatherosclerosis in the experimental model: - Antioxidant effect: increasing TAS serum level (p < 0,05), reduced of increasing active of SOD in red blood cell level in both doses (p < 0.05) Ich tri vuong with a dose of 180 mg/kg/day suppressed the increasing of the MDA serum level in compared with baseline (p > 0.05) - Anti-atherosclerotic effect: Ich tri vương 180 mg/kg/day decreased total cholesterol, LDL serum levels (p < 0.05 These effects were equivalent to atorvastatin mg/kg/day Ich tri vuong capsule decreased lesion degree of aortic atherosclerosis on histological examination Ich tri vuong has effect of antioxidant and improving symptoms of atherosclerosis and safety in carotid atherosclerosis patient - Antioxidant effect: Ich tri vuong has the effect of increasing TAS serum level (0.15 ± 0.23 mmol/L), decreasing activity of SOD in red blood cells level (-133.62 ± 251.20 U/gHb), suppressing the increase of the MDA serum level - Effect on atherosclerosis: improving symptoms of CCCI cause of atherosclerosis after and weeks of treatment by reducing HIT-6 score (4.07 ± 3.13 score; 5.67 ± 3.97 score), reducing DHI score (3.6 ± 1.99 score; 4.67 ± 3.21 score) (p < 0.05), decreasing PSV of ICA on right and left side (11.9 ± 14.73 cm/s; 16.6 ± 20.21 cm/s), decreasing EDV of ICA on right and left side (2.67 ± 6.04 cm/s; 3.87 ± 8.16 cm/s), decreasing RI of ICA on right and left side (0.04 ± 0.07; 0.04 ± 0.1) in compared with baseline (p < 0.05) - Improving traditional medical symptoms of CCCI: Ich tri vuong improved traditional medical symptoms of CCCI after and weeks (p < 0.05) These effects were better in qi and yin deficiency syndrome, phlegm stagnation and blood stasis syndrome and qi stagnation and blood stasis syndrome - No adverse side effects were observed ... 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... 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... 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, % some impact - Had no complication of carotid
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Xem thêm: Đánh giá tác dụng chống oxy hóa và xơ vữa động mạch của viên nang mềm ích trí vương trên thực nghiệm và lâm sàng tt tiếng anh , Đánh giá tác dụng chống oxy hóa và xơ vữa động mạch của viên nang mềm ích trí vương trên thực nghiệm và lâm sàng tt tiếng anh

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