1 RATIONALE Cardiovascular disease has been a major health concern in the world, with the leading cause of mortality and disability According to estimates by the World Health Organization, there are about 17 million people died from cardiovascular disease every year, mainly caused by atherosclerosis Dyslipidemia pattern is one of the most important risk factors but a variable risk factor for the formation and development of atherosclerosis Modern medicine has many drugs used to treat dyslipidemia, but some of them also have undesirable effects such as muscle pain, muscle cramps, impaired liver function, etc HVT remedy is made up of three commonly used medicinal herbs: Folium Nelumbinis nuciferae, Cleistocalyx operculatus Roxb and Pericarpium Citri reticulatae perenne, are prepared into liquid form which act on improving healthy qi, resolving phlegm-dampness and fortifying the spleen Currently, there are no studies evaluating the effects of treatment of HVT on dyslipidemia pattern To demonstrate the effects and toxicity of HVT, as a scientific basis towards the ability to widely use this product in clinical practice, we conduct the research on the topic “A study on the toxicity and effectiveness of HVT liquid drug on dyslipidemia pattern” with the following goals: To study the acute toxicity and semi-chronic toxicity of liquid HVT To study the effect of dyslipidemia adjustment of liquid HVT in experimental animals To evaluate the therapeutic effects and unwanted effects of liquid HVT in patients with dyslipidemia caused by internal phlegm-dampness PRACTICAL SIGNIFICANCE AND NEW CONTRIBUTIONS OF THE STUDY Practical significance Although the treatment of dyslipidemia with modern medicine is effective, it also causes some unwanted effects Therefore, the search for remedies derived from herbs, with few tastes, effective and safe is always a necessity as well as a research direction that is of interest to domestic and international scientists Scientific significance The dissertation has been systematically studied in both experimental and clinical practice The drug is produced in liquid form with ingredients of three traditional medicine drugs which are originated from Vietnamese traditional medicinal drugs, easy to find and convenient for use in treating dyslipidemedia The study has provided scientific evidence on the effect of dyslipidemedia adjustment as well as unwanted effects (if any) on experimental and clinical issues The applied research of a remedy in treatment has made a contribution to the clarification of the theory of traditional medicine At the same time, gradually modernizing traditional medicine is also a scientific and practical significance ORGANIZATION OF THE STUDY The dissertation consists of 128 pages, of which: Rationale (2 pages), Literature review (32 pages), Subjects and research methods (18 pages), Research results (43 pages), Discussions (30 pages), Conclusions (2 pages), Recommendations (1 page) There are 145 references used in the study, of which there are 53 documents in Vietnamese, 92 documents in English and documents in Chinese The dissertation has been presented and illustrated through 61 tables, charts, 18 pictures, diagrams and appendices Chapter LITERATURE REVIEW 1.1 Dyslipidemia from modern medicine point of view 1.1.1 Definition of dyslipidemia Dyslipidemia is a condition of the increase of either total cholesterol (TC) or triglyceride (TG) or both, or the decrease of high-density lipoprotein cholesterol (HDL-C), or the increase of low-density lipoprotein cholesterol (LDL-C) which increases the process of atherosclerosis 1.1.2 Causes of dyslipidemia The cause of dyslipidemia can be primary (due to genetic diseases) or secondary (due to eating habits, lifestyles or some pathologies) Secondary causes may contribute to dyslipidemia due to the causes of the primary which become more severe 1.1.3 Treatment of dyslipidemia * Treatment principles: - Lifestyle changes (proper diet, exercise regime) are the basic and core problem in treatment The time to evaluate the effectiveness of lifestyle changes is usually 2-3 months - Medications when needed - Treatment goals based on tests and assessments of patient risks, in which LDL-C is recommended as the first treatment target TC is the target for treatment if there are no other tests, while non-HDL-C or ApoB is the second target * Drugs for dyslipidemia treatment according to modern medicine: Based on the mechanism of action, drugs for dyslipidemia treatment are divided into main groups as follows: - The group that reduces lipid synthesis: Statins, fibric acid (Fibrat), and nicotinic acid (Niacin) - The group that reduces absorption and increases lipid elimination: bile acid sequestrants (Resin), cholesterol absorption inhibitor (Ezetimib) - In addition, some other drugs are used to treat dyslipidemia, such as PCSK9 inhibitors, MTP inhibitors, CETP inhibitors, and so on 1.2 Dyslipidemia from traditional medicine point of view 1.2.1 Causes In terms of traditional medicine, dyslipidemia is caused by the following syndromes: irregular congentinal factors, uncontrolled diet leading to spleenstomach disharmony; internal injury leading to liver-gallbladder damage; the debilitation of the elderly leading to the debilitation of source qi liver When the function of the viscera and bowels is disordered, it causes phlegm-dampness pattern 1.2.2 Disease mechanism The process of disease development consists of three stages: - The dysfunction of spleen and kidney affects the metabolism of water and food substances causing endogenous dampness turbidity pattern - The function of damaged viscera and bowels causes endogenous phlegmdampness turbidity and pattern of depressed dampness transforming into heat The symptom in this stage is phlegm turbidity depressing fire - The development of the disease causes binding of phlegm stasis, qi damage, yin damage, and yin-yang disharmony which can lead to a more serious condition and damage of the visceral organs, resulting in complications 1.2.3 Clinical classification in terms of traditional medicine - Pattern of internal phlegm-dampness: Body obesity, headache, chest pain, abdominal distention, nausea or vomiting, dry mouth without being thirsty, thin limbs, heavy limbs, pale swollen tongue, white greasy coating tongue, slippery pulse - Pattern of Phlegm-heat and fu-organ excess syndrome: Strong well-being, heavy head, irritability, red face, red eyes, bitter mouth, tight chest, uncomfortable, indigestion, constipation, pink red tongue, yellow greasy coating tongue, slippery pulse - Pattern of Spreen-kidney yang deficiency: puffy face, pain in back and knees, fear of cold, mental fatigue, indigestion, sloppy stool, night urination, pale tongue, edge of tongue with teeth, thick white fur tongue, slow sunken pulse - Pattern of liver-kidney yin deficiency: Pain in back and knees, irritable people, head pain, dizziness, fatigue, tinnitus, nightly sweats, dry and thirsty mouth, red tongue, thin fur tongue, ripid fine pulse 4 - Pattern of phlegm stagnation and blood statis: Fatty body, heavy and numbness limbs, tight chest, headache, dizziness, purple fur & spotted tongue, thick fur tongue, strink-like and slippery pulse or rough pulse - Pattern of liver depression and spleen deficiency: Tight pain in the edge of ribs, unstable pain, headache, dizziness, irritability, poor appetite, mental fatigue, sloppy stool, menstrual disorders, pale tongue, thin fur tongue, strink-like pulse 1.3 Overview of therapeutic remedy research According to folk experiences and documents on traditional medicines, there are many medicinal herbs, remedies for treatment of phlegm-dampness pattern, which are proved to be clinically effective in adjusting dyslipidemia Most remedies have too many herbs or they derive from abroad, making it difficult for patients to take drugs for the prolonged treatment HVT remedy is based on the theory of traditional medicine and some studies of modern medicine on the effectiveness of each herb HVT remedy is made up of Vietnamese medicinal herbs, so they are easy to find, easy to use and have been commonly used by people: + Folium Nelumbinis nuciferae which acts on upbearing the clear, dissipating stasis, moving water, removing phlegm-dampness There have been many domestic and foreign studies published results that Folium Nelumbinis nuciferae has the effects of lowering blood pressure, lowering blood sugar, preventing obesity, adjusting dyslipidemia, so it has the effect of preventing atherosclerosis + Cleistocalyx operculatus Roxb is a drink that has been used for many generations in Vietnam as well as in many countries around the world It has the effect of fortifying the spleen and removing the excess There have been a lot of studies on Cleistocalyx operculatus Roxb which have found that it is not only a healthy drink, but also significantly effective in many activities: anti-microbial, anti-dyslipidemia, lowering atherosclerosis, lowering blood sugar, inhibiting the development of cancer cells, improving congestion, soothing gallbladder, releasing pain and anti-allergy + Pericarpium Citri reticulatae perenne is effective in fortifying spleen, regulating qi, and drying dampness to resolve phlegm Pericarpium Citri reticulatae perenne is widely used as medicine and food in Vietnam and many countries in the world This herb has been presented in more than 10% of Chinese pharmacopoeia formulations There have been many studies proving the effect of Pericarpium Citri reticulatae perenne in treating dyslipidemia, reducing obesity and preventing atherosclerosis The effects of HVT remedy are fortifying spleen, regulating qi, drying dampness and resolving phlegm Chapter SUBJECTS AND METHODS OF RESEARCH 2.1 Research materials 2.1.1 Experimental drug: HVT remedy is produced in liquid form with a ratio of 1:1 (g/ml), bottled with volume of 240ml (Folium Nelumbinis nuciferae 90g, Cleistocalyx operculatus Roxb 90g, Pericarpium Citri reticulatae perenne 60g) by Department of Pharmacology, Military Institute of Traditional Medicine, meeting the basic standards 2.1.2 Control drug (Statin group): Experimental study: Atorvastatin 10mg (Lipistad-Stada Vietnam) Clinical study: Atorvastatin 10mg (Lipitor-Pfizer Pharmaceutic Germany) 2.2 Subjects of research 2.2.1 Research subjects on experimental study - White Swiss mice, healthy, weighing 200 ± 20g, provided by National Institute of Hygiene and Epidemiology - White Wistar rats, healthy, weighing 150 – 180g, provided by Military Medical University 2.2.2 Research subjects on clinical study - Criteria for selecting patients * In terms of modern medicine: the patients over 40 years old, regardless of occupation and gender The patients are diagnosed with dyslipidemia when they have at least one of the following four abnormal indicators: TC > 5.2 mmol/l, TG > 2.3 mmol/l; LDL-C > 3.4 mmol/l; HDL-C < 0.9 mmol/l * In terms of traditional medicine: the patients have manifestations of phlegmdampness such as obesity, pale swollen tongue, white greasy coating tongue, dizziness, severe head pain, numbness of limbs, fatigue, palpitations, insomnia, slippery pulse or string-like pulse - Exclusion criteria: the patients with chronic diseases, liver failure, renal failure, secondary dyslipidemia syndrome or being taking drugs that affect blood lipid index; the patients with hypersensitivity to the drug ingredients; the patients with a history of myocardial infarction, brain stroke, pregnancy or breastfeeding; the patients not abide by the treatment rules 2.3 Research methods 2.3.1 Experimental research methods - Acute toxicity study: According to the method of Litchfield - Wilcoxon, the guidelines of the Vietnam Ministry of Health, WHO and OECD, Swiss white mice are divided into groups with 10 mice per group Mice in each group were taken HVT at the dose from the highest dose (non-lethal dose) to the lowest dose (lethal dose) Mice were completely starved for 12 hours before taking HVT (but drunk freely) The mice were monitored the death rate in the first 72 hours as well as their general condition for days after taking the drug (including eating activity, mental activity, walking, climbing, excretion, and so on) Died mice were operated to evaluate the injuries of organs and then calculated LD50 6 - Semi-chronic toxicity study: According to guidelines of the Vietnam Ministry of Health, WHO and OECD, Wistar white rats were divided into groups with 10 rats per group Rats in control group were drunk distilled water 1ml/100g/day while rats in experimental group were taken low dose HVT of 11.2 g medicinal/kg (dose equivalent to the dose used on humans), and rats in experimental group l2 were taken high-dose HVT of 33.6g medicinal/kg (3 times higher than experimental group 1) Rats were drunk solvents and experimental drugs for weeks, once a day in the morning After weeks, the rats stopped taking the drugs and were monitored for weeks to evaluate the ability of rehalilitation (if there was toxicity) or the causing ability of the slow toxicity of the drug Monitoring indicators before and during the study include general condition, body weight, assessment of hematopoietic function, assessment of liver and kidney function and histopathology of liver and kidney of white rats - Studying the effect of HVT liquid on dyslipidemia adjustment in the model of exogenous hyperlipidemia Rats were divided into groups Each group had 10 rats with the same male/female ratio All these groups were given medicine for weeks as follows: Group (biological control group) was drunk distilled water 1ml/100g rat Group (model group) was drunk cholesterol oil mixture 1ml/100g, then drunk distilled water 1ml/100g after hours Group (atorvastatin group) was taken ml/100g cholesterol oil mixture, then taken atorvastatin 10 mg/kg after hours Group (the 1st dosage of HVT) was taken cholesterol oil mixture ml/100g, then taken HVT dose 11.2g/kg after hours Group (the 2nd dosage of HVT) was taken cholesterol oil mixture ml/100g, then taken HVT dose 33.6g / kg after hours The rats in all groups were weighed before and after one, two and four weeks of the experiment Then, they were taken blood at their tails to quantative tests of blood lipid indices: TC, TG, HDL-C The non-HDLcholesterol index is calculated by the formula: non-HDL-C = TC - (HDL-C) - Model of endogenous hyperlipidemia: The model of endogenous hyperlipidemia was adjusted by Poloxamer 407 (P-407) according to Millar et al The 50 white mice were divided into groups: Group (white control group), Group (model group), Group (atorvastatin group), Group (HVT dose of 19.2g/kg), and Group (HVT dose of 96g/kg) The mice were taken HVT, atorvastatin or distilled water within days constantly before taking intraperitoneal injection P-407 After taking P-407 injection, the mice were completely starved and drunk freely Within 24 hours after receiving P-407, the mice were taken blood at the carotid arteries to quantative tests of TC, TG, HDL-C, non- HDL- C The index of non-HDLcholeserol was calculated based on formula Non-HDL-C = (TC) – (HDL-C) 2.3.2 Clinical research methods - Prospective study conducted randomized, opened clinical trial with control group, result comparison between pre-treatment and post-treatment The 120 patients compliance with diet and exercise were devided into groups as follows: + Group 1: The experimental group consisted of 60 patients who used HVT liquid with 80gam/day, times per day, 30 minutes after lunch and dinner + Group 2: The control group consisted of 60 patients who used atorvastatin 10mg, tablet per day, hour after dinner The patients were examined, taken case history, performed hematologic tests and taken biochemical blood tests before treatment (D0) and after 30 days of treatment (D30) The patients were taken venous blood in the morning (without eating anything at least 12 hours before the previous meal) Blood biochemical tests were done afterward (TC, TG, LDL-C, HDL-C) Evaluation of treatment results in terms of modern medicine: + We evaluated the change of each lipid index at the times of D0 and D30, and compared the results of each group and between groups as well + The effectiveness of HVT in the patients with dyslipidemia was evaluated by criteria as follows: • Excellent: All blood lipid components returned to normal limits, or one of them achieved the following changes: TC decreased by ≥ 20%, TG decreased by ≥ 40%, HDL- C increased by ≥ 0.26mmol/l, TC-HDL-C/HDL-C (non-HDLC/HDL-C) decreased by ≥ 20% • Good: when achieving one of the following criteria: TC reduced by 10% 20%, TG decreased by 20% - 40%, HDL-C increased by 0.104mmol/l - 0.26 mmol/l, TC-HDL-C/HDL-C (non-HDL-C/HDL-C) decreased by 10% - 20% • Ineffective: Blood lipid components did not achieve the above changes Evaluation of treatment results in terms of traditional medicine + The effectiveness of HVT was evaluated through the methods of inspection, inquiry and palpation + The effectiveness of HVT in the patients with dyslipidemia was evaluated by criteria as follows: • Excellent: There were significant improvements in clinical symptoms with the total decreased score ≥ 70% • Good: There were small changes in clinical symptoms with the total decreased score ≥ 30% • Ineffective: The total decreased score of clinical symptoms was less than 30% Evaluation of unwanted effects of HVT Clinical evaluation: Some symptoms such as abdominal pain, nausea, rash, diarrhea, muscle pain, etc were evaluated 8 Sub-clinical evaluation: The results of hematological test and blood biochemical tests before and after treatment were used as good indicators to assess Data analysis: The data was collected and analyzed by the method and Biomedical statistical algorithm of STATA 14.0 Research Ethics: The study was approved by the Medical Council of Traditional Medicine Hospital, Ministry of Public Security The patients, who voluntarily participated in the study, were performed tests and given treatment without paying any fee All information was kept confidential and only general results were allowed to publish Chapter RESEARCH RESULTS 3.1 Acute toxicity and sub-chronic toxicity of HVT liquid drug 3.1.1 Acute toxicity White mice were taken HVT by increasing doses from the lowest to the highest dose with 600.0g medicinal/kg/24 hours (up to 31.25 times higher than the equivalent dose on the human) but there were no abnormal signs within day follow-up and no mice died within 72 hours after taking the sample drug Therefore, the acute toxicity of LD50 of HVT has not been determined by oral administration 3.1.2 Sub-chronic toxicity * General condition: During the experiment, the rats in all groups were operating normally with bright eyes, smooth hair, good eating, dry feces There were no particular manifestations in these three groups of rats during the study period * Changes in body weight of rats: At 4-8 weeks after taking the sample drugs and weeks after stopping the drugs, the weight of rats in all groups were documented to be increased compared to the weight before the study There was no difference in the level of weight gain of the rats between the control group and the experimental group (p> 0.05) * The effect of HVT on the mice’s blood lipid index Table 3.1 The effect of HVT on the number of rat’s red blood cells Time Before taking drugs weeks after taking drugs The number of red blood cells (T/l) The group The group The control (n=10) (2) (n=10) (3) group (n=10) (1) p2-1, p3-1, p3-2 8,49 ± 0,56 8,27 ± 0,34 8,32 ± 0,55 >0,05 8,54 ± 0,93 8,59 ± 0,45 8,44 ± 0,72 >0,05 weeks after taking drugs weeks after stopping drugs P(before-after) 8,92 ± 0,68 8,72± 0,73 8,63 ± 0,58 >0,05 8,70 ± 0,69 8,48 ± 1,41 8,82 ± 0,68 >0,05 > 0,05 > 0,05 > 0,05 Table 3.2 The effect of HVT on the concentration of hemoglobin in rat blood Times Before taking drugs weeks after taking drugs weeks after taking drugs weeks after stopping drugs P(before-after) The concentration of hemoglobin (g/dl ) The group The group The control (n=10) (2) (n=10) (3) group (n=10) (1) p2-1, p3-1, p3-2 15,32 ± 0,65 15,37 ± 0,76 15,19 ± 0,83 >0,05 14,46 ± 1,25 15,30 ± 0,74 15,12 ± 0,96 >0,05 15,43 ± 0,83 15,38 ± 1,13 14,40 ± 0,98 >0,05 16,48 ± 0,97 16,27 ± 1,00 16,37 ± 2,62 >0,05 > 0,05 > 0,05 > 0,05 Table 3.3 The effect of HVT on the number of rat’s white blood cells Time Before taking drugs weeks after taking drugs weeks after taking drugs weeks after stopping drugs P(before-after) The number of white blood cells (G/l) The control The group The group group (n=10) (1) (n=10) (2) (n=10) (3) p2-1, p31, p3-2 5,12 ± 1,48 4,53 ± 0,80 4,73 ± 1,57 >0,05 5,69 ± 1,41 4,96± 1,22 5,33 ± 1,52 >0,05 5,23 ± 1,30 4,65 ± 1,14 4,90 ± 1,40 >0,05 5,67 ± 0,82 4,90 ± 0,62 5,57 ± 1,50 >0,05 > 0,05 > 0,05 > 0,05 Table 3.4 The effect of HVT on the number of thrombocytes in rat blood 10 Times Before taking drugs weeks after taking drugs weeks after taking drugs weeks after stopping drugs P(before-after) The number of thrombocytes (G/l) The group The group The control group (n=10) (1) (n=10) (2) (n=10) (3) p2-1, p3-1, p3-2 472,5 ± 66,9 478,3 ± 46,6 483,5 ± 131,2 >0,05 418,5 ± 89,2 445,5 ± 66,6 449,1 ± 104,9 >0,05 428,5 ± 36,1 439,2 ± 69,3 443,1 ± 85,9 >0,05 458,2 ± 11,9 433,3 ± 41,1 453,6 ± 118,1 >0,05 > 0,05 > 0,05 > 0,05 After - weeks of taking HVT and after weeks of stopping HVT, the number of red bloods cells, white blood cells, thrombocytes and the hemoglobin concentration in both of the experimental group (low HVT doses) and the experimental group (high HVT doses) did not change in comparision to the time before taking the sample drugs and to the control group (p> 0.05) * Evaluation of liver function Table 3.5 The effect of HVT on the activity of AST (GOT) in rat blood Times Before taking drugs weeks after taking drugs weeks after taking drugs weeks after stopping drugs P(before-after) The activity of AST (UI/l) The control The group The group group (n=10) (1) (n=10) (2) (n=10) (3) p2-1, p3-1, p3-2 105,60 ± 9,58 108,90 ± 14,00 112,90 ± 14,32 >0,05 119,60 ± 22,74 117,50 ± 17,53 118,90 ± 23,65 >0,05 113,80 ± 18,27 112,60 ± 14,50 108,70 ± 11,21 >0,05 111,00 ± 14,20 103,14 ± 5,96 108,14 ± 19,78 >0,05 > 0,05 > 0,05 > 0,05 Table 3.6 The effect of HVT on the activity of ALT (GPT) in rat blood Times Before taking The activity of ALT (UI/l) The control The group The group group (n=10) (1) (n=10) (2) (n=10) (3) 57,30 ± 5,33 61,70 ± 4,76 61,60 ± 7,26 p2-1, p3-1, p3-2 >0,05 11 drugs weeks after taking drugs weeks after taking drugs weeks after stopping drugs P(before-after) 62,80 ± 14,47 60,20 ± 9,10 60,10 ± 9,26 >0,05 59,30 ± 7,10 59,20 ± 6,78 59,90 ± 6,10 >0,05 57,00 ± 5,44 56,71 ± 4,72 52,71 ± 9,62 >0,05 > 0,05 > 0,05 > 0,05 After - weeks of taking HVT and after weeks of stopping HVT, there was not any statistically significant difference in the activities of AST and ALT in rat blood in both of the experimental group (low HVT dose) and the experimental group (high HVT dose), in comparison to the control group and between the two times before and after taking the sample drugs (p> 0.05) * Evaluation of kidney function Table 3.7 The effect of HVT on the concentration of creatinine in rat blood Times Before taking drugs weeks after taking drugs weeks after taking drugs weeks after stopping drugs P(before-after) The concentration of Creatinine (mg/dl) The group The group The control (n=10) (2) (n=10) (3) group (n=10) (1) 1,06 ± 0,05 1,06 ± 0,05 1,07 ± 0,05 p2-1, p3-1, p3-2 >0,05 1,04 ± 0,05 1,05 ± 0,05 1,03 ± 0,05 >0,05 1,05 ± 0,05 1,05 ± 0,05 1,05 ± 0,05 >0,05 1,03 ± 0,08 1,04 ± 0,05 1,04 ± 0,10 >0,05 > 0,05 > 0,05 > 0,05 After - weeks of taking HVT and after weeks of stopping HVT, there was not any statistically significant difference in the concentration of creatinine in both of the experimental group (low HVT dose) and the experimental group (high HVT dose), in comparison to the control group and between the two times before and after taking the sample drugs (p> 0.05) 3.2 The pharmacological effect of HVT in experiment study Table 3.8 The lipid index at the time after weeks of experiment in exogenous model (n=10) Groups Group : The The concentration of blood lipid indices TC TG HDL - C Non-HDL - C 2,29  0,07 0,77  0,02 0,81  0,03 1,48  0,08 12 biological control group Group : The model group Group 3: Atorvastatin group Group 4: The 1st dose of HVT (11,2 g/kg) Group : The 2nd dose of HVT (33,6 g/kg) 4,65  0,21*** 0,93  0,04** 1,76  0,05*** 2,89  0,2*** 3,33  0,18*** 0,85  0,04 1,58 0,09 1,75  0,18** 2,92  0,09*** 0,87  0,03 1,49  0,05** 1,43  0,11*** 2,96  0,11*** 0,89  0,03 1,55  0,04** 1,41  0,11*** Notes: The differences in comparison to the model group: *: p < 0,05; **: p 0.05) Table 3.9 Blood lipid index after the experiment in endogenous model (n = 10) Groups Group 2: The model group Group 3: Atorvastatin group Group 4: HVT 19,2g/kg Group 5: HVT 96,0g/kg TC TG HDL-C Non-HDL-C 6,31 ± 1,60 9,01 ± 2,36 2,11 ± 0,17 4,20 ± 1,68 4,15 ± 0,93** (↓ 34,2%) 8,16 ± 2,65 (↓ 9,4%) 2,02 ± 0,12 2,13 ± 0,94** (↓ 49,3%) 5,89 ± 1,37 (↓ 6,7%) 8,69 ± 3,90 (↓ 3,6%) 2,78 ± 0,38*** (↑ 31,8%) 3,12 ± 1,37 (↓ 25,7%) 4,91 ± 0,51 * (↓ 22,2%) 5,74 ± 1,79** (↓ 36,3%) 2,88 ± 0,48*** (↑ 36,5%) 2,03 ± 0,89** (↓ 51,7%) 13 Notes: The difference in comparison to the model group: *: p < 0,05; **: p 0,05 3,87  0,52 3,72  Indices TC TG HDLC LDLC NonHDLC 1,17  0,32 Atorvastatin 1,28  0,34 p HVT > 0,05 3,93  0,64 Atorvastatin 3,91  0,74 p HVT > 0,05 5,05  0,51 Atorvastatin 5,09  0,66 ↓18,4% ↓20,8% ↓17,1% ↑17,1% ↑15,6% ↓23,9% ↓26,3% ↓23,4% ↓26,9% 0,05 ↓29,2%