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Study on Function of SoftenClean Capsule in Lowering Hyperlipidemia Risk, Treating Unstable Angina and Its Protecting Effects on Vascular Endothelium

Authors: Wenfeng Chung, Fujun Yan, Seth Martin and Wendy Ying

ABSTRACT

Objective: To observe the clinical effect and protection of vascular endothelium of SoftenClean Capsule (SCC) in middle-aged and senior people with unstable angina and hyperlipidemia. Methods: Six hundred and fifty patients with unstable angina were randomly divided into SCC group (340 cases) and control group (310 cases). Conventional statin therapy was given to both groups, with SCC group receiving additional SCC treatment. Data of 216 healthy persons were taken as normal group. Also one hundred and forty-eight patients with hyperlipidemia were taken from SCC group (treated with SCC) and 170 from control group (treated with Simvastatin) respectively. The changes of clinical symptoms and laboratory indexes in all the patients were observed before and after treatment. Results: In patients with unstable angina, the efficacy of treatment of SCC, the withdrawal rate of nitroglycerin, the relieving of symptoms, the improvement of the electrocardiogram, the counts of circulating endothelial cells, the content of platelet P-selectin, the content of plasma endothelin (ET), the activity of superoxide dismutase (SOD) and the activity of malonyldialdehyde (MDA) were all better than those in the control group. In patients with hyperlipidemia, there was significant difference in lipids reduction between SCC group and the control group. In both groups, the total cholesterol (TC), triglyceride (TG), low density lipo-protein-cholesterol (LDL-C), lipoprotein(a) [Lp(a)], ET, oxidized low density lipoprotein, MDA, arteriosclerotic index (AI) all lowered obviously, while the SOD, HDL-C and calcitonin gene-related peptide (CGRP) were all elevated markedly. In the SCC group, the nitric oxide (NO) increased significantly whereas the ET/CGRP and ET/NO decreased markedly. The total effective rate in symptom relieving, the markedly effective rate, the reduction of TC, ET and ET/CGRP, and the elevation of SOD in SCC group were all superior to those in the control group. Conclusion: SoftenClean Capsule could effectively resist myocardial ischemia, relieve angina, reduce blood lipids, protect vascular endothelial cells, inhibit the activation of platelets, and resist lipid peroxidation.

KEY WORDS: unstable angina, hyperlipidemia, SoftenClean capsule, protection of vascular endothelium, therapy of traditional herbal medicine

* Wenfeng Chung is a research fellow at China Academy of Chinese Medical Sciences.
* Fujun Yan is a associate professor at Shanghai University of Traditional Chinese Medicine.
* Seth Martin is faculty member in the Johns Hopkins Center for the Prevention of Heart Disease.
* Wendy Ying is an assistant researcher at Johns Hopkins University School of Medicine.

It is clinically observed that the hyperlipidemia and the angina of coronary heart disease (CHD) both belong to deteriorated vascular function sphere. The injury of vascular endothelium is a key link in the pathogenesis of the two diseases in modern medicine. This study evaluated the therapeutic effect of SoftenClean capsule (SCC) on unstable angina and hyperlipidemia focusing on vascular endothelium protection.

 

METHODS

Diagnostic Standard
Patients who were aged 40-80 years and conformed to one of the following diagnostic standards were eligible for this study.

Unstable angina: CHD was diagnosed according to the “Nomenclature and Diagnostic Standard for Ischemic Heart Disease “(1) proposed by WHO, concerning the diagnostic standard for initial or deteriorative effort angina; resting status in 12 lead of electrocardiogram (ECG) showed marked myocardial ischemia, two limb leads or adjacent chest lead showed sign of depression of S-T segment, equal to or more than 0.05 mV, or inversion of T-wave.

Hyperlipidemia. conforming to the diagnostic standard of “Guiding Principles of Clinical Research on New Chinese Drugs in Treating Hyperlipidemia” (2) .

Subjects of Study
Unstable angina: The 650 patients were randomly divided into two groups according to their grades of angina and TCM symptoms (refer to the “Diagnostic and Therapeutic Regulations on Emergency Cases of Coronary Heart Disease and Angina Pectoris” proposed by the coordinating groups of the State Administration of TCM on the emergency cases of Chest Bi) (3) , 340 cases in SCC group and 310 cases in the control group. Two hundred and sixteen healthy subjects aged 40-80 years were chosen as the normal group. The patients” ages in the three groups ranged from 40 to 80 years, 150 males and 190 females in SCC group, 120 males and 190 females in the control group, and 95 males and 121 females in the normal group. Their vocations included physical and mental workers. There were no significant differences in above-mentioned data, and thus they were comparable~ the average courses of disease in SCC group and control group before treatment were 5.9 years and 5.8 years respectively. Their classifications of angina pectoris were initial type and deteriorative type. Their complications were hypertension, diabetes mellitus and hyperlipidemia. Symptoms manifested were chest pain, chest distress, palpitation, shortness of breath, fatigue, sweating, pallor, vertigo, asthma, feeling tired and unwilling to talk and so on. There were no marked differences in above-mentioned data, and thus they were also comparable.

Hyperlipidemia: According to the total cholesterol (TC) and triglyceride (TG), the 480 cases were randomly divided into two groups in the ratio of two to one. Three hundred and ten cases in SCC group and one hundred seventy cases in Simvastatin control group. In both groups, ages ranged from 40 to 80 years with 170 males and 140 females in SCC group, 100 males and 70 females in the control group. The figure was normal, overweight or fat. Their vocations were cadres, teachers and farmers. Their complications were obesity, hypertension, diabetes mellitus, fatty liver and coronary heart disease. The abnormal lipids included hypercholesteremia, hypertriglyc-eridemia and low blood high density lipoprotein-cholesterol (HDL-C) level. Symptoms manifested were fatigue, poor appetite, stickiness in mouth, nausea, abdominal distention, vertigo, headache, chest pain, sense of suppression in the chest, palpitation, loose stool and so on. There were no significant differences in above-mentioned data, and therefore they were comparable.

Therapeutio and Observative Methods
Unstable angina: patients in both SCC group and the control group during the acute stage should rest in bed for 1-3 days, inhale oxygen and be given ECG surveillance and conventional western medicine therapy, orally administered aspirin 0.3 g, three times a day, isosorbide dinitrate 10 mg, three times a day, atenolol 25-50 mg, twice a day, and nifedipine 10 mg, once per 6 hrs. During the period of attacks, besides resting in bed, nitroglycerin (0.5 mg each tablet) was sublingually administered at the onset of angina. SCC group received additional SCC treatment (SCC, composed of ginseng, ginkgo leaf, notoginseng, extracts from green tea and taurine, 0.4 g each capsule, and produced by Shebal Health Associates, batch number. 920130826), 0.8 g each time, 3 times a day after meals for 3 weeks and then the therapeutic effect was evaluated. Patients in the two groups withdrew from the medication of anti-oxidants 2 weeks before and during the treatment. The changes of clinical symptoms and signs (attack frequencies of angina, heart rate, blood pressure, ECG, the withdrawal rate of nitroglycerin, tongue picture, pulse condition and the relieving of symptoms and so on) were observed before and after treatment. The circulating endothelial cells (CEC) and the platelet P-selectin (CD62p) in peripheral blood were detected with cytometry. The plasma endothelin (ET), the serum malonyldialdehyde (MDA), the nitric oxide (NO), the super-oxide dismutase (SOD), and the blood lipids were also measured.

Hyperlipidemia: The SCC group was treated with SCC, 0.8 g each time, 3 times a day, while the control group treated with Simvastatin (20 mg each tablet, Zocor, batch number: 671401001), 2 capsules each time, 3 times a day for 45 days and then the therapeutic effect was evaluated. The changes of clinical symptoms and signs (heart rate, blood pressure, ECG, tongue picture, pulse condition and the relieving of symptoms and so on) were observed before and after treatment. TC, TG, HDL-C, the low density lipoprotein-cholesterol (LDL-C), the lipoprotein (a) [Lp(a)], ET, the calcitonin gene-related peptide (CGRP), NO, the oxidized low density lipoprotein (OX-LDL), MDA and SOD were all monitored.

Statistical Analysis
Data were expressed by χ^2 test, t test and F test.

 

RESULTS
Effect on Unstable Angina
Standard for efficacy evaluation: The therapeutic effect evaluations of angina and ECG were referred to the standard revised by the National Symposium on the Treatment of CHD and Arrhythmia by Integrated Traditional Chinese and Western Medicine, 1979 (4). The standard for the total effective rate of overall symptoms in TCM and of single symptom were assessed according to “Guiding Principles in Clinical Research on New Chinese Drugs in Treating Senile Diseases “(5).

Therapeutic effects of angina, ECG and symptoms in TCM. The total effective rate of angina in SCC group was 97.06%, and the markedly effective rate 76.47%. Both were much better than those in the control group (87.10% and 48.39%, P <0. 05). The amount of nitroglycerin taken in the two groups after treatment was diminished significantly. The withdrawal rate of nitroglycerin in SCC group was 76.47%, which was markedly higher than that in the control group (54.84%, P <0.05). The total effective rate of ECG in SCC group was 82. 35%, and the markedly effective rate 35.29%, both were much better than those in the control group (61.76% and 12.90%, P <0.05). The total effective rate of symptoms in SCC group was 100%, and the markedly effective rate 88.24%. Both were much better than those in the control group (93.55% and 41.94, P <0.01).

The results of effects on CEC, CD62p NO, ET, SOD and MDA in blood were shown in Table 1.

Effect on Hyperlipidemia
Standard for effect evaluation. The therapeutic effect evaluation of lipid-improving was referred to the standard in “Guiding Principles in Clinical Research on New Chinese Drugs in Treating Hyperlipidemia “(2). According to “Guiding Principles in Clinical Research on New Drugs in Treating Senile Diseases “(5), clinical symptoms and signs were scored by grading to evaluate the therapeutic effect of overall symptoms and single symptom.

Therapeutic effects of lipid-improving, anti-oxidation and clinical symptoms: The efficacy of lipid-improving was classified as markedly effective, effective and ineffective. The total effective rate of lipid-improving in SCC group was 93.50%, while in the control group it was 88.2%. There was insignificant difference between the two groups. The therapeutic effects of clinical symptoms were also classified as markedly effective, effective and ineffective. In SCC group, the markedly effective rate and the total effective rate were 64.5% and 96.8% respectively, which were obviously better than those in the control group (29.4% and 82.4%, P <0.05). See Table 2 and Table 3.

The results of changes of vasoactive substances of both groups were shown in Table 4.

DISCUSSION
The etiology and pathogenesis of hyperlipidemia and CHD in middle-aged and senior people are mostly attributed to deteriorated functions of internal organs especially heart, spleen and kidney. Hyperlipidemia generally originates from insufficiency of the spleen function and defect in oxygen and nutrient transportation and transformation, and is manifested by phlegm and blood stasis in the interior circulation system. Unstable angina that results from blood stasis and phlegm in heart channels is characterized by “insufficiency of metabolism in the heart and spleen organs”. SCC consists of ginseng, Ginkgo leaf, notoginseng, extracts from green tea and taurine. Its function is to “replenish energy, nourish the heart, invigorate the spleen and kidney, promote blood circulation to remove obstruction in the circulation system, resolve phlegm and remove turbidity”. It acts in coordination to invigorate spleen/kidney and remove plaque clots and cures both the root causes and the symptoms, which is the very thing needed for the pathogenesis of the two above-mentioned diseases.

Modern pharmacological study has demonstrated that each ingredient has anti-myocardial ischemia, hyperlipidemia-lowering, anti-oxidation and vascular endothelium protection effects. With its remarkable holistic potencies, it could play a vital role in clinical applications. Therefore, SCC has obtained satisfactory results for both unstable angina and hyperlipidemia, not only in improving hyperlipidemia dramatically, in relieving angina and in getting beneficial response to ECG, but also in ameliorating clinical symptoms.

Vascular endothelial cells (VEC) are the first permeability barrier between vascular walls and blood. It could synthesize and secrete a variety of endothelium-derived vasoactivators such as ET, NO, maintain the stability of ET/NO, ET/CGRP and modulate the contraction and dilation of blood vessels by regulating vascoactive substances. Hyperlipidemia, vascular endothelium injury and angina pectoris are closely interrelated. VEC injury is a vital and initial factor in arteriosclerosis (AS). In the case of hyperlipidemia, high levels of TC, free radicals, LDL and OX-LDL in blood may cause damage to VEC. The lipid peroxidation reaction triggered by oxygen free radicals is an important mechanism of the endothelial injury. OX-LDL produced by oxidative-modification has a toxic effect on VEC, which leads to obvious damage and plays an active role in the formation of AS. The vascular endothelial injury is closely related to the formation and rupture of unstable AS plaque as well as thrombosis and coronary spasm, which is of vital importance to the pathogenesis of unstable angina. The abnormal elevations of ET/CGRP and ET/NO in the presence of vascular endothelial injury reflect the severity of VEC injury. CEC is now considered as the sole indicator of VEC injury specifically and directly (6).

The results showed that CEC and ET in both groups with unstable angina before treatment were much higher than those in the normal group, whereas NO was markedly lower than that in the normal group, which could serve as evidence of the vascular endothelial injury. In addition, in the patients with hyperlipidemia, SCC could increase CGRP and NO significantly,
and lower ET, ET/CGRP and ET/NO. In the patients with unstable angina SCC could drastically decrease CEC and ET, but elevate NO. This indicated that SCC could inhibit the disturbance of the secretion of VEC, alleviate the VEC injury and have a remarkable protective effect on VEC. Moreover, SCC could elevate the activity of SOD and lower the content level of MDA and OX-LDL. This suggested that SCC could enhance the anti-oxidation, relieve the lipid peroxidation injury and inhibit the oxidative-modification of lipoproteins. The mechanism that SCC could protect the vascular endothelium is related to hyperlipidemia-lowering, elevation of HDL-C, reduction of LDL-C and OX-LDL, and anti-oxidation.

Platelet activation is the initial link of thrombosis of unstable angina. CD62p, also known as GMP-140 and mainly expressed on the surface of activated platelets and VEC, could mediate the adhesion between VEC and inflammatory cells as well as between platelets, monocytes and neutrophils, and therefore could give rise to functional disturbance and injury of VEC, and thus it is used as one of the principal markers in platelet activation. This study revealed that the content of CD62p in the patients with unstable angina increased significantly and after treatment with SCC decreased markedly, which is much better than that in the control group. This showed that SCC has the effect of inhibiting platelet activation, helps protect vascular endothelium and alleviates thrombosis and vasospasm induced by rupture of AS plaque. This could be a main pathogenetic factor in treating unstable angina.

Lp (a) has been regarded as an independent, important risk factor in causing AS. The high level of Lp(a) in blood is likely to induce AS by affecting the metabolism of cholesterol and fibrinolysis (7). Compared with after treatment between two groups, the remarkable effect of SCC in reducing Lp(a) helps to reverse and regress AS.

REFERENCES
1. Nomenclature and Criteria for Diagnosis of Ischemic Heart Disease. Report of the Joint International Society and Federation of Cardiology/World Health Organization Task Force on Standardization of Clinical Nomenclature Standardization. International Cardiology Association and WHO. 1981~9 (1): p75.
2. Guiding Principles of Clinical Research on New Chinese Drugs (Part ll). Ministry of Health, PRC 1995: p171.
3. P. Hao, F. Jiang, J. Cheng, L. Ma, Y. Zhang, Y. Zhao, Traditional Chinese Medicine for Cardiovascular Disease, Journal of the American College of Cardiology, Vol 43, Issue 20 2012, p2952-2966.
4. J. Chen, T. Wu, The Research of Congestive Heart Failure by TCM, Chinese Journal of Integrative Medicine on Cardio-Cerebrovascular Disease, 2005-10, p59.
5. Guiding Principles in Clinical Research on New Chinese Drugs in Treating Senile Diseases. Administration of Pharmaceutic Affair, Ministry of Health, PRC. J Chin Med Pharm 1989~ 4 (3) p72.
6. E. David, M. Marco, Circulating endothelial cells in coronary artery disease and acute coronary syndrome, Trends in Cardiovascular Medicine, Volume 25, Issue 7, October 2011, p478-487.
7. M. Rand, W. Sangrar, M. Hancock, M. Taylor, M. Santica, A. Marian, L. Koschinsky. Apolipoprotein (a) Enhances Platelet Responses to the Thrombin Receptor-Activating Peptide SFLLRN. AHA Journals, Arterioscler Thromb Vasc Biol, 1998~18 (9): 1393-1399.
(Received January 30, 2017, Chineses Journal of Intergrative Medicine, Iss.117, p174-180)

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