Research survey and review of the effect of Compound Danshen Dripping Pills on the uric acid metabolism of patients with coronary heart disease

Lin Liuyng（林留洋）， nd Go Xing（高翔）

a： Third affiliated hospital， Beijing university of Chinese medicine， Beijing 100029， Chinab： Xi Yuan Hospital CACMS， Beijing 100700， China



Research survey and review of the effect of Compound Danshen Dripping Pills on the uric acid metabolism of patients with coronary heart disease

Lin Liuyang（林留洋）a， and Gao Xiang（高翔）b

a： Third affiliated hospital， Beijing university of Chinese medicine， Beijing 100029， China
b： Xi Yuan Hospital CACMS， Beijing 100700， China

ABSTRACT

A growing number of studies have reported that serum uric acid （SUA） is associated with coronary heart disease （CHD），which has been increasingly recognized and valued by the medical community. This paper surveys the epidemiological studies of hyperuricemia and CHD and summarizes the clinical study discussing the association between hyperuricemia and coronary heart disease with a prospect of exploring the possible mechanisms of compound Danshen dripping pills in reducing SUA in patients with coronary heart disease.

Coronary heart disease； Serum uric acid；Compound Danshen dripping pills

INTRODUCTION

Coronary heart disease is one of the common fatal diseases in the world. Currently， the common risk factors1for coronary heart diseases are diabetes， hypertension， dyslipidemia， unhealthy life style， etc.. In recent years， a large number of related epidemiological and clinical studies are made and correlations between serum uric acid and coronary artery disease gradually receive more recognition： high level of serum uric acid is closely related to vascular endothelial injury， which may make it an independent risk factor for coronary heart disease. Recent researches and comments on the metabolism of uric acid in the patients with coronary heart disease are as follows.

CORRELATION BETWEEN SERUM URIC ACID AND CORONARY HEART DISEASE Basic concepts and epidemiological studies of uric acid

Uric acid is the end metabolic product of purine nucleotide. It is usually catalysed by xanthine oxidase and generates superoxide anion free radicals in human body. Approximately 75% of uric acid is discharged by the kidneys， another 25% by the digestive tract. The abnormally elevated level of uric acid caused by increased production or decreased discharge can lead to a series of pathophysiological changes. The normal level of serum uric acid in our country is 149-420 μmol/L for men and 89-357 μmol/L for women. Hyperuricemia is usually defined as serum uric acid ＞ 420 μmol/L for men， ＞ 357 μmol/L for women2. Hyperuricemia is associated with age， sex， regional distribution， race and heredity. Intaking of high purine foods such as meat， seafood and animal guts， drinking， or intense physical exercise can increase the serum content of uric acid. Some drugs taken for a long time will ultimately lead to increased serum uric acid， such as thiazide diuretics， low-dose aspirin， compound hypotensive tablet， pyrazinamide， nifedipine and propranolol that can prevent the excretion of uric acid3. Studies demonstrate that the incidence of hyperuricemia is increasing all over the world and its prevalence is related to race， the degree of economic development， diet structure， aging population， medical treatment and so on. Epidemiological data suggest that the prevalence of hyperuricemia will increase as the national economy improves，which is the same with metabolic diseases such as diabetes and hyperlipidemia， which has demonstrated that hyperuricemia is associated with life style. In Europe and the United States，the incidence of hyperuricemia is approximately 2% - 18%4，5. A survey shows that the prevalence of hyperuricemia in China has increased by an average of 10 times from the mid 80's to the mid 90's. According to a recent academic research reporting the prevalence of hyperuricemia， conservatively， there may be 1.2 billion patients with hyperuricemia， accounting for 10 percent of the total population of our country6. It predominantly occurrs to the middle-aged and old males and postmenopausal women. However， the prevalence among the younger is increasing. It is well documented that hyperuricemia is closely correlated with traditional vascular risk factors such as obesity， hypertension，dyslipidemia， insulin resistance， and renal insufficiency7. Moreover， many recent studies suggest that hyperuricemia is an independent risk factor for cardiovascular disease8，9. If hyperuricemia can not be controlled as early as possible， it willincrease the risk of cardiovascular events and cause a variety of cardiovascular and cerebrovascular diseases. Therefore， how to prevent and deal with hyperuricemia effectively has become an important clinical issue.

Relation between serum uric acid and coronary heart disease in clinical study

The relationship between serum uric acid levels and cardiovascular disease has been extensively studied since 1951，when Certlel10first pointed out that the level of serum uric acid was closely related to cardiovascular disease. Freedman's11surveys showed that the increased serum uric acid was an independent risk factor for cardiovascular death and was positively correlated with the mortality of coronary heart disease. It also has a significant impact on the prognosis of patients with coronary heart disease. Deveci12studied 1012 patients undergoing coronary angiography， and the result showed that the level of serum uric acid in patients with coronary heart disease was significantly higher than that of non-CHD group. Study about the effect of different concentrations of uric acid on gene expression of human vascular endothelial cells showed that low，medium concentration uric acid salt stimulates expression of ICAM-1 gene in progenitor cell ， which was significantly higher than that in the control group， and the expression of ICAM-1 gene increases with the increasing of the concentration of uric acid. In vitro study showed that the uric acid salt can increase ICAM-1 in vascular endothelial cells， which in turn caused inflammation， promoted the oxidation of low density lipoprotein，injured vascular endothelium and led to the proliferation of vascular smooth muscle cells and finally promoted the formation and development of atherosclerosis. This eventually leads to the occurrence and development of coronary heart disease.13Additional clinical studies reported that the hyperuricemia group had significantly higher PAI-1 and ET9 compared with the control group which suggested that hyperuricemia can cause vascular endothelial dysfunction and lead to the occurrence and development of coronary heart disease.14

The pathological mechanism of hyperuricemia causing coronary artery disease

The effect of uric acid on vascular endothelial function is a concrete manifestation of the correlation between hyperuricemia and coronary heart diseases： Uric acid is a kind of water soluble substance with low solubility in the blood. As the concentration of uric acid rises， the urate crystals increasingly deposits on the arterial wall， and intima injurs directly.15In the early stage of thrombosis， urate crystals can promote platelet activation，platelet adhesion， aggregation and increase the possibility of coronary artery thrombosis. Uric acid is the endogenous antioxidant， which can be increased by compensating and enhancing the antioxidant capacity， eliminating free radicals damage to the cardiovascular system. It can also promote the oxidation of low density lipoprotein cholesterol and lipid peroxidation， resulting in increased production of oxygen free radicals which are involved in inflammation， and finally leads to the formation of atherosclerosis.16Increased serum uric acid is usually accompanied by enhanced activity of xanthine oxidase，which can decrease the activity of carbon monoxide synthetase and reduce the level of carbon monoxide， increase the level of endothelin， oxygen free radical and lipid peroxidation， lead to accelerated atherosclerosis. Thus， hyperuricemia plays an important role in the occurrence of cardiovascular diseases such as hypertension， coronary heart disease. Hyperuricemia can stimulate the proliferation of vascular smooth muscle cells and induce endothelial dysfunction， lead to endothelin increasing in the blood circulation which will further induce and aggravate the occurrence of coronary heart disease. Hyperuricemia and insulin resistance coexisting can cause hypertension， insulin resistance，lipid metabolism disorders， active growth hormone， vascular wall cell proliferation， cardiac hypertrophy and arterial plaque formation.

STUDY ON THE EFFECT OF COMPOUND DANSHEN DRIPPING PILLS ON CORONARY HEART DISEASE

Coronary heart disease belongs to “chest obstruction”，“heartache” in traditional Chinese medicine， locating in the“heart”， the main pathogenesis is “deficiency with excess complication”.17Chinese medicine has a long history in the treatment of coronary heart disease by strengthening the body resistance to eliminate pathogenic factors. Compound Danshen dripping pills can protect the cardiovascular system by multiple components， multi level and multi targeting effects. Vascular endothelial dysfunction is the early change in the pathogenesis of atherosclerosis. It appears before the morphological changes of the blood vessels and it is of vital importance for clinical practice targeting on improving endothelial function to prevent cardiovascular diseases. Compound Danshen dripping pills，which activate blood circulation and remove blood stasis，regulate qi and relieve pain， is a classical drug of traditionalChinese medicine for the treatment of coronary heart disease whose therapeutic effects has been validated. Study revealed that the active component of compound Danshen dripping pills may be Salvia miltiorrhiza. It has the protective effect on vascular endothelium by regulating the expression of mRNA ET-1 in vascular endothelial cells， controlling the production and secretion of ET and increasing the concentration of NO in blood. Tanshinone II A inhibits xanthine oxidase （XO） activity，and XO is the key enzyme in the synthesis of UA.18So the drug can increase coronary blood supply， improve microcirculation，scavenge free radicals， prevent platelet aggregation， improve blood rheology and has been widely used in the prevention，treatment and first aid of coronary heart diseases.

Content and application of Compound Danshen Dripping Pills

Compound Danshen Dripping Pills are mainly composed of Salvia miltiorrhiza， Radix notoginseng and borneol and its main active components are Danshensu， protocatechuic aldehyde，tanshinone II A， Notoginsenoside R1， Ginsenoside Rg1，ginsenoside Rb1.19It is a newly improved type of compound medicine on the basis of the original Compound Salvia Tablet using advanced technology the guidance of monarch， minister，assistant theory， the constructions of prescription were divided into principal agents and lesser agent. A combination of these three drugs can have complementary synergy effects on removing blood stasis， regulating qi and relieving pain.20Since its marketing in 1994， it has achieved great success for small， quick，convenient characteristics of modern Chinese medicine. After being approved successfully by FDA in USA， it has become the first TCM patent medicine entering the international market in 2010. Compound Danshen Dropping Pills has overcome the disadvantages of low efficacy and gastric mucosal stimulation of Compound Danshen tablet. The active ingredient has high purity， uniform dispersion and high dissolution rate， which can be directly absorbed into the blood by the mucous membrane，without the passing effect on the liver， and greatly improving the bioavailability. At present， it has been widely used in the treatment of coronary heart disease and many other diseases and has become the first choice for the treatment of cardiovascular diseases. The newly developed drug has expanded the areas of clinical application of Compound Danshen dripping pills and opened up a new path for reducing uric acid in the treatment of coronary heart disease.

Study on the correlation between serum uric acid and Compound Danshen Dripping Pills

Compound Danshen dripping pills have an important clinical effect on the metabolism of serum uric acid in patients with coronary heart disease. A study was conducted to observe the changes of serum high sensitivity C-reactive protein （hs-CRP），adiponectin （APN） and UA of CHD patients before and after treatment of compound Danshen dripping pills. Sixty-four CHD patients were randomized into the observation group and control group. The CHD patients in both groups were given meto-prolol， aspirin and nitroglycerin injection. Patients in the observation group were additionally given compound Danshen dripping pills. Results showed that the total efficiency in the observation group was significantly higher than that in the control group（ 93.75% vs 68.75%， P＜0.05）. The researchers concluded that the changes of serum hs-CRP， APN and UA is related to the occurrence and development of CHD and that Compound Danshen dripping pills can effectively reduce the serum hs-CRP， UA and raise serum APN. Besides， it can improve the prognosis of CHD.21Another research studies the effect of ethanol extract of Salvia miltiorrhiza Bge on hyperuricema mice and investigates the possible mechanism. Different doses of ethanol extract of Salvia miltiorrhiza Bge were administrated to hyperuricemia mice induced by intraperitoneal injection of potassium oxonate and xanthine. Then the serum uric acid，urinary uric acid and the hepatic xanthine oxidase activities of mice were observed. The researchers concluded that the middle and low dose groups of ethanol extract of Salvia miltiorrhiza Bge can significantly reduce the level of SUA and promoted the discharge of UUA， the ethanol extract of Salvia miltiorrhiza Bge can reduce the level of SUA in hyperuricema mice by promoting the discharge of UUA.22On the basis of past researches， Liu et al has successfully established the mice hyperuricemia model. The conclusion is that the uric acid level of mice hyperuricemia model could be decreased significantly by VitB2， VitB6， VitB12，folic acid and the Compound Danshen Dripping Pills. Compared with allopurinol，VB6， VB 12 and folic acid almost have the same effect on UNC acid level decrease， VB2 can not reach the effect of allopurin. The Compound Danshen Dripping Pills have a better effect than allopurinol and other vitamins B.23There are some researches provided a new therapy for reducing uric acid（UA） by studying the role of Compound Danshen dripping pills in reducing UA and protecting endothelium in a hyperuricemia animal model. Thirty-eight SPF-class male Kunming mice were randomly divided into the control group （group A， n=12），allopurinol treatment group （group B， n=13）， and Compound Danshen dripping pills treatment group （group C， n=13）. After three weeks， serum UA and NO levels of the mice in 3 groups were detected and thoracico-abdominal aorta was isolated and cut into sections which were stained with H&E. Expressions of NF-κB and VCAM-1 were detected with immunohistochemical staining. The serum UA level was significantly lower whereas the serum NO level was significantly higher in groups B and C than that in group A ［（372.71±22.16）µmol/L and（328.65±28.78）µmol/L vs （605.67±54.76） µmol/L， P＜0.01； （29.55±1.55）µmol/L and （35.11±2.03）µmol/L vs （20.89±1.70） µmol/L， P ＜0.01）］. Conclusion： compound Danshen dripping pill can reduce the serum UA level， down-regulate the expression of NF-κB and VCAM-1， and increase the serum NO level in hyperuricemia mice.24Some studies investigate the effect of Compound danshen dripping pills on Xanthine oxidase activity in human. The contents of four major metabolites of caffeine， 5-acetylamino-6-formylamino-3-methyluracil（AFMU）， 1-methylxanthine（1X），1-methyluric acid（1U） and 1，17-dimethyluricacid（17U）in the urine were determined by RP-HPLC method and then evaluated the activity o Xanthine oxidase by calculating the 1U/（1X+1U）. Results showed that the average activities of XO were 0.33±0.05，0.32±0.07， 0.31±0.04 before treatment after taking medicine 14 and 28 days respectively. There was statistical significance between before treatment and after taking medicine 14 days and there was statistical significance between before treatment and after taking medicine 28 days. Danshen dripping pills if used for a long time can inhibit XO activity to a certain extent.25Wu et al thought that xanthine oxidase plays an important role in the uric acid production process. It is an important human metabolic enzyme. Compound Danshen dripping pills are not only the first choice for the treatment of cardiovascular diseases， but also the applicability is still expanding. By investigating the effect of Compound Danshen dripping pills on CYPlA2，CYP2A6，NAT2 and XO activities in human， she concluded that Compound Danshen dripping pills may have a certain inhibition on XO activity.26Another study investigated the effect of Compound Danshen dripping pills on five enzymes in the cerebral ischemiareperfusion injury rat model. The changes of content of NO，MDA， activity of SOD， GSH-PX and XOD in serum were detected. Results showed that the levels of NO and MDA were reduced （P ＜0.05）. The activity of GSH-PX and SOD was increased （P＜0.05）， whereas the activity of XOD was increased（P＜0.05）. Therefore， Compound Danshen dripping pills can reduce the content of NO and MDA and the activity of XOD， and increase the activity of GSH-PX and SOD.27Thus， the Compound Danshen Dripping Pills can promote the metabolism of uric acid， and has important clinical significance in the treatment of coronary heart disease and other related vascular diseases.

DISCUSSION AND PROSPECT

The relationship between serum uric acid and coronary heart disease （CHD） is very complex. It remains controversial whether hyperuricemia affecting vascular endothelium is independent risk factors for coronary heart disease， and some mechanism is not yet clear. However， most of researches has provided evidence that hyperuricemia is closely related to coronary heart disease， which is helpful for us to recognize high risk earlier. The vascular endothelium is an important protective barrier of the blood vessel and its dysfunction can promote the formation and development of atherosclerosis. Therefore， improving endothelial function is a key point in the prevention and treatment of atherosclerosis. Compound Danshen dripping pills has multiple components， multi-level， multi-targeting protective effect on cardiovascular system. Experts has confirmed that vascular endothelium dependent diastolic function damage in patients with coronary heart disease risk factors is reversible and Compound Danshen dripping pills can reverse this dysfunction. According to literatures of recent years， it is uric acid that plays an important role in vascular endothelium dysfunction. Subsequently， researchers hypothesize that it is by lowering the SUA that the Compound Danshen dripping pills protect the vascular endothelium. Remarkable achievements have been made on the basis of this hypothesis： therapeutic effects of Compound Danshen dripping pills on coronary heart disease have been validated； risk factors of coronary heart disease have been greatly reduced， and the formation and development of atherosclerosis have been effectively slowed down. So it helps to expand the areas of clinical application of Compound Danshen dripping pills and open up a new path for reducing uric acid in patients with coronary heart disease. The unique perspective indicates that our researchers are in search of multiple pathogenic factors to pursue the predisposing factors of coronary heart disease. However such studies are quite few and most of them are of a quite small scale. Further large scale studies are still needed to confirm this conclusion. Therefore， such studies should be further advocated and pathological mechanism of uric acid inducing coronary heart disease needs to be clarified in addition， more risk factors for coronary heart disease should be identified in order to provide a better treatment strategy for coronary heart disease.If more attention is given to the hyperuricemia patients with the coronary heart disease in clinical work and early diet and lifestyle intervention or drugs are given to prevent elevation of SUA and urate depoistion， the occurrence of these diseases will be delayed or prevented.

REFERENCES

1 Ross R. The pathogenesis of atherosclerosis： a perspective for the 1990s. Nature， 1993， 362（6423）：801-809.

2 Gao AN. Analysis of the relationship between different levels of uric acid and metabolic syndrome and coronary heart disease. Dalian： Dalian Medical University，2012.

3 Feng PL， Jiang YF， Yuan D， et al. Relationship between concentration of serum uric acid and risk factors of cardiovascular disease in population of healthy examination. South China Journal of Cardiovascular Diseases， 2010，16（6）：456， 478.

4 Puddu PE， Lanti M， Menotti A， et al. Serum uric acid for short—term prediction of cardiovascular disease in the Gubbio population study. Acta Cardiol， 2001， 56（4）：243-251.

5 Niskanen LK，Laaksonen DE，NYYSSONEN K， et al.Uric acid level as a risk factor for cardio-vascular and all-cause mortality in middle-aged men： A prospective cohort study. Arch Intern Med， 2004， 164（14）：1546-1551.

6 Li Y. The relationship between plasma homocysteine and lipoprotein （a） and serum uric acid in male patients with carotid atherosclerosis. Chinese Journal of Clinical Medicine， 2011，18（3）：320-321.

7 Chinese College of Cardiovascalur Physicians. Chinese expert consensus on the diagnosis and treatment of asymptomatic hyperuricemia combined with cardiovascular disease. Chinese Journal for Clinicians， 2011， 39（2）：73，77.

8 Verhaar MC， Wever RMF， Kastelein JJP， et al.5-methyltetrahydrofolate，the active from of folic acid，imp roves endothelial function in familial Hypercholesterolemia. Circulation， 1998， 97：237-241.

9 Lewis AS， Murphy L， McCalla C， et a1. Inhibition of mammalian xanthine oxidase by folate compounds and amethopterin. J Biol Chem， 1984， 259（1）：12-15.

10 Gertler MM， Garn SM， Levinr SA. Serum uric acid in relation to age and physique in health and in coronary heart disease.An Intern Med， 1951， 34（6）：1421-1431.

11 Freedman DS， Williamson DF， Gentr EW， et al. Relation of serum acid to mortality and ischemic heart disease. The NHANNESI Eoidemiologic Follow-up study. Am J Epidemiol， 2011， 141（7）：637-644.

12 Sinan Devecio， KabakciG， OkutucuS， etc al. The association between serum uric acid level and coronary artery disease. International journal of clinical practice， 2010， 64：900-907.

13 Xu H， Yang RC， Hong H， et al. Effect of uric acid on the expression of intercellular adhesion molecule -1 in vascular endothelial cells.Journal of Medical Research， 2006， 35（8）：22-24.

14 Jia SD， Wang YG， Miao ZM. The effects of hyperuricemia on function of vascular endothelial cells.Acta Aacademiae Medicinae Qingdao Universitatis，2004，40（3）.

15 Edwards NL.The role of hyperuricemia in vascular disorders. Curr Opin Rheumatol， 2009， 21（2） ： 132-137.

16 Chen W， Hou XL， Wang WH， et al. Relationship between serum concentration of uric acid and coronary heart disease. Chinese Journal of Cardiovascular Rehabilitation Medicine，2011， 20（3）.

17 Liu CW， Huang MB， Mai BY. Study on the cause and clinical significance of hypertension complicated with hyperuricemia. Chinese Circulation Journal， 1993，12：720-721+766.

18 Jing YY.A meta analysis of the relationship between serum uric acid levels and coronary heart disease.Yan'an：Yan'an University，2013.

19 Zhang ZJ. Determination of 6 components in Compound Danshen Dripping Pills by HPLC-UV-ELSD. Herald of Medicine， 2014：10.

20 Wang YH. Efficacy analysis of Compound Danshen dripping pills combined with aspirin in the treatment of 62 cases of coronary heart disease.Journal of Clinical Medicine in Practice， 2013：17（16）.

21 Liu XQ， Yang HX， Wu NL. Influence of Compound Danshen dripping pills on serum high sensitivity C-reactive protein，adiponectin and uric acid of coronary heart disease patients. Journal of Xinxiang Medical College， 2012， 29（4）.

22 Liu Y， Meng ZQ， Zhang CF， et al. Study on the antihyperuricemia effect of Salvia miltiorrhiza Bge. Strait Pharmaceutical Journal， 2013， 25（1）.

23 Liu G. The influence of different vitamins B and Compound Danshen Dripping Pill on uric acid level of hyperuricemia mice. Chinese people's Liberation Army Medical College， 2012.

24 Liu G， Zhu P. Role of compound red sage root dripping pill in reducing uric acid （UA） and protecting endothelium：an animal experimental study. Academic Journal of Chinese PLA Medical School， 2013（4）.

25 Zhang X. Study on the effect of compound Danshen drippingpills on xanthine oxidase activity in human. Chinese Journal of Hospital Pharmacy， 2009， 29（19）.

26 Wu H. Effects of Compound Danshen Dripping Pill on human drug metabolism enzyme CYP1A2， CYP2A6， NAT2 and XO. Ji'nan： Shandong University，2007.

27 Feng J， Xu YP， Pei BX. Effect of Fufang Danshen Diwan on five enzymes.Journal of Chinese Practical Diagnosis and herapy， 2006， 20（6）.