Journal of Ethnopharmacology 168 (2015) 129–135

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Use of traditional Chinese medicine in patients with hyperlipidemia: A population-based study in Taiwan Shih-Meng Chu a, Wei-Tai Shih a,b, Yao-Hsu Yang a,b,c, Pau-Chung Chen b,d,e, Yen-Hua Chu a,n a

Department for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Chia-Yi 61363, Taiwan Institute of Occupational Medicine and Industrial Hygiene, National Taiwan University College of Public Health, Taipei 10055, Taiwan c Center of Excellence for Chang Gung Research Datalink, Chang Gung Memorial Hospital, Chiayi, Taiwan d Department of Public Health, National Taiwan University College of Public Health, Taipei 10055, Taiwan e Department of Environmental and Occupational Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10055, Taiwan b

art ic l e i nf o

a b s t r a c t

Article history: Received 23 October 2014 Received in revised form 18 March 2015 Accepted 19 March 2015 Available online 28 March 2015

Ethno-pharmacological relevance: Chinese herbal products (CHPs) are commonly used in patients with hyperlipidemia in traditional Chinese medicine (TCM). Because hyperlipidemia and related disease are common issues worldwide, this study analyzed the prescription patterns and frequencies of CHPs for treating patients with hyperlipidemia in Taiwan. Background: Traditional Chinese medicine (TCM) has become popular as a therapy for controlling symptoms in patients with hyperlipidemia. This study aimed to analyze the prescription patterns of TCM for patients with hyperlipidemia in Taiwan. Methods: The study population was recruited from a random-sampled cohort of 1,000,000 people from the National Health Insurance Research Database between 2003 and 2009. We identified 30,784 outpatient visits related with hyperlipidemia diagnosis and collected these medical records. Association rules of data mining were conducted to explore the co-prescription patterns for Chinese herbal products (CHPs). Results: The most commonly prescribed herbal formula for hyperlipidemia treatment was Xue-Fu-ZhuYu-Tang (16.1%), and Shan Zha (Crataegi fructus; 25.0%) was the most commonly prescribed single herb. The most commonly prescribed combination of an herbal formula and a single herb was Xue-Fu-Zhu-YuTang and Dan Shen (Radix Salviae Miltiorrhizae), and the most commonly prescribed combination of couplet herbs was Dan Shen and Shan Zha. Conclusion: Xue-Fu-Zhu-Yu-Tang is the most frequently prescribed formula and is typically prescribed with Shan Zha, Dan Shen, and He Shou Wu for patients with hyperlipidemia. Clinical trials are warranted in future research to investigate the effects of the CHPs in terms of safety and efficacy and in particular to evaluate potential interactions with conventional treatments. & 2015 Published by Elsevier Ireland Ltd.

Chemical compounds studied in this article: Triterpenic acids (PubChem CID: 451674) Hyperin (PubChem CID: 5281643) Ursolic acid (PubChem CID: 64945) Keywords: Chinese herbal products Prescription pattern Hyperlipidemia NHIRD Traditional chinese medicine

1. Introduction Hyperlipidemia involves abnormally elevated levels of one or more lipids and/or lipoproteins in the blood triglyceride (TG) or cholesterol and pathological lipid qualities, such as elevated levels of low-density lipoprotein (LDL), the most common form of dyslipidemia. Hyperlipidemia results from complex interactions between genetic and environmental factors and is a significant factor in the progress of atherosclerosis and coronary artery disease (Haffner, 1999). Hyperlipidemia can be treated with dietary alterations and

n

Corresponding author. Tel.: þ 886 5 3621000x2069. E-mail address: [email protected] (Y.-H. Chu).

http://dx.doi.org/10.1016/j.jep.2015.03.047 0378-8741/& 2015 Published by Elsevier Ireland Ltd.

medications that regulate lipid metabolism through various mechanisms. Statins are the first-line therapy for lowering LDL levels and act by inhibiting 3-hydroxy-3-methylglutaryl-coenzymeA (HMG-CoA) reductase. However, statins have adverse effects, including muscle myopathy and derangements in hepatic function (Maggo et al., 2011). Although numerous drugs other than statins are also available, many of the conventional drugs (fibrates, ezetimibe, bile sequestrants and niacin) cause significant adverse effects, such as increased serum creatinine concentration, absorption of other drugs, flushing, nausea, vomiting, diarrhea, and anorexia (Al-Mohaissen et al., 2010; Filippatos and Mikhailidis, 2009; Jun et al., 2010). Thus, managing hyperlipidemia in patients intolerant to the adverse effects of such conventional drugs remains a major challenge.

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In addition to Western medical treatment, traditional Chinese medicine (TCM) is highly accessible and widely used in Taiwan. Even before TCM was incorporated into the National Health Insurance (NHI) program, more than one-third of Taiwanese people used TCM, and 79% of them regarded TCM as slower in action but more effective than Western medicine for treating diseases (Chiu et al., 1990; Pan et al., 2013). The NHI program, implemented in Taiwan in 1995, provides unified, universal, and comprehensive health insurance to all residents of Taiwan. In 2010, 99% of the entire population, 23 million people, was enrolled in the NHI program, and the Bureau of NHI (BNHI) has established contracts with 92% of the medical institutions in Taiwan. The NHI Research Database (NHIRD) provides data of prescriptions with well-defined registration for research (Cheng et al., 2011). In this study, we used the NHIRD to analyze the frequency and prescription patterns of TCM among patients with hyperlipidemia; concomitant use of TCM/CHPs with conventional (synthetic) antihyperlipidemia drugs has not been evaluated.

One million cohort random sample of NHIRD Exclusion of patients without hyperlipidemia diagnosis Patients with hyperlipidemia diagnosed from NHIRD

Patients who utilized outpatient visits with hyperlipidemia diagnosis less than 3 times within one year were excluded

Study population N=91,041

TCM non-users N=15,520

TCM users N=75,521

2. Materials and methods 2.1. Data source The NHIRD includes detailed medical records, including each clinic visit date, sex, date of birth, medical care facilities and specialties, prescribed drugs with the duration of medication, and/or management for treatment, transferred identification number, and three major diagnosis codes in the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) format. Both TCM and Western medicine physicians follow the standard diagnosis protocol of using the ICD-9-CM coding system when claiming for reimbursement. Furthermore, the BNHI of Taiwan conducts crosschecks and validates the charts to ensure the accuracy of diagnosis coding. The NHI system stores the longitudinal data of the beneficiaries of TCM and Western medicine. Thus, a random sample database of 1,000,000 patients (approximately 4.5% of the total population) was obtained for the current study. In this study, we included patients with hyperlipidemia diagnosis (ICD-9-CM codes 272.0, 272.1, 272.2, 272.3, and 272.4) who made outpatient visits more than 2 times within one year and evaluated their medical records (Fig. 1).

Hyperlipidemia related outpatient visits

Most prescribed

Most prescribed

Association rules

Chinese herbal formulae

Chinese single herb

for prescription patterns

Fig. 1. Flow recruitment chart of subjects from the one million random samples obtained from the National Health Insurance Research Database (NHIRD), 2003– 2009, in Taiwan.

All prescriptions

2.2. List of TCM remedies Based on the TCM philosophy, each prescription can contain one or more Chinese herbal drugs of various doses and/or a standard formula (remedy, Fu-Fang or Fang-Ji) composed of medicinal plants, animal products, and minerals in fixed doses, as mentioned in ancient TCM textbooks. In this study, all herbal materials with therapeutic effects were referred as Chinese herbal products (CHPs). CHPs are presented as concentrated powder prepared by extraction, fractionation and purification processes. Single herbs (SH) were CHPs with single medicinal substances only; these were often used together with other CHPs. Herbal formulas (HF) were CHPs composed of multiple SH with fixed proportion that were used alone or with other CHPs (World Health Organization, 2007.). The list of CHPs covered by the NHI program was downloaded from the BNHI website (National Health Insurance Administration, 2014). The corresponding drug information of the respective mixtures was then obtained from the Committee on Chinese Medicine and Pharmacy website, including the proportions of each ingredient, date and period of approval as a drug, code, and the name of the manufacturer (Committee on Chinese Medicine and Pharmacy, 2009).

A∩B

support factor=A∩B /Allprescriptions confidence factor=A ∩ B / A Fig. 2. Basic concepts and algorithms of association rules.

2.3. Statistical analysis The prescribed frequencies and percentages, including the dosage and duration, of herbal formulae and/or single herbs were analyzed.

S.-M. Chu et al. / Journal of Ethnopharmacology 168 (2015) 129–135

In addition, we used data mining techniques to investigate the association rules of co-prescriptions for lipid metabolism. We focused on two parameters: (1) the support factor (the proportion of the co-prescriptions of Medications A and B among all prescriptions) and (2) the confidence factor (the proportion of the co-prescriptions of Medications A and B among all prescriptions containing Medication A) (Fig. 2). SAS Version 9.1 software (SAS Institute Inc. Cary, NC, USA) was used for data linkage and descriptive statistics of drug use patterns.

3. Results The database was collected from 91,041 patients with hyperlipidemia diagnosis who made outpatient visits more than 2 times within one year from 2003 to 2009. We identified 30,784 hyperlipidemia related TCM outpatient visits made by 75,521 TCM users; the demographics are presented in Table 1 according to the status of TCM use. Hypertension was the most common comorbidity, followed by diabetes and coronary artery disease. The proportion of TCM users in 45–65 age group was higher as compared with other age groups. Notable differences in sex, insurance salaries, and residential area (urban or rural) were observed among the patients. We obtained the most commonly prescribed herbal formulae and single herbs for hyperlipidemia treatment, including the frequency of prescriptions, average daily doses, and average prescription duration (Table 2). In the present study, the average daily dose of herbal formulae was 3.0–10.3 g, and that of a single herb was 1.3–3.2 g. The average duration for prescription was 10– 14 days and the mean average outpatient visits for patients with hyperlipidemia was 7.0 (standard deviation 10.5). The most commonly prescribed herbal formula for hyperlipidemia was Xue-Fu-Zhu-Yu-Tang (16.1%), followed by Jia-Wei-XiaoYao-San (11.9%), Farng-Feng-Tong-Sheng-San (9.6%), Da Chai Hu Tang (5.7%), and Zhi Bai Di Huang Wan (5.3%).

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Shan Zha (Frucuts Crataegi: 25.0%) was the most commonly prescribed single herb for treating patients with hyperlipidemia, followed by Dan Shen (Radix Salviae Miltiorrhizae: 22.9%), He Shou Wu (Radix Polygoni Multiflori: 12.8%), Ze Xie (Rhizoma Alismatis: 8.0%), and Jue Ming Zi (Semen Cassiae: 6.7%). 3.1. Co-prescription patterns for herbal formulae and single herbs According to the association rules, the most commonly prescribed 2-CHPs combination of an herbal formula and a single herb for hyperlipidemia treatment was Xue-Fu-Zhu-Yu-Tang and Dan Shen, with a support factor of 5.08%, followed by Shan Zha, with a support factor of 4.99%. In addition, the most commonly prescribed couplet of herbs was Dan Shen and Shan Zha, with a support factor of 9.22%, followed by He Shou Wu and Shan Zha, with a support factor of 7.58% (Table 3a). Of all the prescribed herbal formulae and herbs with 3-CHPs combination, the most frequently prescribed combination of single herb was He Shou Wu to Dan Shen plus Shan Zha, with a support factor of 3.08%, and the combination of an herbal formula and single herbs was Xue-Fu-Zhu-Yu-Tang to He Shou Wu plus Shan Zha, with a support factor of 2.00% (Table 3b). Our finding that physicians frequently prescribed Xue-Fu-ZhuYu-Tang and Shan Zha in combination for patients with hyperlipidemia suggests that this may be an important co-prescription, which deserves further investigation.

4. Discussion This is the first study to use a random nationwide sample to evaluate prescription patterns of CHPs in patients with hyperlipidemia. Ancient and modern TCM physicians have prescribed various herbal formulae or single herbs for hyperlipidemia. However, prior to this study, the CHPs most commonly used for the treatment of hyperlipidemia were based on clinical experience without validated consensus. Using the NHIRD and association

Table 1 Sociodemographic and characteristics of hyperlipidemia population from one million random sampling cohort of the NHIR database 2003–2009. Characteristics Age o 45 45–65 465 Gender Female Male Insurance salaries (NTa$/month) 0 1–15840 15,841–25000 425,000 Urban levelb 1 2 3 4 Comorbidity (ICD-9-CM) Ischemic heart disease (410–414) Cardiovascular disease (430–438) Atherosclerosis (440) Type 2 diabetes (250.0) HTN (401–405) Total a b

Non-TCM users

TCM users

P value o .0001

2898 (18.7%) 7753 (50.0%) 4869 (31.4%)

15,775 (20.9%) 40,409 (53.5%) 19,337 (25.6%)

5706 (36.8%) 9814 (63.2%)

40,077 (53.1%) 35,444 (46.9%)

2867 2377 6024 4252

(18.5%) (15.3%) (38.8%) (27.4%)

12,604 10,467 34,051 18,399

(16.7%) (13.9%) (45.1%) (24.4%)

5457 6670 2192 1201

(35.2%) (43.0%) (14.1%) (7.7%)

24,832 34,119 10,622 5948

(32.9%) (45.2%) (14.1%) (7.9%)

o .0001

o .0001

o .0001

4626 (29.8%) 2736 (17.6%) 459 (3.0%) 6955 (44.8%) 10,755 (69.3%) 15,520

NT$d/month refers to new Taiwan dollars. Urban level 1¼ the most urbanized region; level 4¼the least urbanized region.

23,888 (31.6%) 13,051 (17.3%) 2190 (2.9%) 31,839 (42.2%) 49,703 (65.8%) 75,521

o .0001 .2976 .6973 o .0001 o .0001

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rule of data mining techniques, we analyzed the prescription patterns of the drugs used for hyperlipidemia and relative diagnostic codes for lipid metabolism disorders. For centuries, TCM physicians have prescribed Xue-Fu-Zhu-YuTang, a famous TCM formula, for treating cardiovascular diseases. Clinically reliable therapeutic effects have been achieved for atherosclerosis and coronary artery diseases (Chu et al., 2010; Hoa et al., 2006). According to a previous study, Xue-Fu-Zhu-YuTang has been reported to induce endothelial progenitor cell angiogenesis and hasten tube formation, particularly in capillary vessels, and to potentiate rt-PA-mediated neuroprotection against Table 2 Top ten herbal formulae and single herb prescribed by traditional Chinese medicine doctors for hyperlipidemia (n¼ 30,784). Frequency of prescription n (%) Herbal formulae Xue Fu Zhu Yu Tang Jia Wei Xiao Yao San Farng Feng Tong Sheng San Da Chai Hu Tang Zhi Bai Di Huang Wan Liu Wei Di Huang Wan Yin Chen Wu Ling San Tian Ma Gou Teng Yin Shu Jing Huo Xue Tang Ma Zi Ren Wan Single Herb Shan Zha (Fructus Crataegi) Dan Shen (Radix Salvia Miltiorrhizae) He Shou Wu (Radix Polygoni Multiflori) Ze Xie(Rhizoma Alismatis) Jue Ming Zi (Semen Cassiae) Da Huang (Radix et Rhizoma Rhei) Chuan Qi (Radix Notoginseng) Ge Gen (Radix Puerariae) Cao Jue Ming (Semen Celosiae) Huang Qi (Radix Astragali)

Average duration for prescription (days)

Average daily dose (g)

4975 3676 2950

(16.1) (11.9) (9.6)

10.8 14.1 9.5

5.7 4.6 7.1

1769 1635

(5.7) (5.3)

9.6 13.5

10.3 4.8

1357

(4.4)

11.5

4.9

1341

(4.3)

10.6

7.0

1304

(4.2)

13.5

4.8

1301

(4.2)

13.0

4.1

1286

(4.2)

13.2

3.0

7702

(25.0)

10.9

1.9

7061

(22.9)

12.4

1.7

3935

(12.8)

10.9

1.8

2482

(8.0)

10.0

1.9

2056

(6.7)

9.8

3.2

1883

(6.1)

10.6

1.2

1880

(6.1)

11.6

2.6

1797

(5.8)

12.4

1.4

1747

(5.7)

10.9

1.3

1601

(5.2)

13.5

1.7

thromboembolic stroke in rats (Lee et al., 2011). In an animal model, Xue-Fu-Zhu-Yu-Tang restored the abnormal metabolic state by interfering with various metabolic pathways to induce partial reverse of energy and lipid metabolism disturbance and decrease the risk of ketoacidosis, atherosclerosis, and fatty liver disease induced by a high-fat diet; these authors concluded that these effects might be due to the antihyperlipidemia, antioxidation, and antiinflammatory activities of its components (Song et al., 2013). Jia-Wei-Xiao-Yao-San, the second most commonly prescribed herbal formula for hyperlipidemia, is also the most commonly used CHPs for the treatment of menopausal symptoms (Chen et al., 2011; Yang et al., 2009). In addition, Jia-Wei-Xiao-Yao-San is prescribed to relieve hot flushes and other menopausal symptoms, including insomnia and emotional disturbance (Chen et al., 2003; Lai et al., 2005). Furthermore, postmenopausal women are reported to have increased serum levels of total cholesterol (TC), LDL, TG, and decreased levels of high-density lipoprotein (HDL) cholesterol. The high prevalence of these conditions might be the reason for Jia-Wei-Xiao-Yao-San being frequently prescribed for hyperlipidemia (Brown et al., 1993; Campos et al., 1988; Matthews et al., 1989; Stevenson et al., 1993). The results show that TCM physicians rarely prescribed Jia-Wei-Xiao-Yao-San as a sole treatment for hyperlipidemia patients; they typically combined JiaWei-Xiao-Yao-San with another herbal formula and/or single herb depending on the patient's symptoms. In our study, Zhi-Bai-DiHuang-Wan (5.3%) and Liu-Wei-Di-Huang-Wan (4.4%) are also frequently prescribed because of their therapeutic effects on vasomotor symptoms, such as hot flush and night sweating (Kwee et al., 2007). Farng-Feng-Tong-Sheng-San (Bofu tsusho shan in Japanese) is typically used to aid weight reduction (Akagiri et al., 2008) and improve impaired glucose tolerance to prevent various disorders, such as lipid metabolism disorder, hyperglycemia, and hypertension, by decreasing visceral lipid accumulation. In addition, several pharmacological studies have reported the ability of Farng-FengTong-Sheng-San to reduce fatty liver disease and atherosclerosis (Shimada et al., 2008). In an animal model study, Azushima et al. (2013) showed that Farng-Feng-Tong-Sheng-San can decrease blood pressure, the epididymal white adipose tissue weight, short-term food intake and the plasma acylated ghrelin levels in KKAy mice, a human metabolic disorder model with visceral obesity, T2DM, hyperlipidemia, and hypertension. As shown in Table 2, the three most commonly prescribed single herbs for patients suffering with hyperlipidemia were Shan Zha, Dan Shen, and He Shou Wu. Shan Zha is used to aid food digestion, dissipate food accumulation, and improve blood circulation (Xie et al., 2012). In vitro studies have demonstrated that the anti-hyperlipidemic effects of Shan Zha might be related to the inhibition of HMG-CoA reductase

Table 3a Co-prescriptions (2-CHPs) of single herbs and herbal formulae for hyperlipidemia population. Herbal associations

Support (%)

Confidence (%)

Single herb to single herb

9.22 7.58 5.28 5.02 4.10 5.08 4.99 4.33 4.09 3.90

37.07 54.44 60.20 36.08 56.38 28.93 28.37 41.53 31.60 30.13

Herbal formula to single herb

Association rule Radix Salvia Miltiorrhizae-Fructus Crataegi Radix Polygoni Multiflori-Fructus Crataegi Rhizoma Alismatis-Fructus Crataegi Radix Polygoni Multiflori- Radix Salvia Miltiorrhizae Semen Cassiae-Fructus Crataegi Xue Fu Zhu Yu Tang-Radix Salvia Miltiorrhizae Xue Fu Zhu Yu Tang-Fructus Crataegi Farng Feng Tong Sheng San-Fructus Crataegi Jia Wei Xiao Yao San-Radix Salvia Miltiorrhizae Jia Wei Xiao Yao San-Fructus Crataegi

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Table 3b Co-prescriptions (3-CHPs) combine of single herbs and herbal formulae for hyperlipidemia population. Herbal associations

Support (%)

Confidence (%)

Single herb to single herb

3.08 2.63 1.85 2.00 1.75 1.59

61.38 77.88 62.83 54.17 35.13 40.62

Herbal formula to single herb

(Ye et al., 2010) and the downregulation of intestinal acyl-coA: cholesterol acyltransferase activity (Lin et al., 2009). Flavonoids and triterpenic acids, the primary active components of C. fructus (Huang et al., 2010; Lin et al., 2011), decrease the serum levels of TC and TG in high-fat/cholesterol rabbit models (Liu and Yang, 2008). Two animal models of hyperlipidemia have been established using mice, and previous studies have shown that the main anti-hyperlipidemic effect constituents of Shan Za are hyperin and ursolic acid. In comparison with control groups, in the experimental group (patients with hyperlipidemia), the TC levels were considerably decreased, and HDL and superoxide dismutase activity were increased. In addition, the TC/HDL ratio was reduced. This effect lessens the damages to vascular endothelium induced by oxygen-free radicals in hyperlipidemia, thereby preventing atherosclerosis (Li et al., 2002; Yang et al., 2008). Dan Shen is considered to benefit patients with hyperlipidemia primarily by improving cardiovascular functions and is widely used to treat patients with coronary artery disease and other cardiovascular diseases by improving microcirculation, inducing coronary vasodilatation, and by suppressing thromboxane formation (Cheng, 2007). Dan Shen has various pharmacological effects such as anti-atherosclerosis, anti-inflammatory, and anti-oxidative damages (Baek et al., 2009; Liu et al., 2007). Previous studies have shown that Dan Shen exerts a protective effect against endothelial cell damage caused by reduced levels of IL-6 and TNF-α in the endothelial progenitor cell supernatant (Ji et al., 2010; Xu et al., 2001). He Shou Wu is considered as an important component of the TCM formulae for hyperlipidemia treatment, is used to “nourish the liver and kidneys”, according to the Chinese medicine philosophy, and has been used for centuries to improve the “essence” of the blood. Earlier studies have shown that He Shou Wu exerts anti-hyperlipidemic effects primarily by targeting the gastrointestinal tract or by reinforcing “tonic effects”, which means that a medicinal preparation intended to improve and strengthen the functioning of the body or increase the feeling of well-being (Bone, 2007; Yu et al., 2014; Zhao et al., 2014). In addition, He Shou Wu demonstrates TC-lowering effects and reduced LDL levels in rat blood and dose-dependent TC- and TG-lowering effects in the liver tissue (Li et al., 2012; Wang et al., 2012). Ancient TCM textbooks recommend prescribing two single herbs as an herb pair for two specific purposes; to increase the efficacy of treatment and to compensate for the insufficiency of a single herb. One example of an herb pair is Shan Zha and Dan Shen. Shan Zha is used to promote food digestion, flatulence reduction, and total cholesterol regulation. Dan Shen is used to promote blood circulation, decrease in total triglyceride, LDL, and pain suppresses. Therefore, Shan Zha and Dan Shen are the most frequently prescribed combination of two single herbs for hyperlipidemia treatment. In addition, the study has shown that this herb pair concept has been applied in herbal formulae–single herb treatment; TCM physicians typically prescribed Xue-Fu-Zhu-YuTang together with one or two single herbs for hyperlipidemia treatment. Because the proportion of a single herb in an herbal formula is fixed, it is prescribed with another single herb to alter

Association rule Radix Polygoni Multiflori-Radix Salvia Miltiorrhizae, Fructus Crataegi Rhizoma Alismatis-Radix Polygoni Multiflori, Fructus Crataegi Rhizoma Alismatis-Radix Salvia Miltiorrhizae, Fructus Crataegi Xue-Fu-Zhu-Yu-Tang-Radix Polygoni Multiflori, Fructus Crataegi Xue-Fu-Zhu-Yu-Tang-Fructus Crataegi, Radix Salvia Miltiorrhizae Jia-Wei-Xiao-Yao-San-Fructus Crataegi, Radix Salvia Miltiorrhizae

its proportions to suit a patient's condition and enhance its therapeutic effect. In general, the principles of diagnosis and treatment of hyperlipidemia in Chinese medicine are primarily based on the manifestations of the syndrome (i.e. the chief signs and symptoms of patients), for which a corresponding prescription is provided (Yu et al., 2006). According to physicians' personal experiences or based on traditional Chinese texts, one or more individual Chinese herbs can be added to deal with some of the hyperlipidemiarelated symptoms during the treatment period. In the previous study, most frequent diagnoses for patients were symptom related; they usually sought medical care in outpatient department (OPD), with the prescription duration of 1 week or less (Hsieh et al., 2008). TCM physicians tend to prescribe short-term prescriptions repeatedly and make these easily to be modified. We speculate that the average duration for each prescription ranges between 10 and 14 days represents the complexity of symptoms related to hyperlipidemia recognized by TCM physicians in Taiwan. 4.1. Limitations The study had a number of limitations. First, it was a retrospective review of claim reimbursement data obtained from the NHIRD and there was a lack of reliable measurement parameters such as physician notes, biochemical data, and imaging studies. Thus, evaluating the efficacy of CHPs for hyperlipidemia patients is not possible. Further studies are needed to evaluate if there are any beneficial effects to the patients. Secondly, the NHI program only reimburses for CHPs prescribed by TCM physicians and therefore, our analyses did not include CHPs, decoctions, and health foods purchased directly from pharmacies. This omission might have led to the underestimation of the frequency of prescription of TCM. However, because the NHI program comprehensively covers CHPs prescribed by TCM physicians, which generally costs less than CHPs or decoctions sold in TCM pharmacies, this underestimation is likely to be low. Thirdly, no suitable disease coding system exists for TCM. In Taiwan, TCM physicians only use the ICD-9-CM coding system for diagnosis. The therapeutic principle and methods of TCM are based on the results of “syndrome differentiation”; therefore, the same disease can be classified into various TCM syndrome subclassifications and treated differently, which might causes variations in the prescription patterns for hyperlipidemia treatment.

5. Conclusion The study has shown that Xue-Fu-Zhu-Yu-Tang is the most frequently prescribed TCM formula used for patients with hyperlipidemia and is typically prescribed in combination with single herbs Shan Zha, Dan Shen, and He Shou Wu. In view of the widespread prevalence of the common concurrent use of TCM and Western medical treatment in Taiwan. The investigation of potential herb–drug interactions and adverse effects may be beneficial to the patients with hyperlipidemia will be necessary, and thus,

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further studies are required to investigate the safety of the Chinese herbal drugs and TCM formulae used in the treatment for patients with hyperlipidemia. Furthermore, the precise role and efficacy of TCM herbal formulations in patients with hyperlipidemia should be evaluated by conducting well-designed randomized, placebocontrolled, and double-blinded clinical trials.

Conflict of interest statement The authors have no conflict of interest to disclose.

Acknowledgments The author's would like to thank Center of Excellence for Chang Gung Research Datalink for the comments and assistance in data analysis. This study was supported by a Grant from Chang Gung Memorial Hospital, Chia-yi Branch (CORPG6D0161). This funding body played no role in study design, analysis, and interpretation of data in this paper. This study was based on a portion of data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health, and was managed by the National Health Insurance Research Institutes, Taiwan. The statistical results and conclusions presented in this paper do not represent those of the Bureau of National Health Insurance, Department of Health, or the National Health Insurance Research Institutes. References Akagiri, S., Naito, Y., Ichikawa, H., Mizushima, K., Takagi, T., Handa, O., Kokura, S., Yoshikawa, T., 2008. Bofutsushosan, an oriental herbal medicine, attenuates the weight gain of white adipose tissue and the increased size of adipocytes associated with the increase in their expression of uncoupling protein 1 in high-fat diet-fed male KK/Ta mice. J. Clin. Biochem. Nutr. 42, 158–166. Al-Mohaissen, M.A., Pun, S.C., Frohlich, J.J., 2010. Niacin: from mechanisms of action to therapeutic uses. Mini Rev. Med. Chem. 10, 204–217. Azushima, K., Tamura, K., Wakui, H., Maeda, A., Ohsawa, M., Uneda, K., Kobayashi, R., Kanaoka, T., Dejima, T., Fujikawa, T., Yamashita, A., Toya, Y., Umemura, S., 2013. Bofu-tsu-shosan, an oriental herbal medicine, exerts a combinatorial favorable metabolic modulation including antihypertensive effect on a mouse model of human metabolic disorders with visceral obesity. PLoS One 8, e75560. Baek, E.B., Yoo, H.Y., Park, S.J., Chung, Y.-S., Hong, E.-K., Kim, S.J., 2009. Inhibition of arterial myogenic responses by a mixed aqueous extract of Salvia miltiorrhiza and Panax notoginseng (PASEL) showing antihypertensive effects. Korean J. Physiol. Pharmacol. 13, 287–293. Bone K. The Ultimate Herbal Compendium. A Desktop Guide for Herbal Prescribers. Warwick: Phytotherapy Press, 2007. ISBN 978-0-646-47602-5. Brown, S.A., Hutchinson, R., Morrisett, J., Boerwinkle, E., Davis, C.E., Gotto Jr., A.M., Patsch, W., 1993. Plasma lipid, lipoprotein cholesterol, and apoprotein distributions in selected US communities. The Atherosclerosis Risk in Communities (ARIC) study. Arterioscler. Thromb: J Vasc. Biol./Am. Heart Assoc., 13; #, pp. 1139–1158. Campos, H., McNamara, J.R., Wilson, P.W., Ordovas, J.M., Schaefer, E.J., 1988. Differences in low density lipoprotein subfractions and apolipoproteins in premenopausal and postmenopausal women. J. Clin. Endocrinol. Metab. 67, 30–35. Chen, H.Y., Lin, Y.H., Wu, J.C., Chen, Y.C., Yang, S.H., Chen, J.L., Chen, T.J., 2011. Prescription patterns of Chinese herbal products for menopausal syndrome: analysis of a nationwide prescription database. J. Ethnopharmacol. 137, 1261–1266. Chen, L.C., Tsao, Y.T., Yen, K.Y., Chen, Y.F., Chou, M.H., Lin, M.F., 2003. A pilot study comparing the clinical effects of Jia-Wey Shiau-Yau San, a traditional Chinese herbal prescription, and a continuous combined hormone replacement therapy in postmenopausal women with climacteric symptoms. Maturitas 44, 55–62. Cheng, C.L., Kao, Y.H., Lin, S.J., Lee, C.H., Lai, M.L., 2011. Validation of the National Health Insurance Research Database with ischemic stroke cases in Taiwan. Pharmacoepidemiol. Drug Saf. 20, 236–242. Cheng, T.O., 2007. Cardiovascular effects of Danshen. Int. J. Cardiol. 121, 9–22. Chiu CH, C.C., Chen, T.H., Ho, P.C., 1990. A study of the condition and demand for Chinese medicine in Taiwan. In: Development, IOE. (Eds.), Executive Yuan, Taipei. Chu, F.Y., Wang, J., Yao, K.W., Li, Z.Z., 2010. Effect of Xuefu Zhuyu Capsule (血府逐瘀 胶囊) on the symptoms and signs and health-related quality of life in the

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Use of traditional Chinese medicine in patients with hyperlipidemia: A population-based study in Taiwan.

Chinese herbal products (CHPs) are commonly used in patients with hyperlipidemia in traditional Chinese medicine (TCM). Because hyperlipidemia and rel...
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