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Journal of Ethnopharmacology 140 (2012) 345– 367

Contents lists available at SciVerse ScienceDirect

Journal of Ethnopharmacology

journa l h o me page: www.elsev ier .com/ locate / je thpharm

merging approaches of traditional Chinese medicine formulas for the treatmentf hyperlipidemia

eidong Xiea, Yunan Zhaob, Lijun Duc,∗

Division of Life Science & Health, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, ChinaLaboratory of Pathological Sciences, Basic Medical College, Nanjing University of Traditional Chinese Medicine, Nanjing 210029, ChinaProtein Science Laboratory of the Ministry of Education, Laboratory of Pharmaceutical Science, School of Life Science, School of Medicine, Tsinghua University, Beijing 100084, China

r t i c l e i n f o

rticle history:eceived 10 November 2011eceived in revised form 14 January 2012ccepted 16 January 2012vailable online 26 January 2012

eywords:yperlipidemiaraditional Chinese medicineipid-lowering drugs

a b s t r a c t

Ethnopharmacological relevance: Traditional Chinese medicine (TCM) formulas have been widely used inChina since ancient times to treat certain diseases (e.g., phlegm, dampness and blood stasis). Recently, theeffects of these medicines have been increasingly demonstrated to be helpful for hyperlipidemic patients.Aim of the study: This manuscript aims to describe the scientific evidence for the efficacy of TCM andattempts to identify potential TCM formulas for treating hyperlipidemia.Materials and methods: TCM formulas approved by the State Food and Drug Administration of China (SFDA)were sourced from the official SFDA website (http://www.sda.gov.cn/). Human and animal evidence forthe hypolipidemic effects of herbs from TCM formulas were reviewed via the Internet (Elsevier, ACS,Wiley Online Library, SpringerLink, PubMed, Web of Science, CNKI, Baidu, and Google) and libraries upto October 31, 2011.Results: More than 50 TCM formulas have been used to treat hyperlipidemia. These herbs can primarilybe grouped into three categories: (1) herbs promoting excretions, generally by reducing food retention,enhancing purgative effects, and promoting diuresis and choleretic effects, e.g., Fructus Crataegi ( ),Radix Polygoni Multiflori ( ), Semen Cassiae ( ), and Radix et Rhizoma Rhei ( ), Rhizomaalismatis ( ), and Herba Artemisiae Scopariae ( ); (2) herbs acting on the cardiovascular system,generally by improving blood circulation based on TCM theories, e.g., Radix Salviae Miltiorrhizae ( ),Radix Puerariae ( ), Rhizoma Chuanxiong ( ), Flos Carthami ( ), and Folium Nelumbinis ( );and (3) herbs that have tonic effects, e.g., Fructus Lycii ( ), Radix Ginseng ( ), and Radix Astragali

( ).Conclusions: Three basic approaches, including excretory function enhancement, cardiovascular systemimprovement, and tonic effect reinforcement, are emerging among TCM formulas for the treatment ofhyperlipidemia. These approaches may be useful in controlling blood lipid levels, preventing cardiovas-cular complications, and adjusting bodily functions in hyperlipidemic patients. However, solid evidenceof the efficacy of these treatments is required.

Abbreviations: BWF, Barbary wolfberry fruit; FC, Fructus Crataegi; HAS,erba Artemisiae Scopariae; HDL-C, high-density lipoprotein cholesterol; HMG-oA, 3-hydroxy-3-methyl-glutaryl-coenzyme A; LDL-C, low-density lipoproteinholesterol; LDLR, low-density lipoprotein receptor; LPL, lipoprotein lipase; MMR,embranous milkvetch root; RA, Rhizoma alismatis; RC, Rhizoma Chuanxiong;

PM, Radix Polygoni Multiflori; RSM, Radix Salviae Miltiorrhizae; RYR, red yeast rice;C, quality control; PPAR�, peroxisome proliferator-activated receptor alpha; SFDA,tate Food and Drug Administration of China; TC, total cholesterol; TCM, traditionalhinese medicine; TGs, triglycerides.∗ Corresponding author. Tel.: +86 10 62773630; fax: +86 10 62773630.

E-mail address: lijundu@mail.tsinghua.edu.cn (L. Du).

378-8741/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved.oi:10.1016/j.jep.2012.01.027

© 2012 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

Dyslipidemia is characterized by increased total cholesterol(TC), triglyceride (TG), and low-density lipoprotein cholesterol(LDL-C) levels and by decreased high-density lipoprotein choles-terol (HDL-C) levels. Dyslipidemic states increase the risk ofcardiovascular diseases. Dyslipidemia can be treated with dietaryalterations and medications that affect lipid metabolism via a vari-ety of mechanisms (Toth, 2010). Statins are the first-line therapiesfor reducing LDL-C serum levels and act by inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase. However,

statins also have adverse effects, including muscle myopathy andderangements in hepatic function (Maggo et al., 2011). Fibratesare second-line drugs that are used for the treatment of dys-lipidemia and reduce serum TG levels by activating peroxisome

346 W. Xie et al. / Journal of Ethnopharmacology 140 (2012) 345– 367

Table 1Differences in the chemical structure, quality control (QC), pharmacological activities, toxicology, and cost between Western drugs and TCM used for the treatment ofhyperlipidemia.

Pharmaceutics Pharmacology Pharmacokinetics Toxicology Costs

Chemistry QC Activities Mechanisms

Western drugs Clear Good Strong Clear Clear Strong HighTCM Unclear Poor Weak Unclear Unclear Weak Low

pihttiog(aceaadad

t2cdlandc

t2wpdeaCaamcat

aCsobThdaw(o

roliferator-activated receptor alpha (PPAR�). However, fibratesncrease serum creatinine concentrations (Jun et al., 2010) andave been correlated with sudden death, pancreatitis, and venoushrombosis (Wierzbicki, 2009). Ezetimibe and bile acid seques-rants are both effective at reducing LDL-C levels by decreasingntestinal cholesterol absorption. However, these drugs, which actn the gastrointestinal tract, are associated with increased adverseastrointestinal effects and affect the absorption of other drugsFilippatos and Mikhailidis, 2009). Niacin reduces serum TG levelsnd increases HDL-C levels primarily by activating the G-protein-oupled receptor GPR109A. However, niacin causes many adverseffects, such as flushing, nausea, vomiting, diarrhea, and anorexia; itlso increases the levels of glucose, uric acid, and hepatic enzymes,mong others (Al-Mohaissen et al., 2010). Thus, the management ofyslipidemia is still a major challenge with respect to patients whore intolerant to the adverse effects of these classic hypolipidemicrugs.

Traditional Chinese medicines (TCM) play an important role inhe treatment of hyperlipidemic patients (Dou et al., 2008; Liu et al.,011; Wang and Zhang, 2007). The hypolipidemic effects of TCM areomparable to or slightly lower than those of classic hypolipidemicrugs (Dou et al., 2008). In addition, TCM are popular among hyper-

ipidemic patients in China because of their low cost and minimaldverse effects (Li et al., 2011a,b; Table 1). Alternatively, TCM areot free of certain weaknesses that also affect classic hypolipidemicrugs, e.g., poor quality control, unclear mechanisms of action, andomplicated pharmacokinetic parameters.

TCM have been widely used in China since ancient times to cer-ain syndromes, such as phlegm, dampness, and blood stasis (Zhang,008). Physicians who prescribe TCM recently realized that patientsith both early and late-stage hyperlipidemia exhibit the sameathological changes as those that are characteristic of phlegm,ampness, and blood stasis (Shi and Li, 2007). Moreover, increasingvidence indicates that the TCM that improve phlegm, dampness,nd blood stasis are useful in treating hyperlipidemic patients inhina (Yang and Zhang, 2011). Although hyperlipidemia is not

TCM term, physicians who practice Chinese medicine in Chinattempt to treat this disease using TCM principles. However, theajority of these traditional approaches are unknown to physi-

ians who practice modern medicine. Moreover, the TCM herbs orpproaches that are thought to exert hypolipidemic effects requirehe same supportive evidence as modern medicines.

For this review, TCM formulas (http://www.sda.gov.cn) that arepproved by the State Food and Drug Administration (SFDA) ofhina were selected. These were chosen because they have beenubjected to a relatively strict drug evaluation process. A great dealf systemic preclinical or clinical data (including data that cannote obtained from open publications) is available for these selectedCM formulas. The herbs that compose these TCM formulas thatave been demonstrated to exhibit human and animal hypolipi-emic effects when tested alone. These TCM were selected for

nalysis in this review to determine the underlying reasons for theiridespread use. We retrieved these data primarily via the Internet

Elsevier, ACS, Wiley Online Library, SpringerLink, PubMed, Webf Science, CNKI, Baidu, and Google) and libraries up to October

31, 2011. In this review, we attempt to identify potential TCMapproaches for the treatment of hyperlipidemia.

2. TCM formulas

TCM theories suggest that that there are many types of hyper-lipidemia and that afflicted patients should be treated differently(Yang and Zhang, 2011). Hence, there is flexibility in terms of whichformulas are used to treat hyperlipidemic patients with differentsyndromes, and there are many different formulas to choose from.Presently, more than 50 TCM formulas have been approved by theSFDA to treat hyperlipidemic patients in mainland China (Table 2).

These formulas are primarily herbal (more than 100 herbs) andhave been developed into many pharmaceuticals that are avail-able in tablets, capsules, pills, oral liquids, etc. Moreover, animal ormineral substances or other chemical components are occasionallyadded to these formulas. Although these herbal TCM formulas arevery complicated, we identified the 29 most frequently prescribedherbs that compose between 5% and 50% of the given formu-las (Fig. 1). We selected the 15 most commonly used herbs thatexhibit pharmacological effects when used alone in human and/oranimal trials (Table 3). In addition to the formulas, FermentumRubrum, Fructus Crataegi (FC), Semen Cassiae, Herba Gynostem-matis, Rhizoma Curcumae Longae, Folium Ligustri Lucidi, etc., wereseparately shown to treat hyperlipidemic patients. In the presentstudy, we briefly review the pharmacological effects of the 15 mostfrequently prescribed herbs in TCM formulas and the most com-monly used herb, Fermentum Rubrum.

3. Herbs

3.1. Fructus Crataegi (Hawthorn Fruit, Shan Zha, )

FC is derived from the dried mature fruit of Crataegus pinnatifidaBunge. Var. major N.E.Br. (Rosaceae) or Crataegus pinnatifida Bunge.(Rosaceae). FC is used to aid in food digestion, to dissipate food accu-mulation, to improve blood circulation, and to disperse blood stasis.It is thought that FC exerts its hypolipidemic effects primarily bytargeting the gastrointestinal system, although it also has certaincardiovascular activities. FC is the most popular TCM herb for thetreatment of hyperlipidemic patients. FC is prescribed in more than50% of the Chinese herb formulas that are approved by the ChineseSFDA. FC aqueous extracts given at an oral dosage of 3.6 g/day for 3months were demonstrated to lower blood TC, TG, and LDL-C levelsin 45 hyperlipidemic volunteers (Xiong et al., 2004). However, nei-ther a placebo nor a positive control were used in this clinical trial.A high-cholesterol diet supplemented with 2 g/100 g of hawthornfruit powder for 12 weeks was demonstrated to have significantlipid-lowering effects in New Zealand white rabbits (Zhang et al.,2002). These effects may be related to FC’s promotion of the excre-tion of neutral and acidic sterols. In vitro studies demonstrated that

FC’s hypolipidemic effects may be related to its inhibition of HMG-CoA reductase (Ye et al., 2010) and the downregulation of intestinalacyl-coA: cholesterol acyltransferase activity (Lin et al., 2009). Anin vivo study of mice that were fed high-fat diets following the

W. Xie et al. / Journal of Ethnopharmacology 140 (2012) 345– 367 347

Table 2Traditional Chinese medicines with antihyperlipidemic effects that are approved by the SFDA in mainland China.

348 W. Xie et al. / Journal of Ethnopharmacology 140 (2012) 345– 367

Table 2 (Continued )

W. Xie et al. / Journal of Ethnopharmacology 140 (2012) 345– 367 349

Table 2 (Continued )

350 W. Xie et al. / Journal of Ethnopharmacology 140 (2012) 345– 367

Table 2 (Continued )

W. Xie et al. / Journal of Ethnopharmacology 140 (2012) 345– 367 351

Table 2 (Continued )

352 W. Xie et al. / Journal of Ethnopharmacology 140 (2012) 345– 367

Table 2 (Continued )

W. Xie et al. / Journal of Ethnopharmacology 140 (2012) 345– 367 353

Table 2 (Continued )

354 W. Xie et al. / Journal of Ethnopharmacology 140 (2012) 345– 367

Table 2 (Continued )

W. Xie et al. / Journal of Ethnopharmacology 140 (2012) 345– 367 355

Table 2 (Continued )

356 W. Xie et al. / Journal of Ethnopharmacology 140 (2012) 345– 367

Table 2 (Continued )

W. Xie et al. / Journal of Ethnopharmacology 140 (2012) 345– 367 357

Table 2 (Continued )

‘Nei Ke Zhong Cheng Yao He Li Ying Yong Shou Ce’, the book was produced by Gao (2009).‘Xin Bian Guo Jia Zhong Cheng Yao’, the book was produced by Song and Guo (2002).

358 W. Xie et al. / Journal of Ethnopharmacology 140 (2012) 345– 367

na an

o7tt(p(aftcstpt

3W

titaiomo

Fig. 1. The frequencies of Chinese herbs that are approved by the SFDA of Chi

ral administration of FC extracts at a dosage of 250 mg/kg day for days indicated that FC’s mechanisms of action may be relatedo increased liver PPAR� levels (Niu et al., 2011). Flavonoids andriterpenic acids may be the primary active components of FCHuang et al., 2010; Lin et al., 2011). However, most flavonoids orhenolic acids are poorly absorbed following oral administrationChang et al., 2005). Ursolic acid, one of the primary triterpeniccids, is also present only in low concentrations in blood and tissuesollowing oral administration (Chen et al., 2011). Consequently, fur-her studies are required to assess the pharmacokinetics of theomponents of FC. This TCM may cause mild rashes, headaches,weating, dizziness, palpitations, sleepiness, agitation, and gas-rointestinal symptoms (Rigelsky and Sweet, 2002). Despite theseotentially severe adverse effects, however, FC is generally wellolerated (Daniele et al., 2006).

.2. Radix Polygoni Multiflori (tuber Fleeceflower Root, He Shouu, )

Radix Polygoni Multiflori (RPM) is derived from the dried rootuber of Fallopia multiflora Thunb. (Polygonaceae). RPM is processednto both raw and prepared pharmaceutical forms. Raw RPM is usedo prevent the recurrence of malaria, to eliminate toxic materials,nd to moisten the intestine, relaxing the bowels. Prepared RPM

s used to nourish the liver and kidneys, to improve the essencef the blood, to blacken the hair and beard, and to strengthen theuscles and bones. RPM is widely used as an important component

f TCM formulas for the treatment of hyperlipidemic patients. RPM

d that are present in TCM formulas used for the treatment of hyperlipidemia.

appears to exert its hypolipidemic effects primarily by targeting thegastrointestinal tract or by reinforcing tonic effects. Orally admin-istered RPM in liquid form (equivalent to 15 g raw herb/day) for 60days significantly lowered serum TC and TG levels and increasedHDL-C levels in 50 hyperlipidemic patients (Ke et al., 2000). How-ever, no placebo or positive controls were performed in this trial.RPM extracts given at an oral dosage of 100 mg/kg for 5 weeks alsoexhibited appreciable lipid-regulating effects in Sprague–Dawley(SD) rats that were fed high-fat diets (Xu and Wang, 2004). Polysac-charides from RPM that were administered at oral dosages of 50and 200 mg/kg/day for 28 days significantly lowered serum TCand TG levels and increased HDL-C levels in mice fed high-fatdiets. This effect may be associated with the increased activitiesof both lipoprotein lipase (LPL) and hepatic lipases (Zhai et al.,2010). RPM was also demonstrated to lower body weights in ratsgiven a high-calorie feed. As determined by in vitro trials, this effectwas likely mediated by the inhibition of fatty acid synthase (FAS)(Tian et al., 2004). As demonstrated in experiments with Bel-7402cells, stilbene glucoside may be a key active component of RPM andinvolved in both inhibiting cholesterol synthesis and in increasingthe expression of low-density lipoprotein receptor (LDLR) mRNA(Han et al., 2008). Stilbene glucoside exhibits favorable pharma-cokinetic profiles in rat plasma, liver, and lung tissues followingoral administration (Lv et al., 2011), providing a reasonable chem-

ical basis for in vivo and in vitro pharmacological studies. RPMalso consists of aloe-emodin, rhein, emodin, chrysophanol, andphyscion, among other chemicals (Wang et al., 2005; Zhou et al.,2008). These anthraquinone components have purgative activities

W.

Xie

et al.

/ Journal

of Ethnopharm

acology 140 (2012) 345– 367

359

Table 3The most frequently prescribed/used Chinese herbs in 57 officially approved TCM formulas.

TCM efficacy Chinese herbs Pharmacological trials: dosages/administration/duration Primary hypolipidemiceffects

Active components References

Relieving foodretentiona

Fructus Crataegi Humans: aqueous extracts, 3.6 g/day, p.o., 3 monthsRabbits: powder, 2 g/100 g diet, p.o., 12 weeksC57BL/6 J mice: fruit extracts, 250 mg/kg/day, p.o., 7 days

TC↓, TGs↓, LDL-C↓ Flavonoids, triterpenic acids Xiong et al. (2004)Zhang et al. (2002)Niu et al. (2011)

Enhancingpurgative effecta

Radix PolygoniMultiflori

Humans: oral liquids, 30 ml, equivalent to 15 g rawherb/day, p.o., 60 daysSD rats: extracts, 100 mg/kg/day, p.o., 5 weeksICR mice: polysaccharides, 50 and 200 mg/kg/day, p.o., 28days

TC↓, TGs↓, HDL-C↑ Anthraquinones,polysaccharides

Ke et al. (2000)Xu and Wang (2004)Zhai et al. (2010)

Semen Cassiae Humans: syrup, equivalent to 45 g raw herb/day, p.o., 1monthSD rats: powder, equivalent to 1 and 4 g raw herb/kg/day,p.o., 15 days.

TC↓, TGs↓, LDL-C↓ Anthraquinones, protein Wang (1987)Li et al. (2002)

Radix et RhizomaRhei

Humans: ground fiber, 27 g/day, p.o., 4 weeksRabbits: 1.4, 4.2, and 12.6 g/rabbit, p.o., 10 weeks

TC↓, TG↓, LDL-C↓,HDL-C↑

Anthraquinones Goel et al. (1997)Xu et al. (2007)

Eliminatingdampness andwatera

Rhizoma Alismatis Mice: extracts, equivalent to 6 g raw herb/kg/day, p.o., 2weeksWistar rats: decoction, equivalent to 4.05, 8.1, and 16.2 graw herb/kg/day, p.o., 30 days.

TC↓, TGs↓ Triterpenes, polysaccharides Yu et al. (2010), Qian et al. (2007)Zheng (2007)

Herba ArtemisiaeScopariae

SD rats: extracts, 2.3 and 6.9 g/kg/day, p.o., 4 weeks;p-hydroxyacetophenone, 75, 150, and 300 mg/kg/day, p.o.,21 days

TC↓, TGs↓, LDL-C↓,HDL-C↑

p-Hydroxyacetophenone Wang et al. (2007)Zhang et al. (2010a,b)

Promoting bloodcirculation andrelieving bloodstasisa

Radix SalviaeMiltiorrhizae

Humans: tablets, 3.24 g/day, p.o., 24 weeksSD rats: aqueous extracts, 50, 100, and 150 mg/kg/day, p.o.,4 weeks

TC↓, TGs↓, HDL-C↑ Tanshinone IIA Bei et al. (2010)Ji and Gong (2008)

Folium Nelumbinis Humans: aqueous extracts, 6.6 g/day, p.o., 40 daysSD Rats: aqueous extracts, 400 mg/kg/day, p.o., 6 weeksHamsters: aqueous extracts, 1% and 2% in diet, p.o, 10weeks

TC↓, TGs↓, LDL-C↓,HDL-C↑

Total alkaloids, flavonoids Guan et al. (2003)Du et al. (2010)Lin et al. (2009)

Radix Notoginseng SD rats: n-butanol extracts, 30, 60, and 100 mg/kg/day,p.o., 4 weeks

TC↓, TGs↓, LDL-C↓ Total saponins Ji and Gong (2007)

Radix Puerariae Humans: aqueous extracts, equivalent to 30, 60, and 90 graw herb/day, p.o., 6 weeksSD rats: aqueous extracts, 1.5 g/kg/day, p.o., 5 weeksWistar rats: flavones, 100 mg/kg/day, p.o., 5 weeks

TC↓, TGs↓, LDL-C↓,HDL-C↑

Puerarin Huang et al. (2007)Lee (2004)

Wang et al. (2004)RhizomaChuanxiong

Rabbits: extracts, 30 times the human dosage, p.o., 90 daysSD Rats: Ferulic acid, 50 mg/kg/day, p.o., 30 days

TC↓, TGs↓, LDL-C↓,HDL-C↑

Ferulic acid, total alkaloids Mei et al. (2000)Ji et al. (2007)

Flos Carthami Humans: injection, 20 ml, IVGTT, 4 weeks; croein,225 mg/day, p.o., 6 weeks.Wistar rats: extracts: 1.5, 3.0, and 6.0 g raw herb/kg/day,p.o., 4 weeks; croein, 25, 50, and 100 mg/kg/day, p.o., 10daysRabbits: croein, 12.5, 25, and 50 mg/kg/day, p.o., 6 weeksPartridge: croein, 25, 50, and 100 mg/kg/day, p.o., 6 weeks

TC↓, TGs↓, LDL-C↓,HDL-C↑

Safflor yellow, croein, saffloweroil

Zhao (2002)Qian (2009a)Yang et al. (2007)Qian (2009b)Zhang et al. (2010a,b)

360 W. Xie et al. / Journal of Ethnopharm

Tabl

e

3

(Con

tinu

ed

)

TCM

effi

cacy

Ch

ines

e

her

bs

Phar

mac

olog

ical

tria

ls:

dos

ages

/ad

min

istr

atio

n/d

ura

tion

Prim

ary

hyp

olip

idem

icef

fect

sA

ctiv

e

com

pon

ents

Ref

eren

ces

Ferm

entu

mR

ubr

um

Hu

man

s:

0.6

and

1.2

g,

p.o

.,

1–2

mon

th(s

)

TC↓,

TGs↓

, LD

L-C↓,

HD

L-C↑

Lova

stat

in, s

tero

ls, i

sofl

avon

es,

isofl

avon

e

glyc

osid

es, M

UFA

Wan

g

et

al. (

1997

),

Gh

eith

et

al.

(200

9)

Rei

nfo

rcin

g

ton

icef

fect

saFr

uct

us

Lyci

iH

um

ans:

30

g/d

ay, p

.o.,

2

mon

ths.

SD

rats

:

pol

ysac

char

ides

, 40,

80, a

nd

120

mg/

kg/d

ay, p

.o.,

28

day

sK

M

mic

e:

pol

ysac

char

ides

, 5, 1

0,

and

20

mg/

kg/d

ay, p

.o.,

6w

eeks

TC↓,

TGs↓

, LD

L-C↓,

HD

L-C↑

Poly

sacc

har

ides

Zhou

et

al. (

2009

)Ji

ang

et

al. (

2010

)Zh

u

and

Zhan

g

(200

5)

Rad

ix

Ast

raga

li

Rat

s:

pol

ysac

char

ides

, 3.5

2,

8.34

, an

d

16.6

8

g/kg

/day

ind

iets

, p.o

.,

12

wee

ksM

ice:

aqu

eou

s

extr

acts

, 4.5

, 9, a

nd

18

g/kg

/day

, p.o

.,

4w

eeks

TC↓,

TGs↓

, LD

L-C↓,

HD

L-C↑

Poly

sacc

har

ides

Ton

g

et

al. (

2006

);

Liu

and

Zhan

g(2

007)

Rad

ix

Gin

sen

g

Rab

bits

:

sap

onin

s,

0.01

g/kg

/day

, p.o

.,

4

wee

ksR

ats:

Gin

sen

osid

e-R

b,

50, 1

00, a

nd

200

mg/

kg/d

ay, p

.o.,

12d

ays;

Poly

sacc

har

ides

, 100

, 200

, 500

, an

d

1000

mg/

kg/d

ay, p

.o.,

3d

ays

TC↓,

TGs↓

, LD

L-C↓,

HD

L-C↑

Sap

onin

s,

pol

ysac

char

ides

Inou

e

et

al. (

1996

)Zh

ang

et

al. (

2004

a,b)

Kw

ak

et

al. (

2010

)

TC, t

otal

chol

este

rol;

TGs,

trig

lyce

rid

es;

LDL-

C, l

ow-d

ensi

ty

lip

opro

tein

chol

este

rol;

HD

L-C

, hig

h-d

ensi

ty

lip

opro

tein

chol

este

rol;

↓,

incr

ease

;

↑,

dec

reas

e.a

Cit

ed

from

“Ch

ines

e

Mat

eria

Med

ica”

by

Zhan

g

(200

8).

acology 140 (2012) 345– 367

and may inhibit intestinal lipid absorption. RPM has no significantadverse effects; however, clinical reports have revealed that RPMexhibits hepatotoxicity following chronic treatment (Zhang et al.,2000). RPM can also cause gastrointestinal disorders and allergicresponses (Xia, 2005).

3.3. Rhizoma alismatis (oriental water plantain rhizome, Ze Xie,)

Rhizoma alismatis (RA) is derived from the dried stem tuber ofAlisma orientale (Sam.) Juzep. (Alismataceae). RA promotes diure-sis to resolve dampness from the lower energizer and to expelheat. RA likely exerts its hypolipidemic effects primarily by tar-geting the urinary system. RA is widely used in TCM formulas asan important component for treating hyperlipidemic patients. Theoral administration of aqueous and alcoholic RA extracts (equiv-alent to 6 g raw herb/kg/day for 2 weeks) resulted in significantdecreases in serum TG and TC levels in mice fed a high-fat diet(Yu et al., 2010; Qian et al., 2007). An RA decoction adminis-tered at oral dosages equivalent to the dosages of 4.05, 8.1, and16.2 g raw herb/kg/day for 30 days also exhibited lipid-loweringeffects in Wistar rats fed a high-fat diet (Zheng, 2007). The mecha-nisms of RA action may be related to the inhibition of intestinal lipidabsorption, the promotion of lipid metabolism, and the inhibitionof lipid synthesis (Li and Wu, 2009). Triterpenes are the primaryactive components responsible for these activities. RA polysaccha-rides also exhibit hypolipidemic effects in mice fed a high-fat diet(Li et al., 2008). The adverse effects of RA are correlated with hep-atotoxicity and nephrotoxicity following overdosage.

3.4. Semen Cassiae (Cassia seed, Jue Ming Zi, )

Semen Cassiae is the ripe seed of Senna obtusifolia Linn.(Fabaceae) or Cassia tora Linn. (Leguminosae). Semen Cassiae clearsaway the liver fire to improve eyesight and moistens the intestinesto relax the bowels. Cassia seed appears to exert its hypolipi-demic effects primarily by targeting the gastrointestinal tract.The oral administration of Semen Cassiae syrup (equivalent to45 g raw herb/day) for 2 months significantly lowered serum TC,TG, and LDL-C levels in 48 hyperlipidemic patients (Wang, 1987).This effect is comparable with clofibrate. However, no placebo con-trol was used in this clinical trial. The oral administration of SemenCassiae powder (equivalent to 1 and 4 g/kg day) for 15 days also sig-nificantly lowered lipid levels in SD rats fed a fat emulsion diet (Liet al., 2002). The mechanisms by which Semen Cassiae lowers lipidlevels may be related to the inhibition of cholesterol synthesis, aswas observed in rat hepatocytes in vitro (He et al., 2003). Proteinsand anthraquinone glucosides are the active components of SemenCassiae that are responsible for such hypolipidemic effects (Li andGuo, 2002). The anthraquinone compounds in the Cassia seedinclude aloe-emodin, rhein, emodin, chrysophanol, and physcion(Jin et al., 2007). These compounds may be related the purgativeeffects of Semen Cassiae in the gastrointestinal tract. A 90-day sub-chronic toxicity study of the Cassia seed in animals suggested thatit should be used cautiously with respect to its dosage and admin-istration because of potential toxicity risks (Gao et al., 2004).

3.5. Radix et Rhizoma Rhei (Rhubarb, Da Huang, )

Radix et Rhizoma Rhei is derived from the root and rhizome ofRheum palmatum Linn. (Polygonaceae), Rheum tanguticum Maxim.Ex Balf. (Polygonaceae), or Rheum officinale Baill (Polygonaceae).

It is used to remove stagnation by purgation, to clear away heatand purge fire, to cool the blood and stop bleeding, to removetoxins, to promote blood circulation and to remove blood stasis.Rhubarb exerts its hypolipidemic effects primarily by targeting the

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astrointestinal tract. Ground rhubarb stalk fiber given at anral dosage of 27 g/day for 4 weeks was demonstrated to beffective in lowering serum TC concentrations, especially LDL-

levels, in hypercholesterolemic men (Goel et al., 1997). Nolacebo or positive controls were used in this clinical trial. Alco-olic extracts of rhubarb administered at oral dosages of 1.4, 4.2,nd 12.6 g/day rabbit for 10 weeks decreased serum TC and LDL-

levels, increased HDL-C levels, reduced liver fatty degeneration,nd protected hepatocyte function in rabbits fed a high-fat dietXu et al., 2007). Aqueous extracts of rhubarb administered atral dosages of 150 and 300 mg/kg were demonstrated to inhibithe formation of postprandial hyperlipidemia in fat-loaded rats,ikely by promoting gastrointestinal transit (Xie et al., 2005). Aloe-modin, emodin, chrysophanol, and physcion are the primaryctive components of RA (Cao and Tao, 2008), and rhein may benother active component (Gao et al., 2010). These compoundsay exert slight purgative effects on the gastrointestinal tract.

he hypolipidemic mechanisms of rhubarb may also be associ-ted with the increased expression of muscle PPAR� in rats fed

high-fat diet (Guo et al., 2006). Furthermore, anthraquinones cannter the bloodstream (Shia et al., 2011) and may exert systemicffects in vivo. The overadministration of rhubarb can cause adverseffects, including vomiting, headache, diarrhea, and abdominalain. Furthermore, the chronic administration of rhubarb can causeecondary constipation, immune system dysfunction, decreasedbsorption of certain intestinal substances, melanosis coli, andther toxic responses (Li and Liu, 2006).

.6. Folium Nelumbinis (Lotus leaf, He Ye, )

Folium Nelumbinis is the dried leaf of Nelumbo nucifera Gaertn.Nymphaeaceae). It is used to clear away summerheat, to lift theucid yang, to cool the blood, and to stop bleeding. It is thoughthat Lotus leaves exert their effects primarily by improving cardio-ascular activities. Aqueous extracts of Lotus leaves administeredt an oral dosage of 6.6 g/day for 40 days significantly decreasederum TC, TG, and LDL-C levels and increased HDL-C levels in 31yperlipidemic patients (Guan et al., 2003). A placebo but no posi-ive control was used in this clinical trial. Aqueous extracts of Lotuseaves administered at an oral dosage of 400 mg/kg/day for 6 weeks

ere demonstrated to lower serum TC, TG, and LDL-C levels in ratsDu et al., 2010). A high-fat diet supplemented with 1–2% aque-us extracts of Lotus leaves was reported to significantly decreaselood lipid levels in hamsters compared with a high-fat diet aloneLin et al., 2009). As demonstrated in the livers of mice that wereed high-fat diets, the mechanisms of action of Lotus leaves may bessociated with suppressed expression of FAS, acetyl-CoA carboxy-ase, and HMG-CoA reductase, and the increased phosphorylationf AMP-activated protein kinase (Wu et al., 2010). The total alka-oids and flavonoids in Lotus leaves may be the primary activeomponents of this TCM (Du et al., 2000; Zhu and Li, 2010). Noignificant adverse effects of Lotus leaf have been reported.

.7. Radix Salviae Miltiorrhizae (Danshen root, Dan Shen, )

Radix Salviae Miltiorrhizae (RSM) is derived from the root andhizome of Salvia miltiorrhiza Bge. (Lamiaceae). It removes bloodtasis, relieves pain, promotes blood circulation, regulates menstru-tion, removes heat from the heart, and tranquilizes the mind. RSMs thought to benefit hyperlipidemic patients primarily by improv-ng cardiovascular functions. RSM is widely used to treat patients

ith coronary artery disease and other cardiovascular diseases by

mproving microcirculation, inducing coronary vasodilatation, andy suppressing thromboxane formation (Cheng, 2007). In China, theral administration of 12 RSM tablets (0.27 g/tablet) for 24 weeksignificantly lowered serum TC, TG, and LDL-C levels and increased

acology 140 (2012) 345– 367 361

HDL-C levels in 92 hypertensive and hyperlipidemic patients (Beiet al., 2010). No placebo or positive controls were used in this trial.Aqueous extracts of RSM administered at oral dosages of 50, 100,and 150 mg/kg/day for 4 weeks largely decreased TC and TG lev-els and increased HDL-C serum levels in hyperlipidemic rats. Theseeffects are likely mediated by RSM acting as a farnesoid X recep-tor/liver X receptor alpha (FXR/LXR�) coagonist (Ji and Gong, 2008).RSM inhibits ApoB and triglyceride secretions in HepG2 cells (Kanget al., 2008). Tanshinone IIA may be one of the primary active com-ponents of RSM. However, tanshinone IIA has a poor absorptionfollowing oral administration (Hao et al., 2006). The injection of tan-shinone IIA can increase the blood concentration of this compoundbut may cause certain adverse effects, such as allergic reactions,gastrointestinal discomfort, headaches, etc. Numerous clinical tri-als have demonstrated that certain Chinese RSM products are safefor oral administration. However, RSM may cause abdominal dis-comfort and decrease appetite following long-term administration.RSM also results in internal tissue bleeding when used in combina-tion with aspirin or warfarin (Li and Zheng, 2010).

3.8. Radix Notoginseng (Sanchi, San Qi, )

Radix Notoginseng is derived from the dried root and rhizome ofPanax pseudoginseng var. notoginseng Wall. (Araliaceae). It removesblood stasis, stops bleeding, promotes blood circulation, and allevi-ates pain. Notoginseng may exert its effects primarily by improvingcardiovascular functions. Sanchi n-butanol extracts administeredat oral dosages of 30, 60, and 100 mg/kg/day for 4 weeks sig-nificantly decreased serum TC, TG, and LDL-C levels in rats feda high-fat/high-cholesterol diet. This effect was likely mediatedby FXR/LXR� (Ji and Gong, 2007). Sanchi was also demonstratedto reduce the activity of hepatic HMG-CoA reductase in the liv-ers of rats fed a high-fat diet (Xia et al., 2011). Saponins are theprimary active components responsible for the hypolipidemiceffects of Radix Notoginseng. However, Notoginseng saponinsexhibit low bioavailability following oral administration (Fenget al., 2011). The injection of Sanchi saponins can increase the bloodconcentration of these compounds but may cause certain severeadverse effects, including allergic responses (shock and rash),abdominal pain, blood in the urine, and hepatitis. The oral admin-istration of Sanchi also causes bleeding and allergic responses (Xia,2005).

3.9. Herba Artemisiae Scopariae (capillary wormwood herb, YinChen, )

Herba Artemisiae Scopariae (HAS) is derived form the over-ground portion of the dried whole herb of Artemisia scoparia Waldst.et Kit (Asteraceae) or Artemisia capillaris Thumb. (Compositae). Itremoves heat, eliminates dampness, and drains the gallbladderto relieve jaundice. HAS is thought to exert its effects primar-ily by targeting the biliary system. HAS extracts administered atoral dosages of 2.3 and 6.9 g/kg/day for 4 weeks were demon-strated to significantly decrease serum TC, TG, and LDL-C levelsand to increase HDL-C levels in rats fed high-fat/glucose diets(Wang et al., 2007). HAS also inhibits the development of fatty liv-ers. p-Hydroxyacetophenone is one of the active components ofHAS (Zhang et al., 2010a,b) and likely promotes bile excretion andimproves digestion. HAS can cause transient dizziness, vomiting,and abdominal distension (Xia, 2005).

3.10. Radix Puerariae (Kudzuvine root, Ge Gen, )

Radix Puerariae is the dried root of Pueraria lobata (Willd.) Ohwi.(Fabaceae). It expels pathogenic factors in the muscles to abate heat,treats skin eruptions, promotes body fluid production to relieve

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hirst, and uplifts the yang to relieve diarrhea. The Kudzuvine rootppears to exert its effects primarily by improving cardiovascu-ar functions. Aqueous extracts of Kudzuvine root administered atppropriate dosages (equivalent to 30, 60, and 90 g raw herb/day)or 6 weeks lowered TC, TG, and LDL-C levels and increased HDL-Cevels in 30 hyperlipidemic patients (Huang et al., 2007). No placebor hypolipidemic positive controls were used in this trial. Aqueousxtracts of Kudzuvine root given at an oral dosage of 1.5 g/kg/dayor 5 weeks were demonstrated to improve lipid metabolism inhe livers of ethanol-treated rats (Lee, 2004). Furthermore, theral administration of Kudzuvine root flavones at 100 mg/kg/dayor 5 weeks was reported to enhance hepatic lipid metabolism invariectomized rats (Wang et al., 2004). An in vitro study in HepG2ells demonstrated that the hypolipidemic effect of the Kudzuvineoot is likely mediated by the attenuation of hepatic lipoproteinroduction and secretion (Lee et al., 2002). Puerarin is one of therimary active compounds of the Kudzuvine root. However, Puer-rin has a low bioavailability following oral administration (Luot al., 2011). Puerarin injections can increase the blood concen-ration of this compound but may cause certain adverse effects,uch as allergic responses, bloody stool, backache, etc. No signifi-ant adverse effects of Puerarin have been reported following oraldministration.

.11. Rhizoma Chuanxiong (Szechuan lovage rhizome, Chuaniong, )

Rhizoma Chuanxiong (RC) is the dried rhizome of Ligusticumhuanxiong Hort. (Umbelliferae). It promotes blood and qi circu-ation, expels wind, and alleviates pain. RC appears to exert itsffects primarily by improving cardiovascular functions. The oraldministration of RC at an equivalent dosage of 30 times that giveno humans for 90 days significantly lowered serum TC and TGevels and increased HDL-C levels in rabbits fed a high-fat dietMei et al., 2000). RC-derived ferulic acid given at an oral dosage of0 mg/kg/day for 30 days significantly lowered serum TC and LDL-C

evels in rats fed a high-fat diet (Ji et al., 2007). The total alkaloidsn RC may play an important role in contributing to hypolipidemicffects of RC (Yang et al., 2000). The oral administration of RC causeseadaches and bleeding in certain patients. The injection of Ligus-razine can also cause bleeding and allegic responses in certainases (Xia, 2005).

.12. Fructus Lycii (Barbary wolfberry fruit, Gou Qi Zi, )

Fructus Lycii is the mature fruit of Lycium barbarum L.Solanaceae). It tonifies the kidney and liver, benefits the essence,nd improves eyesight. Barbary wolfberry fruit (BWF) appears toxert its effects primarily by reinforcing tonic effects. The oraldministration of BWF at a dosage of 30 g/day for 2 months wasemonstrated to significantly lower serum TG, TC, and LDL-C lev-ls and to increase HDL-C levels in 26 hyperlipidemic patientsZhou et al., 2009). High-fat diets supplemented with aqueous BWFxtracts (100 mL/kg diets, equivalent to 5.8 g raw herb/100 g diet)xhibited lipid-lowering effects in SD rats (Yi, 2000). BWF polysac-harides administered at oral dosages of 5, 10, and 20 mg/kg/dayor 6 weeks significantly decreased serum TC and TG levels andncreased HDL-C levels in Chinese Kun Ming mice fed a high-fatiet (Zhu and Zhang, 2005). BWF polysaccharides administered atral dosages of 40, 80, and 120 mg/kg/day for 28 days significantlyeduced serum TC, TG, and LDL-C levels in SD rats fed a high-fatiet (Jiang et al., 2010). BWF polysaccharides effectively prevent

lcoholic fatty liver disease in rats. This action may be attributed toWF’s inhibition of both hepatocyte CYP2E1 expression and lipideroxidation (Gu et al., 2007). In addition, BWF oil administered atral dosages of 1–2 mL for 56 days also regulates lipid metabolism

acology 140 (2012) 345– 367

in rabbits fed a high-fat diet (Dong et al., 2005). This effect maybe associated with the rich, unsaturated fatty acids in BWF. Nosignificant adverse effects have been reported for this TCM.

3.13. Radix Astragali (membranous milkvetch root, Huang Qi,)

Radix Astragali is the dried root of Astragalus propinquus (Fisch.)Bge. var. mongholicus (Bge.) Hsiao (Fabaceae) or Astragalus mem-branaceus (Fish.) Bge. (Fabaceae). It replenishes the qi to invigoratethe yang, benefits the lungs to strengthen the body, promotesdiuresis to relieve edema, relieves skin infection, and promotes tis-sue regeneration. The membranous milkvetch root (MMR) appearsto act primarily by reinforcing tonic effects. Aqueous extracts ofMMR administered at oral dosages of 4.5, 9, and 18 g/kg/day for 4weeks significantly lowered serum TC, TG, and LDL-C levels andincreased HDL-C level in mice fed a fat emulsion diet (Liu andZhang, 2007). MMR polysaccharides administered at oral dosages of3.52, 8.34, and 16.68 g/kg/day for 12 weeks significantly decreasedserum TC and LDL-C levels but did not lower TG levels in ratsfed a high-fat diet (Tong et al., 2006). MMR polysaccharides werealso demonstrated to significantly lower liver TG and TC levels inrats fed a high-fat diet. The hypolipidemic mechanisms of MMRpolysaccharides in vivo may be associated with the increasedexpression of LDLR and 7� hydroxylase mRNAs and the decreasedexpression of HMG-CoA reductase mRNA in the liver (Cheng,2010). No significant adverse effects have been reported for thisTCM, except for certain allergic responses (Xia, 2005).

3.14. Flos Carthami (Safflower, Hong Hua, )

Flos Carthami is the dried flower of Carthamus tinctorius L.(Asteraceae). It improves blood circulation to remove blood stasis,promotes menstruation, and alleviates pain. Flos Carthami appearsto exert effects primarily by improving cardiovascular activities.Intravenous injections of Safflower at 20 mL/day for 4 weeks sig-nificantly reduced TC, TG, and LDL-C levels and increased HDL-Clevels in 60 hyperlipidemic patients (Zhao, 2002). However, noplacebo or positive controls were used in this clinical trial. Safflowerwater extracts given at oral dosages of 1.5, 3.0, and 6.0 g/kg day for4 weeks significantly lowered TC, TG, and LDL-C levels in Wistarrats fed a high-fat diet (Yang et al., 2007). Croein, one of the activecomponents of Safflower, administered at a dosage of 225 mg/dayfor 6 weeks also exhibited lipid-lowering effects in humans withhyperlipidemia (Qian, 2009a). The oral administration of croein atdosages of 25, 50, and 100 mg/kg/day for 10 days was also demon-strated to exert hypolipidemic effects by blocking fat absorptionin the rat intestinal tract. Based on in vitro trials, this effect waslikely mediated by the inhibition of pancreatic lipase activity (Qian,2009b). Intravenous administrations of Safflor yellow at dosagesof 40 and 80 mg/kg/day for 3 days significant decreased TC, TG,and LDL-C levels and increased HDL-C levels in Wistar rats fed ahigh-fat diet (Zhang et al., 2010a,b). Hydroxysafflor yellow A, oneof the primary active compounds of Safflor yellow, has a very lowbioavailability following oral administration (Zhang et al., 2006).The injection of the active components of Safflower can increasetheir blood concentrations but may cause certain adverse effects,such as allergic responses (shock, fever, and rash) and acute impair-ment of renal function (Xia, 2005).

3.15. Radix Ginseng (Ginseng, Ren Shen, )

Radix Ginseng is derived from the dried root and rhizome ofPanax ginseng C.A. Mey. (Araliaceae). It reinforces vital energy,restores the pulse, treats exhaustion, reinforces the spleen to ben-efit the lungs, promotes the production of body fluids, and calms

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he mind to promote intelligence. Ginseng appears to act primarilyy reinforcing tonic effects. P. ginseng has anti-atherogenic actions

n rats and patients with hyperlipidemia (Yamamoto and Kumagai,982). The oral administration of Ginseng saponins at a dosage of.01 g/kg/day for 4 weeks significantly decreased serum TG andholesterol levels by activating LPL activity in a cyclophosphamide-nduced hyperlipidemia model of fasting rabbits (Inoue et al., 1996).he oral administration of Ginsenoside-Rb at dosages of 50, 100,nd 200 mg/kg/day for 12 days significantly lowered serum TC, TG,nd LDL-C levels and increased HDL-C levels in rats fed a high-at diet (Zhang et al., 2004a,b). Acidic polysaccharide was alsoetermined to be one of the active components of Ginseng fol-

owing administration of this compound at oral dosages of 100,00, 500, and 1000 mg/kg/day for 3 days in rat models of acuteyperlipidemia induced by Triton WR1339 and/or intravenously

njected corn oil (Kwak et al., 2010). Ginseng saponins have poorioavailability following oral administration (Chu et al., 2011). The

njection of Ginseng saponins can increase the blood concentra-ion of these compounds but can cause allergic responses. Althoughinseng is very safe for oral administration, an overdose or chronicdministration of Ginseng may stimulate the central nervous andardiovascular systems, cause abdominal distention and certainllergic reactions (Xia, 2005).

.16. Fermentum Rubrum (red yeast rice, Hong Qu, )

Fermentum Rubrum, popularly known as red yeast rice (RYR)as long been used in China and is the fermented product ofice on which Monascus purpureus Went. (Monascaceae) has beenrown. RYR promotes blood circulation to remove blood stasisnd strengthens the spleen to improve digestion. RYR appearso exert its effects primarily by improving cardiovascular activ-ties and by targeting the gastrointestinal tract. Eight weeks ofdministration of RYR alcoholic extracts (1.2 g/day) significantlyecreased TC, LDL-C, and TG levels by 22.7%, 30.9%, and 34.1%,espectively, and increased HDL-C levels by 19.9% in 324 hyper-ipidemic patients (Wang et al., 1997). However, no placebor hypolipidemic positive controls were used in this trial. Theral administration of RYR (1.2 g/day) for 8 weeks significantlyecreased TC, LDL-C, and TG levels by 21.5%, 27.7%, and 15.8%,espectively, in 79 hyperlipidemic patients. This study was random-zed, double-blind, and placebo-controlled; however, no positiveontrol was used. In children and young adults with secondaryyperlipidemia, the hypolipidemic effects of RYR (1.2 g/day, n = 20)

or the first and following months (0.6 g/day) were comparableith those of fluvastatin (20 mg/day, n = 30) after a year of ther-

py (Gheith et al., 2009). This study included negative and positiveontrols. A meta-analysis of randomized controlled trials of RYReported that the hypolipidemic effects of RYR preparations areomparable with those of statins but are less than those of fibratesLiu et al., 2006). However, the long-term effects and safety ofYR should be investigated. RYR contains HMG-CoA reductase

nhibitors (lovastatin) and has similar mechanisms of action astatins. RYR lovastatin has a lower bioavailability than lovastatinlone (Li et al., 2005), but RYR exhibits effects that are similaro those of statins, indicating that RYR may both contain otherctive compounds and have fewer side effects than statins alone.n fact, RYR contains sterols isoflavones, isoflavone glycosides, and

onounsaturated fatty acids, all of which are active compounds.YR was tolerated (statin-associated myalgia) in a population intol-rant to statins (Halbert et al., 2010; Venero et al., 2010). Unliketatins, RYR administered at a low dosage (0.6 g/day) exhibited no

evere side effects, such as myopathy and rhabdomyolysis. Animalafety evaluations indicate that RYR does not cause any toxic effectsn albino rats (Kumari et al., 2009). However, patients treated withYR (1.2 g/day) experienced a few non-serious side effects, such

acology 140 (2012) 345– 367 363

as heartburn, flatulence, dizziness, and gastrointestinal discom-fort. Practitioners should be cautious of the content of mycotoxincitrinin derived from RYR, which may have hepato-nephrotoxicproperties.

4. Discussion and perspectives

4.1. Three primary approaches of TCM for the treatment ofhyperlipidemia

Therefore, among the 15 herbs that are most commonly used totreat hyperlipidemia, 10 have been demonstrated to have clinicalefficacies when used alone in human trials. However, the major-ity of these trials were of low quality, small, poorly controlled, andrequire further validation. These 10 herbs include FC, RPM, SemenCassiae, Radix et Rhizoma Rhei, Folium Nelumbinis, RSM, RadixPuerariae, Flos Carthami, Fructus Lycii, and Radix Ginseng. Theother TCM, namely RA, Herba Artemisiae Scopariae, Radix Noto-ginseng, RC, and Radix Astragali, have been only tested in animals.Aside from these herbs, Fermentum Rubrum, FC, Semen Cassiae,Herba Gynostemmatis, Rhizoma Curcumae Longae, Folium Ligus-tri Lucidi, etc., have been separately developed for the treatmentof hyperlipidemia in mainland China. Particularly, FermentumRubrum is the most commonly used herb for this indication, aswas reported in a previous review (Liu et al., 2011). However, themajority of TCM herbs are primarily used in formulas.

The herbs that have been demonstrated to have hypolipidemiceffects in humans and/or animals can be primarily grouped intothree categories: those excretion-promoting herbs that target thegastrointestinal tract, the urinary and biliary systems, those herbsthat target the cardiovascular system, and those herbs that pos-sess strong tonic effects based on the theories of TCM. The herbsin the first category include FC, RPM, Semen Cassiae, Radix et Rhi-zoma Rhei, RA, and Herba Artemisiae Scopariae, etc. These herbsexert lipid-lowering effects primarily by reducing food retention(FC) having a purgative effect (RPM, Semen Cassiae, and Radix etRhizoma Rhei), and promoting diuresis (RA) and choleretic (HerbaArtemisiae Scopariae) effects (Committee for the Pharmacopoeiaof PR China, 2010; Zhang, 2008). In particular, FC is prescribedin approximately 50% of TCM formulas. The herbs in the secondcategory, including Folium Nelumbinis, Radix Notoginseng, RadixPuerariae, RC, and Flos Carthami, are primarily used to improveblood circulation and to eliminate the complications associatedwith hyperlipidemia. Aside from decreasing the side effects of TCM,the herbs in the third category, including Fructus Lycii, Radix Astra-gali, and Radix Ginseng, are also widely used to lower blood lipidlevels. Hence, TCM formulas for the treatment of hyperlipidemiaprimarily act through three basic approaches. These combinationtherapies may be aimed at systemically improving the positiveeffects and lessening the adverse effects of a given TCM formula(Wang et al., 2006). The SFDA-approved herbs that are frequentlyprescribed in TCM formulas deserve further study. TCM may beimportant natural sources and may serve as alternative or com-plementary medicines for the treatment of hyperlipidemia and itscomplications.

4.2. Theories of TCM

As discussed in this review, TCM theories are important in thedevelopment of appropriate hypolipidemic TCM (O’Brien, 2010;Yang and Zhang, 2011). TCM theories indicate that hyperlipidemiaoriginates from liver qi stagnation, spleen and kidney qi deficien-

cies. These deficiencies are induced by an uncontrolled diet anda non-ideal lifestyle, manifesting as inner phlegm and dampness,and blood stasis (Shi and Li, 2007). The majority of the approachesfor treating hyperlipidemia involve soothing the liver qi, fortifying

364 W. Xie et al. / Journal of Ethnopharm

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he spleen qi, nourishing the kidney qi, resolving phlegm and damp-ess, improving blood stasis, etc., to address the root causes andymptoms (Fig. 2).

Therefore, TCM formulas for the treatment of hyperlipidemiaonsist of: (1) purgatives and food retention-relieving herbs (tottenuate the effects of an uncontrolled diet); (2) phlegm, damp-ess, and blood stasis-removing herbs (to improve cardiovascular

unctions); and (3) restoratives (to improve qi deficiency). Thesections may be similar to enhancing excretory functions of theastrointestinal tract, the urinary and biliary systems, improv-ng cardiovascular function, and having tonic effects in modern

edicine. Among the herbs promoting excretions, most of themarget the gastrointestinal tract. These actions lower blood lipidevels, reduce cardiovascular complications, and activate bodyunctions.

.3. Phytochemical studies

Phytochemical studies on TCM formulas are very difficult toonduct because formulas generally consist of more than twoerbs, and each herb contains hundreds of compounds. A the-ry regarding TCM components has recently been developed.ccording to this theory, a combination of the refined compo-ents of different herbs into new formulas based on TCM theoryay allow for improved quality control and pharmaceutical for-

ulations (Liang et al., 2006). The active compounds of TCM

ormulas with anti-hyperlipidemic activities primarily containavonoids or phenols, triterpenoids, saponins, polysaccharides,lkaloids, anthraquinones, and other specific compounds (Zhang

acology 140 (2012) 345– 367

et al., 2004a,b). Phytochemical and pharmacological studies haveidentified certain active compounds that are well defined or areunder development. The active compounds in herbs targeting thegastrointestinal tract consist of triterpenes and anthraquinonecomponents. The active compounds that target the cardiovascularsystem consist of flavonoids, phenols, saponins, etc. The active com-ponents of herbs with reinforcing tonic effects primarily consist ofpolysaccharides. These refined components may be combined todevelop novel medicines for treating hyperlipidemia (Fig. 3). How-ever, the development of these combinations may require furtherstudy.

4.4. Pharmacological studies

TCM remain alternative treatments for hyperlipidemia becauseof poor quality control and their complex chemical constitution.However, the mechanisms by which TCM exert their hypolipi-demic effects include decreasing intestinal lipid absorption (Li andWu, 2009), inhibiting HMG-CoA reductase activity (Journoud andJones, 2004), activating FXR/LXR� (Ji and Gong, 2008), influenc-ing pancreatic lipase activity, promoting plasma LPL activity (Zhaiet al., 2010), etc. These mechanisms of action are similar to those ofWestern drugs. However, one of the most plausible and accept-able mechanisms for certain TCM is the inhibition of intestinallipid absorption. The compounds that are primarily responsible forthese effects include, but are not limited to, anthraquinones, triter-penoids, and alkaloids. Pharmacokinetic studies indicate that mostactive components exhibit low bioavailability, potentially compli-cating the explanation of certain systemic activities in vivo. Hence,most active compounds may directly target the gastrointestinaltract. For example, Berberine may actually exert its hypolipidemiceffects by targeting gut microbes (Xie et al., 2011). However, manycompounds may be entering the blood (although many of thesemay have not been identified and may be present in very lowconcentrations) and may, along with their metabolites, exert appre-ciable and combined effects. However, validating these effects isdifficult. Nevertheless, several herbs combined into a formula, eachwith different mechanisms of action, may have better hypolipi-demic effects than any single herb administered alone. Given thatTCM formulas consist of many herbs with different mechanisms ofaction, they exert their effects via multiple targets. However, theverification of these effects requires more preclinical and clinicalevidence.

4.5. Toxicity studies

The Western medicines that are currently used to treat dyslipi-demia can have negative side effects; no medicine is both potentand safe. Most TCM formulas with anti-hyperlipidemic effects haveno significant toxic effects and have been used for many years inChina and elsewhere. However, caution is warranted with respectto overdosage or the chronic administration of TCMs. Indeed, it hasbeen increasingly observed that certain herbs can exhibit poten-tial adverse effects and should therefore be subjected to newsafety regulations (Efferth and Kaina, 2011; Xia, 2005). Despite this,TCM formulas are still well tolerated by patients given that theindividual herbs antagonize each other’s side effects. For patientswho are intolerant to statins or other hypolipidemic drugs, TCM for-mulas may serve as alternatives (Klimek et al., 2009). Practitionersshould also be cautious with respect to the interactions betweenTCM and Western drugs. Certain unwanted effects are likely tooccur in patients receiving a combined Western medicine and TCM

treatment. Injections of the active components in TCM generallyincrease the blood concentration of the compound and treat thecardiovascular diseases caused by hyperlipidemia. However, thereare safety concerns regarding TCM injections, and more scientific

W. Xie et al. / Journal of Ethnopharmacology 140 (2012) 345– 367 365

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nd systemic evidence is required to determine how to use TCMafely.

In conclusion, three basic approaches of TCM formulas for havemerged for the treatment of hyperlipidemia: (1) enhancing excre-ory functions primarily by targeting the gastrointestinal tract,2) improving cardiovascular system, and (3) reinforcing tonicffects. These approaches are primarily used to exert systemicnd harmonious antihyperlipidemic effects by controlling bloodipid levels, improving cardiovascular complications, and antago-izing the adverse effects of TCM themselves by adjusting entireody functions. TCM theories and modern phytochemical, phar-acological, and toxicological methods play important roles in

nderstanding and developing TCM. However, more evidence isequired with respect to the quality control, efficacy, and safety ofCM formulas or TCM used alone.

cknowledgements

This study was supported by the National Natural Sci-

nce Foundation of China (81072680, 30973896, 30801523nd 81073092), the Natural Science Foundation of Guangdongrovince (10151805702000002), the National S&T Major Specialroject for New Drug R&D Program of China (2009ZX09103-301,

c TCM components, each with different mechanisms of action.

2011ZX09101-002-11 and 2012ZX09103-201-041), and the Spe-cialized Research Fund for the Doctoral Program of HigherEducation of China (20100002120017).

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