Review Traditional Medicine Research 2018 March; 3(2): 70-81

Clinical evidence and potential mechanisms of Chinese medicines for the treatment
of diabetic retinopathy
Jian Huo1, Ke-Yu Zhu1, Qian Yang1, Wen Liu2, Jun-Guo Duan1*

Academy of Ophthalmology, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
1

Chengdu University of Traditional Chinese Medicine Affiliated Ineye Hospital, Chengdu, Sichuan, China.
2

Correspondence to: Jun-Guo Duan, Chengdu University of Traditional Chinese Medicine, 37 Shierqiao Road,
*

Chengdu, Sichuan, China. E-mail: duanjg@vip.sina.com.

Highlights Editor’s Summary

This article summarizes the application of Chinese More and more Chinese formulaes have been used by
medicines and their mechanisms of action in the China FDA for the prevention and treatment of diabetic
treatment of diabetic retinopathy. retinopathy. And their mechanisms of action have gained
increasing attention around the world.

Citation: Huo J, Zhu KY, Yang Q, et al. Clinical evidence and potential mechanisms of Chinese medicines for the
treatment of diabetic retinopathy. Traditional Medicine Research, 2018, 3(2): 70-81.
DOI: 10.12032/TMR201810066
Submitted: 8 October 2017, Accepted: 15 December 2017, Online: 21 January 2018.

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Review Traditional Medicine Research 2018 March; 3(2): 70-81

Abstract
Diabetic retinopathy is one of the main causes of visual impairment and blindness on a global scale. At present, the
limitations of anti-vascular endothelial growth factor agents, steroids, laser photocoagulation, and vitreous surgery have
led to a growing awareness of the role of Chinese medicines in the treatment of diabetic retinopathy. This review first
describes the ingredients and characteristics of the formulae including Chinese herbal formulaes, Chinese patent drugs
and ancient processed drugs and summarizes the application of Chinese medicines and their mechanisms of action in the
treatment of diabetic retinopathy. Due to the complexity of Chinese medicines, in-depth mechanisms, side effects of herb,
and drug interactions need to be elaborated in future research. Chinese medicines have the potencial to protect the
residual eyesight and delay the progression of disease, thereby offering a beneficial, exploitable option in the
treatment/prevention of diabetic retinopathy.
Keywords: Diabetic retinopathy, Chinese medicines, Formula, Chinese patent drugs

摘要

糖尿病视网膜病变是导致患者视力损害和失明的主要原因之一。目前，由于抗 VEGF 制剂、类固醇

激素、激光光凝和玻璃体手术在治疗糖尿病视网膜病变中的局限性，使得人们越来越重视中医药在糖
尿病视网膜病变中的治疗作用。本文就中药配方(包括复方制剂、专利药和古方)的组成及其特点，中
药在糖尿病视网膜病变中临床应用及作用机制方面的研究进行综述。由于中药的复杂性，关于中药的
作用机制、副作用以及药物之间的相互作用等方面的问题，需要进一步深入的研究。中医药可防止病
变进一步发展和恶化，保护残余视力，延缓病变发展；在糖尿病视网膜病变的预防和治疗中存在显著
优势。
关键词：糖尿病视网膜病变；中医药；配方；中成药

Abbreviations: DR, Diabetic retinopathy; VEGF, Vascular endothelial growth factor; TCM, Traditional Chinese
medicine; HF, Heyingqingre Formula; AGEs, Advanced glycation end products; BHD, Buyanghuanwu Decoction;
JBHD, Jiawei Buyanghuanwu Decoction; ET-1, Endothelin-1; DM, Diabetes mellitus; QM, Qiming; IGF-1, Insulin-like
growth factor 1; FXT, Fufang Xueshuantong; NPDR, Non-proliferative DR; ICAM-1, Intercellular adhesion molecule-1;
PEDF, Pigment epithelium-derived factor; CDDP, Compound Danshen Dripping Pill; GB, Yinxing; GBL, Yinxingye;
GBE, Ginkgo biloba extract; QSYQ, Qishenyiqi; LDP, Liuweidihuang Pill; GLT, Ginkgo leaf Tablet; NXT, Naoxintong.
Competing interests: The authors declare that there is no conflict of interests regarding the publication of this paper.
Copyright: © 2018 TMR Publishing Group. This is an open access article distributed under the terms of the Creative
Commons Attribution Non Commercial License.
Executive Editor: Jing Liang.

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Review Traditional Medicine Research 2018 March; 3(2): 70-81

pathogeneses of DR [5, 6]. DR develops because of blood

Background stasis, which causes hemorrhage, microaneurysms, and
angiogenesis [7]. Several Chinese herbs, including
Diabetic retinopathy (DR) is one of the main causes of Huangqi (Radix Astragali seu Hedysari), Dihuang (Radix
visual impairment and blindness on a global scale [1]. Rehmanniae), and Danshen (Radix Salviae Miltiorrhizae),
Major complications of DR include intraocular have the effect of tonifying Qi, nourishing Yin, and
neovascularization, intraretinal edema, hemorrhage, removing blood stasis. Some well-established Chinese
exudates, and microaneurysms. DR is the result of several herbal formulae and Chinese patent drugs have also been
hyperglycemia-induced pathological changes, such as shown to effectively treat DR in basic and clinical studies.
increased oxidative stress-induced apoptosis of retinal According to the Guidelines for Diagnosis and Treatment
endothelial and neuronal cells, angiogenesis, and of DR in Chinese Medicine [7], there are some formulaes
inflammatory responses [2]. At present, strict control of for DR that are based on syndrome differentiation and are
blood sugar, blood pressure, and blood lipid levels within listed in Table 1. This review focuses on both clinical and
the normal range is still vital to delay the development of basic researches to summarize the application of Chinese
DR. Treatments for DR include anti-vascular endothelial medicines and their mechanisms of action in the
growth factor (VEGF) agents, steroids, laser treatment of DR (Table 2).
photocoagulation, and vitreous surgery. However, these
therapeutic methods cannot reverse the existing retinal Method of literature search
damage. Moreover, some adverse events are associated
with these treatments [3]. This review was conducted with a comprehensive
Traditional Chinese medicine (TCM) is an alternative Pubmed and China National Knowledge Infrastructure
therapy that has been used for thousands of years in (www.cnki.net) search of references related to the
China, which regards DR as Yin deficiency of the liver following key words: diabetic retinopathy, herbal,
and kidney, Yin deficiency with dryness-heat, Yin medicine, traditional, Heyingqingre, Buyanghuanwu
deficiency with fluid inadequacy, and Yin deficiency with Decoction, Zhenwu Decoction, Giming Granule, Fufang
blood stasis [4]. “Qi is the essence of the body” means Xueshuantong, Fufang Danshen Dripping Pill, Yinxing,
that blood flow and body fluid transfusion depend on Qi Qishenyiqi Dropping Pill, Liuweidihuang, and
promotion. Further, Qi can control blood circulation in Naoxintong. The search included non-English language
the vessels. Qi-Yin insufficiency is the root cause of DR, articles. All articles published from 2000 to March 2017
while Qi stagnation and blood stasis are the symptoms of were searched.
DR. Qi-Yin deficiency and blood stasis are the key
Table 1 Formulaes for diabetic retinopathy based on syndrome differentiation
Symptom Therapeutic
Formulaes Ingredients
analysis principle
Danshen (Radix Salviae Miltiorrhizae), Maidong (Radix
Tonify Qi and
Qi and Yin Shengmai ophiopogonis), Wuweizi (Fructus Schisandrae Chinensis),
nourish Yin,
deficiency, and Powder and Gouqizi (Fructus Lycii), Juhua (Chrysanthemum), Shudihuang
regulate blood
meridian Qijudihuang (Rehmanniae Radix Praeparata), Shanzhuyu (Fructus Corni),
circulation and
stagnation Pill Shanyao (Rhizoma Dioscoreae), Fuling (Poria), Zexie
open colleteral
(Rhizoma Alismatis), Mudanpi (Cortex Moutan)
Liver and
Tonify liver
kidney Shudihuang (Rehmanniae Radix Praeparata), Shanzhuyu
and kidney,
deficiency, and Liuweidihuang (Fructus Corni), Mudanpi (Cortex Moutan), Shanyao
nourish the
colletoral of Pill (Rhizoma Dioscoreae), Fuling (Poria), Zexie (Rhizoma
dryness and
eyes cannot be Alismatis)
generate fluid
nourished
Zuogui Pill: Shudihuang (Rehmanniae Radix Praeparata),
Shanyao (Rhizoma Dioscoreae), Shanzhuyu (Fructus Corni),
Tusizi (Semen cuscutae), Gouqizi (Fructus Lycii), Chuanniuxi
(Radix cyathulae), Lujiaojiao (Colla Corni Cervi), Guijiajiao
Yin and Yang
Tonify Yin and (Tortoise shell and plastron glue)
deficiency, with Zuogui Pill
Yang, get rid Yougui Pill: Shudihuang (Rehmanniae Radix Praeparata),
blood stasis and and
of phlegm and Shanyao (Rhizoma Dioscoreae), Shanzhuyu (Fructus Corni),
phlegm Yougui Pill
stasis Gouqizi (Fructus Lycii), Tusizi (Semen cuscutae), Lujiaojiao
stagnation
(Colla Corni Cervi), Duzhong (Cortex Eucommiae), Rougui
(Cortex Cinnamomi), Danggui (Radix Angelicae Sinensis),
Zhifuzi (Processed Radix aconiti lateralis)
Foumulae should be modified according to specific syndromes and clinical manifestations.

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Review Traditional Medicine Research 2018 March; 3(2): 70-81

Table 2 Experimental evidence of formulaes/herbs for diabetic retinopathy

Formula/herb Ingredients Experimental evidence

Heyingqingre Jinyinhua (Flos Lonicerae), Danggui (Radix Inhibit AGEs; recover on endothelial
Formula Angelicae Sinensis), Xuanshen (Radix dysfunction via modulation of tight
Scrophulariae), Gancao (Radix Glycyrrhizae), junction and AGEs downstream signaling.
Shengdi (Rehmannia glutinosa), Gouqi (Fructus
Lycii) and Huangjing (Rhizoma Polygonati)
Jiawei Huangqi (Radix Astragali seu Hedysari), Guiwei Decrease blood viscosity; descend plasma
Buyanghuanwu (Angelica tail), Chishao (Radix Paeoniae Rubra), ET-1; inhibit the apoptosis of retinal
Decoction Honghua (Flos Carthami), Taoren (Semen persicae), microvessel pericytes of DR.
Chuanxiong (Rhizoma Ligustici Chuanxiong),
Shengdi (Rehmannia glutinosa), Xuanshen (Radix
Scrophulariae), Shanyao (Rhizoma Dioscoreae),
Fuling (Poria) and Cangzhu (Atractylodes Rhizome)

Zhenwu Fuzi (Radix Aconiti Lateralis Praeparata), Reduce the level of plasma endothelin.
Decoction Shengjiang (Rhizoma Zingiberis Recens), Fuling
(Poria), Baizhu (Atractylodis Macrocephalae) and
Baishao (Radix Paeoniae Alba)
Qiming Huangqi (Radix Astragali seu Hedysari), Gegen Inhibit the polyol pathway; affect oxidative
Granule (Radix Puerariae), Dihuang (Radix Rehmanniae), stress; regulate the level of VEGF and
Gouqizi (Fructus Lycii), Juemingzi (Cassia Seed), IGF-1; accelerate retinal microvascular
Chongweizi (Motherwort Fruit), Puhuang (Cattail blood circulation.
Pollen) and Shuizhi (Hirudo)
Fufang Sanqi (Radix Notoginseng), Huanqi (Radix Astragali Improve hemodynamic indexes; affect
Xueshuantong seu Hedysari), Danshen (Radix Salviae anti-oxidative stress; inhibit of hyper-level
Capsule Miltiorrhizae) and Xuanshen (Radix Scrophulariae) of VEGF, ICAM-1, ET-1, and AR
hyper-activity, up-regulate of the
hypo-expression of PEDF and occludin.
Fufang Danshen (Radix Salviae Miltiorrhizae), Sanqi (Radix Inhibit ET-1 and ICAM-1 production;
Danshen Notoginseng) and Bingpian (Borneol) reduce inflammatory response; improve
Dripping Pill the role of vascular endothelial function.
Ginkgo biloba Yinxingye (Folium Ginkgo) Reduce the malondialdehyde; increase
erythrocyte deformability, blood flow
velocity and the oxygen transport
efficiency value of the blood; affect retinal
VEGF protein levels and retinal cell
apoptosis.
Qishenyiqi Huangqi (Radix Astragali seu Hedysari), Danshen Decrease the expression of retinal AGEs,
Dropping Pill (Radix Salviae Miltiorrhizae), Sanqi (Radix ICAM-1, VEGF and RAGE mRNA,
Notoginseng) and Jiangxiang (Dalbergia odorifera) ICAM-1-mRNA, VEGF mRNA; increase
the expression of retinal PEDF and PEDF
mRNA; promote the level of retinal
GLAST and GS; reduce the high
concentrations of the role of glutamate
excitotoxicity.
Liuweidihuang Shudihuang (Rehmanniae Radix Praeparata), Improve insulin resistance, anti-apoptosis
Pill Shanzhuyu (Fructus Corni), Mudanpi (Cortex and anti-oxidation.
(Decoction) Moutan), Shanyao (Rhizoma Dioscoreae), Fuling
(Poria) and Zexie (Rhizoma Alismatis)

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Review Traditional Medicine Research 2018 March; 3(2): 70-81

Table 2: Continued.
Naoxintong Huangqi (Radix Astragali seu Hedysari), Chishao Decrease fasting blood glucose levels;
Capsule (Radix Paeoniae Rubra), Danshen (Radix Salviae inhibit the diabetes-induced retinal vascular
Miltiorrhizae), Danggui (Radix Angelicae abnormalities; inhibite the diabetes-induced
Sinensis), Honghua (Flos Carthami), Chuanxiong expression of CAS-3, MMP-2, MMP-9,
(Rhizoma Ligustici Chuanxiong), Taoren (Semen and TNFα in the retina.
persicae), Niuxi (Radix et Rhizome Achyranthes),
Jixueteng (Caulis Spatholobi), Sangzhi (Mulberry
Twig), Guizhi (Ramulus Cinnamomi), Ruxiang
(Olibanum), Moyao (Myrrha), Shuizhi (Hirudo),
Quanxie (Scorpion) and Dilong (Lumbricus)

AGEs, Advanced glycation end products; DR, Diabetic retinopathy; ET-1, Endothelin-1; IGF-1, Insulin-like growth
factor 1; VEGF, Vascular endothelial growth factor; ICAM-1, Intercellular adhesion molecule-1; AR, Aldose
reductase; PEDF, Pigment epithelium-derived factor; RAGE, Receptor for AGEs; GLAST, Glutamate-aspartate
transporters; GS, Glutamine synthetase; CAS-3, Caspase-3; MMP-2, Matrix metalloproteinase-2; MMP-9, Matrix
metalloproteinase-9; TNFα, Tumor necrosis factor α.

Chinese herbal formulaes
Heyingqingre Formula
Heyingqingre Formula (HF) is a formula modified from
Simiaoyongan Decoction by Zou Jusheng, a prominent
TCM doctor. Simiaoyongan Decoction emerged in the
Qing Dynasty of China (1644 B.C.-1912B.C.) and has
also been shown more recently to be beneficial for
vascular diseases. It can clear heat and activate blood
flow owing to the presence of Jinyinhua (Flos Lonicerae),
Danggui (Radix Angelicae Sinensis), Xuanshen (Radix
Scrophulariae), and Gancao (Radix Glycyrrhizae). HF
has been used in a local hospital for decades as a
complementary treatment method for DR with retinal
vascular dysfunction. HF was modified for effective DR
treatment by adding some herbs as nourishing Yin, such
as Shengdi (Rehmannia glutinosa), Gouqi (Fructus Lycii),
and Huangjing (Rhizoma Polygonati). Furthermore,
chlorogenic acid, ferulic acid, and arctin have been
identified as the major components of HF [8].
Clinical reports revealed that HF could ameliorate
visual defects, microaneurysms, hemorrhages, and
macular edema. In a clinical report [9] of 61 patients
(Heyingqingre group: 31 cases, 52 eyes; Calcium
dobesilate group: 30 cases, 50 eyes) with DR in the
non-proliferative stage, use of HF for 3 months was much
more effective compared with the control group (calcium
dobesilate) with respect to visual acuity, fundus
examination, and TCM syndrome, indicating that HF has
definite effects on DR in the non-proliferative stage.
Compared with the results of laser treatment alone, the
combination of laser and HF decreased fundus
hemorrhages, exudation, and macular edema, which
indicated that HF is a potential complementary treatment
for DR [10]. Wang et al. [8] investigated the anti-DR
action of HF and its underlying mechanism
experimentally in a rodent model of DR. The data
indicated that HF suppresses retinal vasculature
degeneration and blood-retina-barrier permeability
damage without significant inhibition of hyperglycemia
in vitro and in vivo. HF also reduced the formation of
advanced glycation end products (AGEs) and
AGE-induced migration as well as the permeability of
retinal vascular endothelial cells. The level of the tight
junction proteins, Zo-1 and Claudin-1 was increased,
while activation of the AGE receptor and downstream
signaling to Akt was suppressed upon HF treatment.
Therefore, HF exhibits protective effects against DR,
which might be associated with inhibition of AGEs and
recovery of endothelial dysfunction via modulation of
tight junctions and AGE downstream signaling.
Jiawei Buyanghuanwu Decoction (JBHD)
Buyanghuanwu Decoction (BHD) is a classic traditional
Chinese herbal prescription for stroke, which was first
recorded in the Yilingaicuo written by Wang Qingren in
1830 B.C. during the late Qing Dynasty of China [11].
BHD is composed of seven types of Chinese medicine:
Huangqi (Radix Astragali seu Hedysari), Guiwei
(Angelica root tail), Chishao (Radix Paeoniae Rubra),
Dilong (Lumbricus), Honghua (Flos Carthami), Taoren
(Semen persicae) and Chuanxiong (Rhizoma Ligustici
Chuanxiong), with functions of tonifying Qi, invigorating
blood circulation, and dredging collaterals. Based on the
TCM theory of concerted application, the main
characteristics of BHD arise from the use of its principal
drug, Huangqi (Radix Astragali seu Hedysari), in larger
doses, invigorating Qi to activate blood circulation. In
modern times, BHD is still widely used throughout China
and elsewhere in the world for the treatment of ischemic
stroke [12]. In addition, it has been confirmed that BHD
has curative effects on cardiovascular diseases,
cerebrovascular diseases, and other disorders with Qi
deficiency and blood stasis patterns [13, 14].
Based on the TCM theory of treating different diseases
with the same method, BHD is a classical representative
prescription of the Qi-tonifying and stasis-eliminating
method [15]. BHD has also been used to treat diabetes
and its complications [16]. Based on BHD, JBHD is
modified for effective DR treatment by removing Dilong

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Review
(Lumbricus) and adding Shengdi (Rehmannia glutinosa)
and Xuanshen (Radix Scrophulariae), whose function to
nourish Yin, as well as adding Shanyao (Rhizoma
Dioscoreae), Fuling (Poria), and Cangzhu (Atractylodes
Rhizome), whose function to regulate “Qi-flowing” for
spleen strengthening. According to TCM, JBHD is
suitable for the treatment of non-proliferative DR (NPDR)
with the syndrome of Qi and Yin deficiency and blood
stasis [17].
JBHD can effectively improve a hypercoagulable state,
retinal microcirculation, and retinal function; it can also
retrogress macular edema, decrease blood viscosity,
reduce plasma endothelin-1 (ET-1), and inhibit apoptosis
of retinal microvascular pericytes in DR. In a preliminary
clinical study [18], Tang and his colleagues concluded
that 8-week oral administration of JBHD could improve
hemorheologic indexes in 60 patients with simple DR. A
favorable effect of JBHD was observed in the treatment
of DR in that it protected visual acuity and improved
macular edema retrogression by analyzing fluorescence
fundus angiography after 3-12 months of medication in a
clinical trial (58 cases, 116 eyes of DR patients). The
study showed that the combination of retinal laser
photocoagulation (532 nm double frequency laser) and
JBHD is an effective method to treat DR, which could
protect visual acuity and improve macular edema
retrogression [19]. A similar finding was observed by Jin
and his colleagues indicating that JBHD and retinal laser
photocoagulation could improve retinal microcirculation
and retinal function partially when treating NPDR, and
that JBHD could reduce the ET-1 in NPDR [20].
Furthermore, in another report by Dong et al., apoptosis
of retinal microvascular pericytes was observed in rats
with diabetes mellitus (DM) on the twelfth week, and
JBHD could inhibit this apoptosis [17]. However,
multicenter, randomized, parallel controlled clinical trials
are required to determine the effect of JBHD on DR.
Zhenwu Decoction
Zhenwu Decoction was first introduced by Zhang
Zhongjing in the third century. His book, Shanghanlun
has been widely used for the treatment of internal,
external, and gynecological diseases, and for many other
clinical treatments [21]. There are five components in
Zhenwu Decoction: Fuzi (Radix Aconiti Lateralis
Praeparata), Shengjiang (Rhizoma Zingiberis Recens),
Fuling (Poria), Baizhu (Atractylodis macrocephala), and
Baishao (Radix Paeoniae Alba). In the prescription, Fuzi
(Radix Aconiti Lateralis Praeparata) dispels cold;
Shengjiang (Rhizoma Zingiberis Recens) helps to dispel
cold and expel the cold fluid; both Fuling (Poria) and
Baizhu (Atractylodis macrocephala) invigorate the spleen
for diuresis; and Baishao (Radix Paeoniae Alba) helps
nourish the blood [22].
Zhenwu Decoction exhibited a beneficial effect in
patients with DR. In a preliminary, double-blind clinical
study of 80 elderly patients with type 2 DR, Zhenwu
Decoction combined with western medicine for treating
DR, reduced the level of plasma ET-1 [23]. A similar
report by Zhu KJ, et al. also indicated that Zhenwu
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Traditional Medicine Research 2018 March; 3(2): 70-81
Decoction had a significant therapeutic effect on DR [24].
Chinese patent drugs
Modern developed drugs
Qiming Granule. The Chinese compound medicine,
Qiming (QM) Granule, is the first drug approved by
China FDA for the treatmen of DR. It was studied by
Professor Liao Pinzheng and Professor Duan Junguo of
Chengdu University of TCM. The functions of QM
Granule is to replenish Qi, produce Yin, nourish the liver
and kidney, and activate eye channels to improve eyesight
[25]. QM Granule is suitable for the treatment of NPDR.
In addition , based on syndrome differentiation in TCM,
QM Granule is suitable for deficiency of both Qi and Yin
[26].
QM Granule consists of eight traditional plants, namely
Huangqi (Radix Astragali seu Hedysari), Gegen (Radix
Puerariae), Dihuang (Radix Rehmanniae), Gouqi
(Fructus Lycii), Juemingzi (Cassia Seed), Chongweizi
(Motherwort Fruit), Puhuang (Cattail Pollen), and
Shuizhi (Hirudo) [27]. Huangqi (Radix Astragali seu
Hedysari) contains saponins, flavonoids, amino acids,
proteins, vitamins, glycans, organic acids,
polysaccharides, and other substances. It is used to treat
Qi deficiency and blood stagnation syndrome. Gegen
(Radix Puerariae) helps produce saliva, slake thirst, and
invigorating spleen Yang. Puerarin is the main active
compound extracted from Gegen (Radix Puerariae).
Dihuang (Radix Rehmanniae) has the effect of
heat-clearing and blood-cooling, nourishing Yin, and
generating body fluid [28]. The main chemical
constituents of Dihuang (Radix Rehmanniae) are
polysaccharides [29], iridoid glycosides [30],
phenylethanoid glycosides [31], nucleosides [32], and
other ingredients.
In a 3-month, randomized, controlled, double-blind,
multicenter clinical trial, with 212 eyes from 212 patients
with NPDR (QM Granule group, 107 patients;
Doxium®-controlled group, 105 patients), QM Granule
was more effective than Doxium® with respect to the
excellence rate and total effective rate of the TCM. The
adverse effect rate in the QM Granule group was 0.935%,
while that of the Doxium®-controlled group was 7.619%,
indicating that the QM Granule was safe. Therefore, the
QM Granule may be superior to Doxium® Tablets in
treating NPDR [26]. A favorable effect of QM Granule in
the treatment of DR that was observed by analyzing
fluorescence fundus angiography after 3 months of
medication in a multicenter, randomized, parallel
controlled clinical trial (360 DR patients) was improved
retinal blood circulation, indicating that QM Granule
might alleviate retinal hypoxia and ischemia by
increasing retinal blood flow and improving blood
circulation [33]. QM Granule combined with calcium
dobesilate therapy could improve choroidal circulation,
inhibit angiogenesis mediated by a variety of cytokines in
the retina, and alter branched chain amino acid
metabolism [34]. Feng HJ, et al. reported a clinical study
on NPDR patients treated with QM Granule combined
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Review
with Xueshuantong Capsule, and planned to evaluate the
efficiency and safety of QM Granule in patients with DR.
The data obtained from the research showed that the
effect in the observation group (QM Granule combined
with Xueshuangtong Capsule) was significantly better
than the effect in the control group (Xueshuantong
Capsule); the patients in both groups had no drug-related
complications, and the mechanism may have involved
lower VEGF and insulin-like growth factor 1 (IGF-1)
levels [35]. Furthermore, panretinal photocoagulation
combined with medication (QM Granule and/or calcium
dobesilate) therapy was not only effective in promoting
regression of neovascularization, but it also improved
DR-induced vision loss in patients receiving panretinal
photocoagulation [36]. These studies provide evidence of
the clinical utility of QM Granule for the treatment of
DR.
QM Granule can delay the progression of DR. The
therapeutic effect and mechanism of QM Granule may
occur through inhibition of the polyol pathway
(increasing synthesis of inositol, thus reducing histiocytic
damage) [37], affecting oxidative stress (reducing the
content of malondialdehyde, increasing the activity of
superoxide dismutase and glutathione peroxidase) [38],
regulating the expression of VEGF [39] and IGF-1 [39,
40], and accelerating retinal microvascular blood
circulation [41].
Fufang Xueshuantong Capsule. Fufang Xueshuantong
(FXT) Capsule is a herbal formula licensed for clinical
use in China [42], which is composed of Sanqi (Radix
Notoginseng), Huangqi (Radix Astragali seu Hedysari),
Danshen (Radix Salviae Miltiorrhizae), and Xuanshen
(Radix Scrophulariae) [43], with functions of dilating the
vessels, increasing blood flow, improving blood
circulation, and improving microcirculation [44]. The
saponins of Sanqi (Radix Notoginseng), harpagoside,
cryptotanshinone, tanshinone I, and astragaloside A, are
the core constituents of FXT Capsule [45].
FXT Capsule has beneficial effects on DR [46], which
could improve retinal blood perfusion for NPDR after
photocoagulation [47]. A clinical study reported that FXT
Capsule could improve hemodynamic indexes (including
peak systolic velocity, end diastolic velocity, mean
velocity, pulsatility index, and resistance index in the
central retinal artery, as well as maximum velocity and
minimum velocity in the central retinal vein) in the
retinas of NPDR patients and improve their vision [48].
In another clinic study, FXT Capsule administered to DR
patients for 5 months induced a decrease in the levels of
high-sensitivity C-reactive protein, VEGF, and IGF-1.
From these data, it was concluded that FXT Capsule
combined with calcium dobesilate could reduce the
recurrence rate and delay the proliferation of blood
vessels more than oral calcium dobesilate alone [49].
FXT Capsule could play a role in the treatment of DR
by decreasing pericyte loss and reducing acellular
capillaries [45]. Its mechanism might involve reducing
oxidative stress [50]; inhibition of the hyperexpression of
VEGF [45, 50, 51], intercellular adhesion molecule-1
(ICAM-1), and ET-1; reversal of the hyperactivation of
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Traditional Medicine Research 2018 March; 3(2): 70-81
aldose reductase; or upregulation of the hypoexpression
of pigment epithelium-derived factor (PEDF) and
occludin [45, 51]. Animal studies showed that the
antioxidative and antihypoxic effects of FXT Capsule on
diabetic retinas might be mediated by ameliorating the
state of ischemia and hypoxia, downregulating the
expression of hypoxia-inducible factor 1 alpha, enhancing
the activity of superoxide dismutase, and upregulating the
expression of CuZn superoxide dismutase [52]. In
addition, FXT Capsule could attenuate whole blood
viscosity, plasma viscosity, and erythrocyte aggregation.
However, FXT Capsule had no effect on body weight
gain and blood glucose level [51].
Fufang Danshen Dripping Pill. Fufang Danshen
Dripping Pill, also known as compound Danshen
Dripping Pill (CDDP), is a well-established formulation
as the first new drug through the American FDA II
clinical trials, which is used to treat cardiovascular
diseases [53]. CDDP is a Chinese formula that consists of
Danshen (Radix Salviae Miltiorrhizae), Sanqi (Radix
Notoginseng), and Bingpian (Borneol). It has the effect of
promoting blood circulation to remove blood stasis,
regulating Qi, and relieving pain. Danshen (Radix Salviae
Miltiorrhizae) is a common TCM often used to treat
many medical conditions, especially blood stasis. CDDP
is still appropriate for treatment of DR with blood stasis
syndrome [7]. According to Chinese Pharmacopoeia
records, CDDP, through a water extraction process,
contains water-soluble tanshinol (Danshensu), salvianolic
acid B, protocatechuic aldehyde, notoginseng saponins,
and other major components [54].
CDDP could improve visual acuity, control
microhemorrhage and microaneurysm of fundus, and
affect visual functional recovery in DR [55]. Lian and
colleagues reported that CDDP had definite efficacy and
safety for treating NPDR. In their controlled clinical trial
involving 223 patients with NPDR, the ratio of
“Excellent” and “Effective” in the high-dose (30 pills
three times per day) and mid-dose (20 pills three times
per day) CDDP groups was significantly greater than that
in the placebo group after a 24-week treatment, as
assessed by fluorescence fundus angiography and
fundoscopic examination. No adverse events with clinical
significance occurred [56]. In another randomized,
double-dummy, double-blind study, after 3-month
treatment, there was no statistical difference in each index
(including the best corrected visual acuity, visual field,
hemorrhage area of the fundus, microaneurysm number,
fluorescent leakage area, and capillary nonperfusion area)
between the treated group (CDDP) and the control group
(calcium dobesilate). The results showed that CDDP
showed a similar improvement of NPDR and safety
profile as calcium dobesilate. CDDP might be considered
the auxiliary drug for DR [57].
Studies have shown that CDDP, through
anti-inflammatory and vascular endothelium-protective
effects, plays a therapeutic role in DR [58]. DR is a
chronic, low-grade inflammatory disease [59] and
impaired endothelial function is a common denominator
of pathogenesis in DR [60]. Yang and colleagues found
TMR | March 2018 | vol. 3 | no. 2 | 76
Review
that, after CDDP treatment of early DR patients, the
endothelium-dependent flow-mediated dilatation could be
greatly improved, and ET-1 and ICAM-1 production
could be inhibited, thereby reducing blood vessel
contraction and spasm to improve vascular endothelial
function [58]. This indicated that CDDP could effectively
reduce early DR in patients by improving inflammatory
response and vascular endothelial function [60].
Ginkgo biloba. Yinxing (Ginkgo biloba, GB) is an
ancient medicinal tree species that has been in existence
for millennia without undergoing changes due to its
resistance to environmental stresses [61]; it has been used
in TCM for approximately 5000 years [62]. As early as
the Shennongbencaojing, GB has been recorded to have
medicinal properties, such as moistening the lung and
acting as an anti-asthmatic and antitussive agent [63]. The
extracts from the leaves of GB have been used as a
standardized preparation Egb 761 [64]. Yinxingye
(Folium Ginkgo, GBL) has the function of curing
diseases of the lung and asthma, promoting blood
circulation, and relieving pain. The chemical constituents
responsible for the bioactivities of GBL have been
identified as biflavones, terpene trilactones (ginkgolides
A, B, C, J, P and Q, and bilobalides), flavonol glycosides
(quercetin, catechin), and proanthocyanidins [65, 66].
Ginkgo biloba extract (GBE) has been found to be useful
in the treatment of cerebral infarction, Alzheimer’s
disease, hypertension, coronary heart disease, DM and its
complications, chronic glomerulonephritis, and especially
chronic diseases [67]. GBE has pharmacological
functions, including antioxidant, free radical-scavenging,
and anti-platelet activating factor activities, as well as
regulation of vascular activity, augmentation of blood
flow, and neuroprotection [62, 63]. Early studies
indicated a potential role in age-related macular
degeneration [68] and some types of glaucoma [69].
GBE has also shown a beneficial effect in DR. In a
preliminary clinical study, Huang and colleagues
concluded that 3 months of oral administration of Egb
761 for type 2 diabetic patients with retinopathy could
reduce fibrinogen levels, plasma viscosity, and
malondialdehyde content of erythrocyte membranes (i.e.,
reduce lipid peroxidation stress), as well as increase
erythrocyte deformability. This improves blood viscosity
and viscoelasticity, further increasing blood flow velocity
and the oxygen transport efficiency value of the blood.
These factors could all contribute to improving or
lowering peripheral circulation disorders among diabetic
patients. The data indicated that providing Egb 761 to
type 2 DM patients can result in a meaningful impact on
their blood circulation and reduction in retinopathy
occurrence [70]. Zhu and associates explored the clinical
efficacy of GBE with 80 patients (150 eyes) with mild or
moderate NPDR. After 6 months of treatment, the total
effective rate in the treatment group (enteric-coated
aspirin tablets plus GBE, 75.6%) was significantly higher
than that in the control group (enteric-coated aspirin
tablets, 58.7%); this showed that GBE could reduce
retinal hemorrhage and exudation, improve visual acuity
and visual field, and reduce retinal vascular endothelial
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Traditional Medicine Research 2018 March; 3(2): 70-81
cell damage [71]. Therefore, we believe that GBE has a
definite effect on the prevention and treatment of DR.
A previous study demonstrated that GBE affects retinal
VEGF protein levels and retinal cell apoptosis. The
expression of diabetic retinal VEGF could be reduced and
retinal ganglion cell apoptosis could be attenuated by
GBE in non-obese diabetic mice with diabetes [72].
However, the molecular mechanisms underlying these
actions should be further elucidated, and more clinical
trials are required to explore the effect of GBL on DR.
Qishenyiqi Dropping Pill. Qishenyiqi (QSYQ) Dropping
Pill is a Chinese medicine prescription approved by the
State Food and Drug Administration of China [73]. The
QSYQ Dropping Pill is composed of Huangqi (Radix
Astragali seu Hedysari), Danshen (Radix Salviae
Miltiorrhizae), Sanqi (Radix Notoginseng), and
Jiangxiang (Dalbergia odorifera), and has the effect of
tonifying Qi, promoting blood circulation, and relieving
pain. Hence, it has been widely used to treat
cardiovascular diseases with Qi deficiency and blood
stasis syndrome [74, 75], including myocardial infarction,
angina, myocarditis, myocardial fibrosis, and heart failure
[76-78]. Twelve compounds are the main components of
QSYQ, including astragaloside IV, calycosin, and
formononetin from Huangqi (Radix Astragali seu
Hedysari); Danshensu, protocatechuic aldehyde, and
rosmarinic acid from Danshen (Radix Salviae
Miltiorrhizae); ginsenoside Rg1, ginsenoside Rb1, and
notoginsenoside R1 from Sanqi (Radix Notoginseng); and
trans-nerolidol, (3S,6S,7R)-3,7,11-trimethyl-3,6-epoxy
-1,10-dodecadien-7-ol, and (3S, 6R,7R)-3,7,11-
trimethyl-3,6-epoxy-1,10-dodecadien-7-ol from
Jiangxiang (Dalbergia odorifera). These compounds are
absorbed into the blood and distributed into the tissues
after oral administration [79].
Recently, it was reported that QSYQ Dropping Pill
could delay the progression of DR in animal studies. The
mechanism of QSYQ may occur by decreasing the
expression of retinal AGEs, ICAM-1, and VEGF;
reducing the mRNA expression of the receptor for AGEs,
ICAM-1, and VEGF; increasing the expression of retinal
PEDF and PEDF mRNA; promoting the expression of
retinal glutamate-aspartate transporters and glutamine
synthetase; and reducing the effect of high concentrations
of glutamate on excitotoxicity [80-83]. All of these
studies also provide an experimental basis for the clinical
application of Chinese patent medicine to prevent and
cure DR.
Ancient processed drugs
Liuweidihuang Pill (Decoction). Liuweidihuang Pill
(LDP) was initially created by Qian Yi in 1119 B.C., who
was the famous doctor of TCM in the Song Dynasty of
China. It was originally used to treat dysplasia in children
[84]. LDP was derived from the Jinguiyaolue written by
Zhang Zhongjing. The herbal formula of LDP consists of
Shudihuang (Rehmanniae Radix Praeparata), Shanzhuyu
(Fructus Corni), Mudanpi (Cortex Moutan), Shanyao
(Rhizoma Dioscoreae), Fuling (Poria), and Zexie
(Rhizoma Alismatis), with the effects of enriching Yin
TMR | March 2018 | vol. 3 | no. 2 | 77
Review
and tonifying the kidney. Three of the six ingredients in
the formula are nutrients, while the other three facilitate
drainage. Because of its unique composition and affirmed
therapeutic effect, the main indications of the efficacy of
this formula have been expanded. It was widely applied
in the treatment of different diseases in internal medicine,
surgery, gynecology, pediatrics, and other diseases, for
syndromes differentiated as kidney Yin deficiency, liver
and kidney Yin deficiency, and hyperactivity of deficient
fire. Modern pharmacological research indicated that it
has obvious effects of strengthening immunization,
anti-aging, anti-fatigue, anti-low temperature, hypoxia
tolerance, decreasing blood fat, blood pressure and blood
sugar reduction, and improving renal function, among
other activities. LDP has a long history in treating
diabetes. Pharmacology research indicated that it is
effective in improving insulin resistance, inhibiting
apoptosis, and reducing oxidative stress [85]. Adding
LDP to Western medicine could improve treatment
outcomes of diabetes [86].
In a randomized, double-blind and placebo-controlled
clinical trial of 140 outpatients with type 2 diabetes, after
36 months of treatment, the urinary creatinine ratio
(Umalb/cr), diabetic nephropathy prevalence, and DR
prevalence in the treatment group (LDP and Ginkgo leaf
Tablet (GLT) were all significantly lower than those of
the control group (Placebo) [87]. An analogous clinical
trial was reported by An XF, et al [88]; it showed that the
incidence rate of DR was significantly lower in the
treatment group (LDP and GLT) than in the control group
(Placebo). These results indicate that LDP and GLT are
beneficial to DR and will prevent and treat the
development of DR.
Naoxintong Capsule. Naoxintong (NXT) is an empirical
formula based on the principle of TCM by Professor
Zhao Buchang, based on Wang Qingren’s “Buyang
-huanwu Soup” from the Qing Dynasty of China (1644
B.C.-1912B.C.), with the functions of replenishing Qi and
promoting blood circulation to remove blood stasis [89].
NXT has been approved by the China Food and Drug
Administration (Z20025001) [90] and has been
recognized as a treatment for coronary heart disease, Qi
deficiency, blood stasis syndrome, and cerebrovascular
diseases in clinical trials [91]; it has good clinical effect
and is cost-effective [92]. NXT contains sixteen types of
TCM, including Huangqi (Radix Astragali seu Hedysari),
Chishao (Radix Paeoniae Rubra), Danshen (Radix
Salviae Miltiorrhizae), Danggui (Radix Angelicae
Sinensis), Honghua (Flos Carthami), Chuanxiong
(Ligusticum chuanxiong Hort), Taoren (Semen persicae),
Niuxi (Radix et Rhizome Achyranthes), Jixueteng (Caulis
Spatholobi), Sangzhi (Mulberry Twig), Guizhi (Ramulus
Cinnamomi), Ruxiang (Olibanum), Moyao (Myrrh), and
animal medicines, including Shuizhi (Hirudo), Quanxie
(Scorpion), and Dilong (Lumbricus). Modern
pharmacological studies have demonstrated that [93],
Huangqi (Radix Astragali seu Hedysari) has
hypolipidemic and antioxidant effects; Quanxie (Scorpion)
can reduce the content and activity of thrombin
plasminogen activator and has antithrombotic effects;
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Traditional Medicine Research 2018 March; 3(2): 70-81
Dilong (Lumbricus) and Quanxie (Scorpion) contain a
large number of hydrolytic proteases with thrombolytic
factors, and can reduce cholesterol, atherosclerotic
plaques, and dissolve thrombi; Danshen (Radix Salviae
Miltiorrhizae) can reduce the blood content of
low-density lipoprotein and triacylglycerol; Danggui
(Radix Angelicae Sinensis) and Chuanxiong (Ligusticum
chuanxiong Hort) have antithrombotic and hypolipidemic
effects; and Honghua (Flos Carthami) and Chuanxiong
(Ligusticum chuanxiong Hort) have inhibitory effects on
platelet aggregation and disaggregation.
The formation of DR is associated with pathological
progression of the microvascular system. Therefore, we
surmise that NXT can reduce the development of DR. A
recent study by Liu MY, et al. evaluated the effect of
NXT in a mouse model of DR [94]. In this study, NXT
decreased fasting blood glucose levels, inhibited
diabetes-induced retinal vascular abnormalities, and
inhibited diabetes-induced expression of caspase-3,
matrix metalloproteinase-2, matrix metalloproteinase-9,
and tumor necrosis factor α in the retina. This research
indicated that NXT inhibits the development of DR in
mice, which implies an important and potential
application of NXT for treatment of diabetic retinopathy
in the clinic.
Conclusion
Chinese medicines are being currently explored to find
safer alternative treatments for DR. Despite heterogeneity
in clinical trials, they have shown positive results in
alleviating the hyperglycemia-induced pathological
conditions. Some objective limitations should be
considered based on existing research. A well-designed
randomized controlled trial and a better understanding of
the mechanisms of Chinese herbs should be elaborated in
future studies. Chinese medicines are a complex system,
even with guidance from TCM. The compounds
contained in one herb, even in an extract of one herb, are
very complicated. Therefore, the side effects of herbs and
their drug interactions should be explored and taken into
account. Chinese medicine needs to continue
development, based on the theory of TCM, to show the
characteristics of TCM. Hopefully, Chinese medicine will
have a broader usage to treat or prevent DR as an
alternative or as a combination therapy.
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