Journal of Ethnopharmacology 213 (2018) 92–100

Contents lists available at ScienceDirect

Journal of Ethnopharmacology
journal homepage: www.elsevier.com/locate/jethpharm

Characteristics of Chinese herbal medicine usage and its effect on survival of T

lung cancer patients in Taiwan
Te-Mao Lia, Yang-Hao Yub, Fuu-Jen Tsaia,c,d, Chi-Fung Chenge, Yang-Chang Wua,
Tsung-Jung Hoa, Xiang Liuf, Hsinyi Tsangf, Ting-Hsu Linc, Chiu-Chu Liaoc, Shao-Mei Huangc,
⁎ ⁎
Ju-Pi Lia,g, Jung-Chun Linh, Chih-Chien Lini, Wen-Miin Liange, , Ying-Ju Lina,c,
a
School of Chinese Medicine, China Medical University, Taichung, Taiwan
b
Divisions of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
c
Genetic Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
d
Asia University, Taichung, Taiwan
e
Graduate Institute of Biostatistics, School of Public Health, China Medical University, Taichung, Taiwan
f
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
g
Rheumatism Research Center, China Medical University Hospital, Taichung, Taiwan
h
School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
i
Department of Cosmetic Science, Providence University, Taichung, Taiwan

A R T I C L E I N F O A B S T R A C T

Keywords: Ethnopharmacological relevance: In Taiwan, lung cancer remains one of the deadliest cancers. Survival of lung
Lung cancer cancer patients remains low, ranging from 6% to 18%. Studies have shown that Chinese herbal medicine (CHM)
Chinese herbal medicine can be used to induce cell apoptosis and exhibit anti-inflammatoryanti-inflammatory activities in cancer cells.
Survival Aim of the study: This study aimed to investigate the frequencies and patterns of CHM treatment for lung cancer
patients and the effect of CHM on their survival probability in Taiwan.
Materials and methods: We identified 6939 lung cancer patients (ICD-9-CM: 162). We allocated 264 CHM users
and 528 CHM-non users, matched for age, gender, duration, and regular treatment. Chi-square test, conditional
multivariable logistic regression, Kaplan-Meier method, and the log-rank test were used in this study.
Results: The CHM group was characterized by a longer follow up time and more cases of hyperlipidemia and
liver cirrhosis. This group exhibited a lower mortality hazard ratio (0.48, 95% confidence interval [0.39–0.61],
p < 0.001), after adjusting for comorbidities. The trend was also observed that the cumulative survival prob-
ability was higher in CHM than in non-CHM users (p < 0.0001, log rank test). Analysis of their CHM prescription
pattern revealed that Bu-Zhong-Yi-Qi-Tang (BZYQT), Xiang-Sha-Liu-Jun-Zi-Tang (XSLJZT), and Bai-He-Gu-Jin-
Tang (BHGJT); and Bei-Mu (BM), Xing-Ren (XR) and Ge-Gen (GG) were found to be the top three formulas and
herbs, respectively. Among them, BM was the core CHM of the major cluster, and Jie-Geng (JG) and Mai-Men-
Dong-Tang (MMDT) were important CHMs by CHM network analysis.
Conclusion: The use of CHM as an adjunctive therapy may reduce the mortality hazard ratio of lung cancer
patients. The investigation of their comprehensive CHM prescription patterns might be useful in future large-
scale, randomized clinical investigations of agent effectiveness, safety, and potential interactions with conven-
tional treatments for lung cancer patients.

1. Introduction
Cancer remains the leading cause of mortality worldwide. According
to the World Health Organization (WHO) reports, there were approxi-
mately 8.8 million deaths due to cancers in 2015 (Collaborators, 2016)
(http://www.who.int/mediacentre/factsheets/fs297/en/). Among them,
the mortality rate of lung cancer patients is still noteworthy, and 1.69
million deaths have been reported. In Taiwan, lung cancer also represents
the most common cancer death. Survival of lung cancer patients remains
poor, ranging from 6% to 18% (Chiang et al., 2016; Wang et al., 2013).
The mechanism and etiology of lung cancer are interesting topics and
remain to be clarified. Inflammation is an important response in re-
spiratory diseases including acute lung injury, asthma, and lung cancer
(Al-Harbi et al., 2016). Exosomes from lung tumors induce a pro-

⁎
Correspondence to: No. 91, Hsueh-Shih Road, Taichung, Taiwan.
E-mail addresses: wmliang@mail.cmu.edu.tw (W.-M. Liang), yjlin.kath@gmail.com (Y.-J. Lin).

https://doi.org/10.1016/j.jep.2017.10.031
Received 11 July 2017; Received in revised form 27 October 2017; Accepted 29 October 2017
Available online 31 October 2017
0378-8741/ © 2017 Elsevier B.V. All rights reserved.
T.-M. Li et al. Journal of Ethnopharmacology 213 (2018) 92–100

inflammatory phenotype in mesenchymal stem cells, suggesting that

nuclear factor-kappa B (NF-kB) may play important roles in cancer cell
inflammation (Li et al., 2016). Cancer cell apoptosis is characterized by
mitochondrial outer membrane permeabilization and cell death factors
including cytochrome c release into the cytoplasm, leading to caspase
activation and apoptosis (Liang et al., 2012). Interestingly, studies have
shown that Chinese herbal medicine (CHM) induces cell apoptosis and
suppresses the inflammatory response in cancer cells (Lu, 2016; Niu
et al., 2011; Zhang et al., 2012; Zhong et al., 2013).
CHM is an important element in the health care system in Taiwan
(Lee et al., 2010). People of Taiwan can choose regular Western medical
treatments, CHM, or both. The CHM usage pattern has been in-
vestigated for diseases such as childhood asthma (Huang et al., 2013),
breast cancer (Hsu et al., 2015), and diabetes (Tsai et al., 2017). The
National Health Insurance Research Database (NHIRD) provides a
platform to explore the utilization and therapeutic effects of Chinese
herbal therapies prescribed by these traditional Chinese medicine
(TCM) doctors in Taiwan.
There is still limited information about the effect of CHM usage on
the survival rate of lung cancer patients. To better understand the role
of CHM as an adjunctive therapy in lung cancer patients, we utilized a
population-based database to investigate the demographic character-
istics, overall survival, and CHM prescribing patterns for these patients.
We found that CHM users had the higher cumulative survival prob-
ability among lung cancer patients. Among these CHM users, we ob-
tained their most commonly used prescription patterns of herbal for-
mulas, single herbs, and their combinations. By using this large-scale
population-based analysis, we were further able to investigate whether
the integration of CHM and regular anti-lung cancer medications im-
proved the overall survival rate of lung cancer patients in Taiwan.
Fig. 1. Flow diagram for enrollment of lung cancer patients.

2. Materials and methods

2.1. Database
The National Health Insurance Research database (NHIRD; http://
nhird.nhri.org.tw/) provides detailed medical records of all outpatients
and hospitalizations as well as the inpatient orders, ambulatory care,
sociodemographic factors, regular treatments, drugs, and/or prescribed
CHM. This database also provides longitudinally linked data for the
1996–2012 period and is available only for research purposes to sci-
entists in Taiwan. Diseases in this NHIRD are categorized by using the
International Classification of Disease, 9th Revision, Clinical
Modification (ICD-9-CM). For this study, we obtained patient in-
formation through the ‘Longitudinal Health Insurance Database
(LHID2000 and LHID2005)’. Each LHID contained a random sample of
1 million people registered in the NHIRD in 2000 or 2005, respectively.
This study was a population-based retrospective analysis to explore the
effect of CHM treatment on the overall survival rate of lung cancer
patients. Lung cancer patients were diagnosed by qualified pathologists
and then were registered in this NHIRD. All data for each individual are
decoded and therefore we could not obtain their informed consent. We
then searched for these lung cancer patients in this database. This study
was evaluated and approved by the Institutional Review Board of the
China Medical University Hospital.
2.2. Identification of lung cancer patients
We included 6939 lung cancer patients (ICD-9-CM 162) entered into
the database between 2000 and 2009 (Fig. 1). Excluded individuals
were those with all other cancers diagnosed before lung cancer or who
were diagnosed with lung cancer before 2000 or after 2009. Finally,
3678 study subjects were included in the study.
Individuals were defined as CHM users with a cumulative number of
CHM treatment days of more than 14 within the first year after their
lung cancer diagnosis (n = 425, Fig. 1). Study subjects were defined as
non-CHM users if they did not use any CHM (n = 3253). Furthermore,
to reduce potential confounding variables, non-CHM users were se-
lected after frequency matching for age, gender, duration, and regular
treatment. For matched study subjects, 264 subjects were CHM users
and 528 subjects were non-CHM users (Table 1). The index date was
designated as the time when the criterion of 14 CHM prescription cu-
mulative days was accomplished. These CHM users continued using
CHM products during this study period (from the index date to the
study endpoint). The study end was defined as date of death, date of
withdrawal from the NHI program, or date of termination of follow-up
(December 31, 2012).
The demographic characteristics are presented in Table 1. These
included age, gender, follow up year, duration, comorbidity, and reg-
ular treatment. We also identified the comorbidities that had been di-
agnosed in the study subjects before their diagnosis of lung cancer.
These comorbidities were hypertension (ICD-9-CM 401–405), diabetes
(ICD-9-CM 250), hyperlipidemia (ICD-9-CM 272), liver cirrhosis (ICD-
9-CM 571), and chronic renal failure (ICD-9-CM 585, V45.11).
2.3. Chinese herbal medicine
All CHM prescriptions for herbal formulas and single herbs were
collected, grouped, and listed on the Taiwan NHI website (http://www.
nhi.gov.tw/webdata/webdata.aspx?menu=21&menu_id=713&
webdata_id=932). In this study, the number (%), person-year, number
of prescription, average daily dose (g), and average duration for pre-
scription (days) were calculated from the index date to the study end
for these CHM users (Table 3). Herbal formulations contain a combi-
nation of more than two single herbs and are described in traditional
Chinese medicine classics or ancient medical books. These formulas
have been used for hundreds of years in China. Single herbs are from
plant, animal, or mineral sources. These single herbs can be mixed with
other single herbs or herbal formulas to create CHM prescriptions ac-
cording to the licensed CHM doctors’ experience. In Taiwan, these

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T.-M. Li et al. Journal of Ethnopharmacology 213 (2018) 92–100

Table 1
Demographic characteristics of total subjects and frequency matched subjects with lung cancer patients according to CHM usage.

Characteristics Total subjects Matched subjects

CHM group Non-CHM group p value CHM group Non-CHM group p value
N = 425 N = 3253 N = 264 N = 528
N (%) N (%) N (%) N (%)

Age < 0.001 1

< 60 yrs 176 (41.41%) 750 (23.06%) 69 (26.27%) 139 (26.27%)
60–80 yrs 223 (52.47%) 1809 (55.61%) 176 (66.67%) 352 (66.67%)
> = 80 yrs 26 (6.12%) 694 (21.33%) 19 (7.06%) 37 (7.06%)
Gender < 0.001 1
Male 227 (53.41%) 2224 (68.37%) 181 (68.63%) 362 (68.63%)
Female 198 (46.59%) 1029 (31.63%) 83 (31.37%) 166 (31.37%)
Follow up year 978.2 ± 953 1078 ± 987.8 0.011 895.57 ± 910.10 609.92 ± 840.40 < 0.001
Durationa _ 133.3 ± 102.1 131.7 ± 102.8 131.7 ± 102.8 1
Comorbidity
Hypertension < 0.001 0.413
No 236 (55.53%) 2498 (76.79%) 130 (49.41%) 277 (52.55%)
Yes 189 (44.47%) 755 (23.21%) 134 (50.59%) 251 (47.45%)
Diabetes < 0.001 0.674
No 343 (80.71%) 2915 (89.61%) 204 (77.25%) 401 (75.88%)
Yes 82 (19.29%) 338 (10.39%) 60 (22.75%) 127 (24.12%)
Hyperlipidaemia < 0.001 0.037
No 320 (75.29%) 2986 (91.79%) 194 (73.33%) 422 (80%)
Yes 105 (24.71%) 267 (8.21%) 70 (26.67%) 106 (20%)
Liver cirrhosis < 0.001 0.046
No 338 (79.53%) 3033 (93.24%) 210 (79.61%) 450 (85.29%)
Yes 87 (20.47%) 220 ( 6.76%) 54 (20.39%) 78 (14.71%)
Chronic renal failure 0.006 0.496
No 411 (96.71%) 3205 (98.52%) 253 (95.69%) 510 (96.67%)
Yes 14 (3.29%) 48 (1.48%) 11 (4.31%) 18 (3.33%)
Regular treatment
RT only 0.718 _
No 425 (100%) 3252 (99.97%) 264 (100%) 528 (100%)
Yes 0 (0.00%) 1 (0.03%) 0 (0.00%) 0 (0.00%)
CT only < 0.001 1
No 226 (53.18%) 2482 (76.3%) 113 (42.75%) 226 (42.75%)
Yes 199 (46.82%) 771 (23.7%) 151 (57.25%) 302 (57.25%)
Surg only – –
No 425 (100%) 3253 (100%) 264 (100%) 528 (100%)
Yes 0 (0.00%) 0 (0.00%) 0 (0.00%) 0 (0%)
RT(+), CT(+), Surg(-) < 0.001 1
No 281 (66.12%) 2972 (91.36%) 184 (69.8%) 369 (69.8%)
Yes 144 (33.88%) 281 (8.64%) 80 (30.2%) 159 (30.2%)
RT(+), Surg(+), CT(-) – –
No 425 (100%) 3253 (100%) 264 (100%) 528 (100%)
Yes 0 (0.00%) 0 (0.00%) 0 (0.00%) 0 (0.00%)
CT(+), Surg(+), RT(-) < 0.001 1
No 393 (92.47%) 3142 (96.59%) 248 (94.12%) 497 (94.12%)
Yes 32 (7.53%) 111 (3.41%) 16 (5.88%) 31 (5.88%)
RT(+), CT(+), Surg(+) < 0.001 1
No 397 (93.41%) 3205 (98.52%) 258 (97.65%) 516 (97.65%)
Yes 28 (6.59%) 48 ( 1.48%) 6 (2.35%) 12 (2.35%)
RT(-), CT(-), Surg(-) < 0.001 1
No 403 (94.82%) 1212 (37.26%) 253 (95.69%) 505 (95.69%)
Yes 22 (5.18%) 2041 (62.74%) 11 (4.31%) 23 (4.31%)

CHM, Chinese herbal medicine; RT, radiation therapy; CT, chemotherapy; Surg, surgery.
Chi-squared tests were performed between CHM and non-CHM users.
a
Duration is between onest of lung cancer and the index date (days).

herbal formulas and single herbs are all manufactured by pharmaceu-
tical companies with Good Manufacturing Practice certification. These
pharmaceutical companies are Sun Ten Pharmaceutical Co. Ltd.
(http://www.sunten.com.tw/), Chuang Song Zong Pharmaceutical Co.
Ltd. (http://www.csz.com.tw/), Shang Chang Pharmaceutical Co. Ltd.
(http://www.herb.com.tw/about_en.php), KO DA Pharmaceutical Co.
Ltd. (http://www.koda.com.tw/), and Kaiser Pharmaceutical Co. Ltd
(http://www.kpc.com/).
2.4. Statistical analysis
All data management and statistical analyses were performed using
SAS software (version 9.4; SAS Institute, Cary, NC, USA). The
demographic characteristics of CHM and non-CHM users were com-
pared for categorical variables. Categorical data are shown as absolute
numbers and percentages. These categorical data included age, gender,
comorbidity, and regular treatment. Chi-squared tests were performed
to determine statistical significance between CHM and non-CHM users
(Table 1). The Kaplan-Meier survival graph was applied for the overall
survival analysis (Fig. 2) and the distant metastasis to bone analysis
(Fig. S1). The log-rank test was used to explore the effect of CHM on the
overall survival analysis (Fig. 2) and the distant metastasis to bone
analysis (Fig. S1). Exploratory analyses of hazard ratios (HR) for mor-
tality in lung cancer patients was performed by using a Cox propor-
tional hazard model with the adjustments of CHM use and comorbid-
ities with a 95% confidence interval (CI) (Table 2; Table S1; Table S2;

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T.-M. Li et al. Journal of Ethnopharmacology 213 (2018) 92–100

treatment between the two groups. The CHM group was characterized
as younger, female, and having more cases of comorbidities. After
matching these two groups for age, gender, duration, and regular
treatment, frequency-matched CHM and non-CHM users were com-
pared (Table 1). Both groups presented similar characteristics. How-
ever, there were significant differences in number of follow up years,
the frequency distributions for hyperlipidemia, and liver cirrhosis
(P < 0.05). The matched CHM group was characterized by longer
follow up time and more cases of hyperlipidemia and liver cirrhosis.

3.2. Survival analysis in lung cancer patients according to CHM usage

As shown in Table 2, after adjusting for comorbidities, the CHM

users displayed a lower mortality hazard ratio (HR) (0.48, 95% con-
fidence interval [CI 0.39–0.61], p < 0.001) when compared with the
non-CHM users. The difference in survival probability between these
Fig. 2. Kaplan-Meier survival probability of lung cancer patients according to Chinese
two groups was also investigated using a Kaplan-Meier survival graph
herbal medicine (CHM) use.
(Fig. 2). The trend was observed of the cumulative survival probability
being higher in CHM users than in non-CHM users (p < 0.0001, log
rank test).
Table 2
Hazard ratios for mortality according to CHM user and comorbidities among frequency 3.3. Most commonly prescribed Chinese herbal formula, single herb, and
matched lung cancer patients.
CHM network for lung cancer patients with better survival probability
Hazard ratio (95%CI) p value
The 12 most commonly prescribed Chinese herbal formulas and
CHM user (Yes v.s. No) 0.48 (0.39–0.61) < 0.001 single herbs are shown (Table 3). These commonly prescribed CHM
Comorbidities
patterns were associated with lung cancer patients with better survival
Hypertension (Yes v.s. No) 1.02 (0.77–1.36) 0.872
Diabetes (Yes v.s. No) 1.18 (0.86–1.63) 0.304 probability. The composition of these herbal formulas and single herbs
Hyperlipidaemia (Yes v.s. No) 1.07 (0.78–1.49) 0.671 is also displayed (Table 3). Sorted by the percentage of usage, Bu-
Liver cirrhosis (Yes v.s. No) 0.85 (0.60–1.19) 0.338 Zhong-Yi-Qi-Tang (BZYQT; 23.1%) was the most commonly prescribed
Chronic renal failure (Yes v.s. No) 1.27 (0.63–2.54) 0.504 herbal formula, with an average daily dosage of 3.8 g. The second and
third most common formulas were Xiang-Sha-Liu-Jun-Zi-Tang (XSLJZT;
CHM, Chinese herbal medicine; CI, confidence interval.
Models adjusted for CHM use and comorbidities. 21.2%) and Bai-He-Gu-Jin-Tang (BHGJT; 19.3%), with average daily
Cox's proportional hazards model was applied in this analysis. dosages of 4.2 and 3.9 g, respectively. The top 12 single herbs used for
lung cancer patients are also listed in Table 3. Bei-Mu (BM; Bulbus
Fig. S2; Fig. S3). The frequency and usage patterns of the top 12 most Fritillariae Cirrhosae, 26.5%) was the most commonly prescribed single
common herbal formulas and single herbs used are presented in herb, with an average daily dosage of 1.2 g, followed by Xing-Ren (XR;
Table 3. All P-values less than 0.05 were considered to be statistically Semen Armeniacae, 20.8%) and Ge-Gen (GG; Radix Puerariae, 20.5%)
significant. with average daily dosages of 1.1 and 1.0 g, respectively.
CHM users showed a lower mortality hazard ratio when compared
with the non-CHM users even after adjusting for comorbidities
2.5. Network analysis
(Table 2). To explore the core treatment, CHM combinations and their
constituted networks were identified from these CHM users among lung
The social network analysis of SAS Visual Analytics was applied to
cancer patients (Fig. 3). The CHM network exhibited complicated re-
explore the CHM network and core treatments for these lung cancer
lationships among herbal formulas and single herbs. During the study
patients from the NHIRD database in Taiwan. The connection line be-
period, 264 lung cancer patients used CHMs and 4283 prescriptions
tween CHMs represents user numbers for the CHM combinations. A
were made by licensed TCM doctors. As shown in Fig. 3, the major
more important connection between CHMs is indicated by a thicker and
cluster was found, and was constituted by a core CHM and its related
darker connection line. The size of the circle represents the user number
combinations. BM was the core CHM of the major cluster. In this
of each CHM. The larger circle means higher frequencies of user
cluster, JG and Mai-Men-Dong-Tang (MMDT) were important CHMs.
numbers. The red color indicates herbal formula, and the green color
indicates a single herb (http://blogs.sas.com/content/sascom/2014/
4. Discussion
02/19/exploring-social-networks-with-sas-visual-analytics/).
To our knowledge, there are no data regarding CHM as an ad-
3. Results junctive therapy for lung cancer patients. In this retrospective study, we
reported population-based CHM pharmaco-epidemiological results and
3.1. Characteristics of lung cancer patients found that CHM treatment is associated with a reduction in mortality.
The cumulative survival probability was also a little higher in CHM
The recruitment procedure is described in Fig. 1. There were in- users than in non-CHM users. The twelve most commonly used herbal
itially 6939 patients who had lung cancer in Taiwan from 2000 to 2009. formulas, single herbs, and their CHM network were identified from
After the exclusion criteria were applied, 3678 lung cancer patients CHM users. Thus, our results provide a CHM comprehensive list and the
were included in this study. Among these, 425 (11.6%) were assigned investigation of CHM prescription patterns might be useful in future
to the CHM group and 3253 (88.4%) were in the non-CHM group. The large-scale, randomized clinical investigations of agent effectiveness,
demographic characteristics of these two groups are shown in Table 1. safety, and potential interactions with conventional treatments in lung
For the total subjects, statistically significant differences were found for cancer patients.
age, gender, follow up year, duration, comorbidity, and regular During the duration between the onset of lung cancer and the index

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 Table 3
Twelve most common herbal formulas and single herbs for frequency matched lung cancer pateints.

Formulas Chinese Number of Composition (Pin-yin name (latin name; botanical plant name)) Number (%) Person-year Number of Average daily Average duration for
T.-M. Li et al.

name herbs prescriptions dose (g) prescription (days)

Total 264 (100) 660.6 4283 12.2 9.9

Herbal formula (Pin- 259 (98.1) 651 3861 8.6 9.6
yin name)
Bu-Zhong-Yi-Qi-Tang 補中益氣湯 8 Huang-Qi (Radix Astragali; Astragalus membranaceus (Fisch.) Bunge), Ren- 61 (23.1) 182 236 3.8 11.5
Shen (Radix Ginseng; Panax ginseng C.A.Mey.), Bai-Zhu (Rhizoma Atractylodis;
Atractylodes macrocephala Koidz.), Gan-Cao (Radix Glycyrrhizae Preparata;
Glycyrrhiza uralensis Fisch.), Dang-Gui (Radix Angelicae Sinensi; Angelica
sinensis (Oliv.) Diels), Chen-Pi (Pericarpium Citri Reticulatae; Citrus reticulata
Blanco), Sheng-Ma (Rhizoma Cimicifugae; Cimicifuga foetida L.), Chai-Hu
(Radix Bupleuri; Bupleurum chinense DC.)
Xiang-Sha-Liu-Jun-Zi- 香砂六君子 8 Ren-Shen (Radix Ginseng; Panax ginseng C.A.Mey.), Bai-Zhu (Rhizoma 56 (21.2) 169.8 165 4.2 9.8
Tang Atractylodis; Atractylodes macrocephala Koidz.), Fu-Ling (Poria; Wolfiporia
extensa (Peck) Ginns), Gan-Cao (Radix Glycyrrhizae Preparata; Glycyrrhiza
uralensis Fisch.), Chen-Pi (Pericarpium Citri Reticulatae; Citrus reticulata Blanco),
Zhi-Ban-Xia (Rhizoma Pinelliae Preparatum; Pinellia ternata (Thunb.) Makino),
Sha-Ren (Fructus Amomi; Amomum villosum Lour.), Mu-Xiang (Radix
Aucklandiae; Vladimiria souliei (Franch.) Ling)
Bai-He-Gu-Jin-Tang 百合固金湯 10 Bai-He (Bulbus Lilii; Lilium brownii F.E.Br. ex Miellez), Sheng-Di-Huang (Radix 51 (19.3) 155 248 3.9 11.6
Rehmanniae; Rehmannia glutinosa (Gaertn.) DC.), Shu-Di-Huang (Radix
Rehmanniae Preparata; Rehmannia glutinosa (Gaertn.) DC.), Mai-Men-Dong
(Radix Ophiopogonis; Ophiopogon japonicus (Thunb.) Ker Gawl.), Xuan-Shen
(Radix Scrophulariae; Scrophularia microdonta Franch), Chuan-Bei-Mu (Bulbus
Fritillariae Cirrhosae; Fritillaria cirrhosa D.Don), Jie-Geng (Radix Platycodi;
Platycodon grandiflorus (Jacq.) A.DC.), Dang-Gui (Radix Angelicae Sinensi;

96
Angelica sinensis (Oliv.) Diels.), Bai-Shao (Radix Paeoniae Alba; Paeonia
lactiflora Pall.), Gan-Cao (Radix Glycyrrhizae Preparata; Glycyrrhiza uralensis
Fisch.)
Qing-Zao-Jiu-Fei-Tang 清燥救肺湯 9 Sang-Ye (Folium Mori; Morus alba L.), Shi-Gao (Gypsum Fibrosum), Mai- 48 (18.2) 169.2 365 3.7 11.3
Men-Dong (Radix Ophiopogonis; Ophiopogon japonicus (Thunb.) Ker Gawl.), E-
Jiao (Colla Corii Asini); Hei-Zhi-Ma (Semen Sesame Nigrum; Sesamum indicum
L.), Xing-Ren (Semen Armeniacae; Prunus armeniaca L.), Pi-Pa-Ye (Folium
Eriobotryae; Eriobotrya japonica (Thunb.) Lindl.), Ren-Shen (Radix Ginseng;
Panax ginseng C.A.Mey.), Gan-Cao (Radix Glycyrrhizae Preparata;
Glycyrrhiza uralensis Fisch.)
Mai-Men-Dong-Tang 麥門冬湯 6 Mai-Men-Dong (Radix Ophiopogonis; Ophiopogon japonicus (Thunb.) Ker 47 (17.8) 169.1 189 3.9 10.4
Gawl.), Ren-Shen (Radix Ginseng; Panax ginseng C.A.Mey.), Geng-Mi (Semen
Oryzae; Oryza sativa L.), Da-Zao (Fructus Jujube; Ziziphus jujuba Mill.), Gan-Cao
(Radix Glycyrrhizae Preparata; Glycyrrhiza uralensis Fisch.), Zhi-Ban-Xia
(Rhizoma Pinelliae Preparatum; Pinellia ternata (Thunb.) Makino)
Ma-Xing-Shi-Gan- 麻杏甘石湯 4 Ma-Huang (Herba Ephedrae; Ephedra sinica Stapf), Xing-Ren (Semen 47 (17.8) 156.6 112 3.8 7.1
Tang Armeniacae; Prunus armeniaca L.), Shi-Gao (Gypsum Fibrosum), Gan-Cao
(Radix Glycyrrhizae Preparata; Glycyrrhiza uralensis Fisch.)
Ping-Wei-San 平胃散 6 Chao-Cang-Zhu (Rhizoma Atractylodis; Atractylodes lancea (Thunb.) DC.), 45 (17.0) 126.1 119 3.3 10.4
Jiang-Chao-Hou-Po (Cortex Magnoliae Officinalis; Magnolia officinalis Rehder &
E.H.Wilson), Chen-Pi (Pericarpium Citri Reticulatae; Citrus reticulata Blanco),
Gan-Cao (Radix Glycyrrhizae Preparata; Glycyrrhiza uralensis Fisch.), Sheng-
Jiang (Rhizoma Zingiberis Recens; Zingiber officinale Roscoe), Da-Zao (Fructus
Jujube; Ziziphus jujuba Mill.)
(continued on next page)
Journal of Ethnopharmacology 213 (2018) 92–100
 Table 3 (continued)

Formulas Chinese Number of Composition (Pin-yin name (latin name; botanical plant name)) Number (%) Person-year Number of Average daily Average duration for
name herbs prescriptions dose (g) prescription (days)
T.-M. Li et al.

Xiao-Chai-Hu-Tang 小柴胡湯 7 Chai-Hu (Radix Bupleuri; Bupleurum chinense DC.), Huang-Qin (Radix 41 (15.5) 150.7 122 3.6 7.2
Scutellariae; Scutellaria baicalensis Georgi), Ban-Xia (Pinellia Rhizome; Pinellia
ternata (Thunb.) Makino), Sheng-Jiang (Rhizoma Zingiberis Recens; Zingiber
officinale Roscoe), Ren-Shen ( Radix Ginseng; Panax ginseng C.A.Mey.), Gan-
Cao ( Radix Glycyrrhizae Preparata; Glycyrrhiza uralensis Fisch.), Da-Zao
(Fructus Jujube; Ziziphus jujuba Mill.)
Gan-Lu-Yin 甘露飲 10 Di-Huang (Radix Rehmanniae; Rehmannia glutinosa (Gaertn.) DC.), Shu-Di- 41 (15.5) 139 129 3.6 8.3
Huang (Radix Rehmanniae Preparata; Rehmannia glutinosa (Gaertn.) DC.), Shi-
Hu (Herba Dendrobii; Dendrobium moniliforme (L.) Sw.), Tian-Men-Dong
(Radix Asparagi; Asparagus cochinchinensis (Lour.) Merr.), Mai-Men-Dong
(Radix Ophiopogonis; Ophiopogon japonicus (Thunb.) Ker Gawl.), Huang-Qin
(Radix Scutellariae; Scutellaria baicalensis Georgi), Yin-Chen-Hao (Herba
Artemisiae Scopariae; Artemisia capillaris Thunb.), Zhi-Shi (Fructus Aurantii
Immaturus; Citrus aurantium L.), Pi-Pa-Ye (Folium Eriobotryae; Eriobotrya
japonica (Thunb.) Lindl.), Gan-Cao (Radix Glycyrrhizae Preparata; Glycyrrhiza
uralensis Fisch.)
Wen-Dan-Tang 溫膽湯 8 Zhu-Ru (Caulis Bambusae in Taeniam; Arundarbor angulata (Munro) Kuntze.), 40 (15.2) 167.3 150 4.8 10.2
Zhi-Shi (Fructus Aurantii Immaturus; Citrus × aurantium L.), Zhi-Ban-Xia
(Rhizoma Pinelliae Preparatum; Pinellia ternata (Thunb.) Makino), Chen-Pi
(Pericarpium Citri Reticulatae; Citrus reticulata Blanco), Fu-Ling (Poria;
Wolfiporia extensa (Peck) Ginns), Gan-Cao ( Radix Glycyrrhizae Preparata;
Glycyrrhiza uralensis Fisch.), Da-Zao (Fructus Jujube; Ziziphus jujuba Mill.),
Sheng-Jiang (Rhizoma Zingiberis Recens; Zingiber officinale Roscoe)
Zhi-Gan-Cao-Tang 炙甘草湯 11 Gan-Cao (Radix Glycyrrhizae Preparata; Glycyrrhiza uralensis Fisch.), Ren-Shen 37 (14.0) 106.8 141 3.6 7.9
(Radix Ginseng; Panax ginseng C.A.Mey.), Dan-Shen (Radix Salviae

97
Miltiorrhizae; Salvia miltiorrhiza Bunge), Gui-Zhi (Cinnamomi ramulus;
Cinnamomum cassia (L.) J.Presl), Sheng-Di-Huang (Radix Rehmanniae;
Rehmannia glutinosa (Gaertn.) DC.), Mai-Men-Dong (Radix Ophiopogonis;
Ophiopogon japonicus (Thunb.) Ker Gawl.), E-Jiao ( Colla Corii Asini; Equus
asinus L.), Huo-Ma-Ren (Semen Cannabis; Cannabis sativa L.), Sheng-Jiang
(Rhizoma Zingiberis Recens; Zingiber officinale Roscoe), Da-Zao ( Fructus Jujube;
Ziziphus jujuba Mill.), White Wine
Shao-Yao-Gan-Cao- 芍藥甘草湯 2 Bai-Shao (Radix Paeoniae Alba; Paeonia lactiflora Pall.), Gan-Cao (Radix 36 (13.6) 131.9 133 3 7.8
Tang Glycyrrhizae Preparata; Glycyrrhiza uralensis Fisch.)
Single herbs (Pin-yin 247 (93.6) 641.9 3655 5.2 10.2
name)
Bei-Mu 貝母 1 Bei-Mu (Bulbus Fritillariae Cirrhosae; Fritillaria cirrhosa D.Don) 70 (26.5) 213 223 1.2 9.6
Xing-Ren 杏仁 1 Xing-Ren (Semen Armeniacae; Prunus armeniaca L.) 55 (20.8) 157.5 238 1.1 12.5
Ge-Gen 葛根 1 Ge-Gen (Radix Puerariae; Pueraria lobata (Willd.) Ohwi) 54 (20.5) 192.9 173 1 11.2
Bai-Hua-She-She-Cao 白花蛇舌草 1 Bai-Hua-She-She-Cao (Herba Hedyotis Diffusae; Oldenlandia diffusa (Willd.) 53 (20.1) 155.2 418 1.6 14.7
Roxb.)
Jie-Geng 桔梗 1 Jie-Geng (Radix Platycodi; Platycodon grandiflorus (Jacq.) A.DC.) 53 (20.1) 172.8 318 1.3 8.5
Huang-Qin 黃芩 1 Huang-Qin (Radix Scutellariae; Scutellaria baicalensis Georgi) 51 (19.3) 153.6 207 1 9
Huang-Qi 黃耆 1 Huang-Qi (Radix Astragali; Astragalus membranaceus (Fisch.) Bunge) 49 (18.6) 168.2 167 1.4 10.6
Dan-Shen 丹參 1 Dan-Shen (Radix Salviae Miltiorrhizae; Salvia miltiorrhiza Bunge) 48 (18.2) 134.7 273 1.3 13.7
Yan-Hu-Suo 延胡索 1 Yan-Hu-Suo (Rhizoma Corydalis; Corydalis yanhusuo) 48 (18.2) 168.2 217 0.9 9.1
Xuan-Shen 玄參 1 Xuan-Shen (Radix Scrophulariae; Scrophularia microdonta Franch) 45 (17.0) 139.3 126 1.1 6.9
Bai-Zhu 白朮 1 Bai-Zhu (Rhizoma Atractylodis; Atractylodes macrocephala Koidz.) 44 (16.7) 139.4 200 1.2 12.3
Ban-Xia 半夏 1 Ban-Xia (Pinellia Rhizome; Pinellia ternata (Thunb.) Makino) 42 (15.9) 103.9 136 1 9

Sorted by number (%).

CHM, Chinese herbal medicine.
Number (%): number of lung cancer patients who used the indicated CHM; Person-year: person × year; Number of prescriptions: number of prescriptions for the indicated CHM; Average daily dose (g): average of daily dose (g) of the indicated
CHM; Average duration for prescription (days): average prescription duration (days) for the indicated CHM.
Information are obtained from the websites (http://www.americandragon.com/index.htm; http://old.tcmwiki.com/; http://www.shen-nong.com/eng/front/index.html; http://www.ipni.org/; http://www.theplantlist.org/).
Journal of Ethnopharmacology 213 (2018) 92–100
T.-M. Li et al. Journal of Ethnopharmacology 213 (2018) 92–100

date, regular treatments for lung cancer patients were investigated

between CHM and non-CHM users. Among all subjects, CHM users
tended to receive more regular treatments than non-CHM users, which
suggested that the disease stage might be more advanced in CHM users.
Many non-CHM users decided not to receive any regular treatments. To
reduce the potential bias, we then performed a matching method for
these two groups. The matched CHM users showed a lower mortality
hazard ratio when compared with the matched non-CHM users among
these lung cancer patients even after adjusting for comorbidities, sug-
gesting that CHM may exhibit anti-cancer pharmacological activities.
This benefit might have been due to the components of CHM, which are
predominantly medicinal plant materials, showing anti-lung cancer
activities (Chen et al., 2014; Lai et al., 2013; Li et al., 2013, 2014; Lu,
2016; Ni et al., 2015; Xie et al., 2016; Zhang et al., 2014). Among these
CHMs, Fei-Liu-Ping is a herbal formula that exerts anti-inflammatory
properties in the tumor microenvironment and may prevent lung cancer
metastasis (Li et al., 2014; Liu et al., 2015; Zheng et al., 2017). Fei-Liu-
Ping includes the roots of Astragalus membranaceus (Fisch.) Bge. var.
mongholicus (Bge.) Hsiao (Huang-Qi), Panax quinquefolium L. (Xi-Yang-
Shen), Ophiopogon japonicas (Thunb.) Ker-Gawl. (Mai-Dong), Glehnia
littoralis Fr. Schmidt ex Miq. (Bei-Sha-Shen), Agrimonia pilosa Ledeb.
(Xian-He-Cao), Polygonum bistorta L. (Quan-Shen), Patrinia villosa
(Thunb.) Juss. (Bai-Jiang-Cao), Panax notoginseng (Burk.) F.H. Chen
Fig. 3. CHM network for lung cancer patients. The connection lines between CHMs
(San-Qi), Fritillaria cirrhosa D. Don (Chuan-Bei-Mu), Glycyrrhiza uralensis
represent the count of CHM combinations. A thicker and darker connection line between
Fisch. (Gan-Cao), and Cordyceps sinensis (Berk.) Sacc. (Dong-Cong-Xia- CHMs indicates a more important connection. The size of the circle represents the user
Cao) and the fruits of Prunus persica (L.) Batsch (Tao-Ren) and Prunus numbers for the CHM.
armeniaca L. var ansu Maxim. (Xing-Ren). Another herbal formula, LQ,
was also efficacious against primary and metastatic lung cancer (Zhang
Xiu-Yuan Chen in 1801 and is composed of 8 single herbs. It regulates
et al., 2014). LQ included Sinapis alba (Bai-Jie-Zi), Atractylodes macro-
the digestion in Spleen Qi deficiency and enhances appetite. Currently,
cephala (Bai-Zhu), Coix lacryma-jobi (Yi-Yi- Ren), and Polyporus adusta.
XSLJZT has also been used to treat dyspepsia (Feng, 1992; Xiao et al.,
A single Chinese herb- Trichosanthes kirilowii fruits inhibited non-small
2012), allergic rhinitis (Yang et al., 2002), and cancer (Hung et al.,
cell lung cancer cell proliferation, migration, invasion, tumorigenicity,
2017; B.R. Wang et al., 2014; Wu et al., 2017). Specifically, this formula
and tumor growth (Ni et al., 2015). Natural components, such as tan-
has been used to treat breast cancer (B.R. Wang et al., 2014), gastric
shinone IIA from Salvia miltiorrhiza (Dan-Shen), andrographolide from
cancer (Hung et al., 2017), and colorectal cancer (Wu et al., 2017).
Andrographis paniculata [Burm. f.] Nees. (Chuan-Xin-Lian), and hy-
BHGJT is derived from the classic Chinese literature, Yi-Fang-Ji-Jie
peroside, found in some Chinese herbs, inhibit malignant biological
(Wang Ang's Collected and Analyzed Medical Formulas), collected by Dr.
behavior, and suppress tumor growth and invasion in lung cancer (Lai
Ang Wang in the Qing dynasty, and is composed of 10 single herbs.
et al., 2013; Lu, 2016; Xie et al., 2016). These pharmacological benefits
BHGJT is a famous CHM that protects lung function and treats lung
might partially explain why a lower mortality HR was observed in CHM
discomforts including dry cough and dry throat (https://www.
users among these lung cancer patients.
activeherb.com/baihe/). However, no anti-lung cancer activities have
Furthermore, the pharmaco-epidemiological data of these products
been reported for XSLJZT and BHGJT.
provides us with the clinical information necessary to further in-
Bei-Mu (BM) is composed of Fritillaria cirrhosa D.Don, family
vestigate their pharmacological activities in lung cancer patients. The
Liliaceae. It has been widely used in China for a long time for its
most commonly used herbal formula was Bu-Zhong-Yi-Qi-Tang
therapeutic effects on respiratory diseases, including cough, pneu-
(BZYQT), followed by Xiang-Sha-Liu-Jun-Zi-Tang (XSLJZT) and Bai-He-
monia, and bronchial inflammation. Recent studies have also indicated
Gu-Jin-Tang (BHGJT). BZYQT is also called Bu-Zhong-Yi-Qi decoction,
that BM exhibits antitussive, expectorant, anti-inflammatory, and anti-
Bojungikki-tang, or Hochu-ekki-to and is composed of 8 single herbs
tuberculosis effects, and attenuates acute lung injury (Liang et al., 2017;
(Amitani et al., 2015; Jeong et al., 2010; Lee et al., 2014; Sato et al.,
Wang et al., 2016, 2011). Furthermore, BM also showed antitumor
2015; Yu et al., 2017). BZYQT in traditional Chinese medicine is widely
activity (D.D. Wang et al., 2014). Our results suggested that BM is the
used to refill the body's vital energy and to promote physical strength. It
most commonly used single herb for the treatment of lung cancer pa-
is derived from the classic Chinese literature, Pi-Wei-Lun (The Treatise
tients. Xing-Ren (XR) (Prunus armeniaca L., family Rosaceae, 20.8%),
on the Spleen and Stomach) edited by Dr. Dong-Yuan Li. Recently, it
and Ge-Gen (GG) (Pueraria lobata (Willd.) Ohwi, family Fabaceae,
was reported that BZYQT is effective for the improvement of chronic
20.5%) are the second and third most commonly used single herbs,
fatigue syndrome (Chen et al., 2009; Jeong et al., 2010; Ouyang et al.,
respectively. XR has been used to relieve cough and wheezing for a long
2014), anti-influenza virus infection and replication (Mori et al., 1999;
time in China. Currently, studies have also showed that XR is used to
Ohgitani et al., 2014; Takanashi et al., 2017), and the enhancement of
treat asthma (Chen et al., 2013; Huang et al., 2013) and lung disorders
anti-cancer effects (Kuo et al., 2014; Utsuyama et al., 2001; Yu et al.,
(Gao et al., 2011). Furthermore, XR showed anti-inflammatory effects
2017; Zhu et al., 2005). Specifically, this formula has been reported to
in lipopolysaccharide-induced inflammation in mouse BV2 microglial
enhance cisplatin cytotoxicity in human lung carcinoma cells (Yu et al.,
cells (Chang et al., 2005) and ulcerative colitis in rats (Minaiyan et al.,
2017), to induce gastric cancer cell death in combination with mito-
2014). Ge-Gen (GG) belongs to Pueraria lobata (Willd.) Ohwi in the
mycin c (Kuo et al., 2014), and to inhibit the growth of several human
botanical family Leguminosae. GG has been used to treat several dis-
ovarian cancer cell lines (Zhu et al., 2005).
eases including vertigo (Tsai et al., 2016), dementia (Chen et al., 2017),
Xiang-Sha-Liu-Jun-Zi-Tang (XSLJZT) and Bai-He-Gu-Jin-Tang
hypertension with type two diabetes (Lin et al., 2015), ischemic heart
(BHGJT) were the second and third most commonly used formulas,
disease (Hung et al., 2015), and breast cancer (Hu et al., 2015). Fur-
respectively. XSLJZT is derived from the classic Chinese literature, Shi-
thermore, Kakkalide in GG inhibits reactive oxygen species-associated
Fang-Ge-Kuo (Compendium of Songs on Modern Formulas), written by Dr.

98
T.-M. Li et al.
inflammation and ameliorates insulin-resistant endothelial dysfunction
(Zhang et al., 2013). Another report showed that puerarin in GG at-
tenuates myocardial hypoxia/reoxygenation injury (Tang et al., 2017)
and exerts significant protective effects against diabetic retinopathy via
regulating IL-1β-mediated leukostasis and apoptosis (Zhu et al., 2014).
However, no anti-lung cancer activities have been reported for XR and
GG. To our knowledge, we are the first to reveal that adjunctive CHM
use might be beneficial for increased survival among these patients. The
investigation of their comprehensive CHM prescription patterns might
be useful in future large-scale, randomized clinical investigations of
agent effectiveness, safety, and potential interactions with conventional
treatments in lung cancer patients.
4.1. Limitations
Our results might provide evidence supporting the use of CHM as a
complementary and alternative therapy in lung cancer patients. The
main limitation is the lack of clinical laboratory examination results
and TNM stages listed in the database. However, our results showed
that CHM may reduce the mortality risk of lung cancer patients after the
two groups were matched for age, gender, duration of treatment, and
regular treatment, and we provide a comprehensive list of CHM pro-
ducts that might be useful for future investigation of their safety and
efficacy. Further functional investigations of their anti-tumor activities
are also warranted. Moreover, further large-scale, randomized clinical
trials should be performed to determine the effectiveness and safety of
these CHM products and to evaluate their potential interactions with
regular treatments for lung cancer patients.
5. Conclusion
We were able to investigate the adjunctive CHM effect on the
treatment of diseases by analyzing the National Health Insurance
Research Database (NHIRD) in Taiwan. Among lung cancer patients,
the CHM users showed a lower mortality hazard ratio when compared
with the non-CHM users. In the analysis of their CHM prescription
pattern, Bu-Zhong-Yi-Qi-Tang (BZYQT), Xiang-Sha-Liu-Jun-Zi-Tang
(XSLJZT), and Bai-He-Gu-Jin-Tang (BHGJT); and Bei-Mu (BM), Xing-
Ren (XR), and Ge-Gen (GG) were found to be the top three formulas and
herbs, respectively. Among them, BM was the core CHM of the major
cluster, and JG and MMDT were important CHMs determined by CHM
network analysis. Our study provides a comprehensive list of the herbal
medicine that might be useful in lung cancer patients for future large-
scale, randomized clinical investigations of effectiveness, safety, and
potential interactions with regular treatments.
Acknowledgements
This study was supported by grants from the China Medical
University (CMU102-PH-01 and CMU100-S-01), the China Medical
University Hospital (DMR-105-031, DMR-105-098, and DMR-106-155),
the Ministry of Science and Technology, Taiwan (MOST 103-2320-B-
039-006-MY3, MOST 105-2314-B-039-037-MY3, and MOST 106-2320-
B-039-017-MY3), and China Medical University under the Aim for Top
University Plan of the Ministry of Education, Taiwan. This study was
based in part on data from the National Health Insurance Research
Database provided by the Bureau of National Health Insurance,
Department of Health and managed by National Health Research
Institutes. The interpretation and conclusions contained herein do not
represent those of the National Health Insurance Administration,
Department of Health, or National Health Research Institutes. The au-
thors wish to thank the Division of Chinese Medicine, China Medical
University, Beigang Hospital for administrative assistance and con-
sultation and the Aim for Top University Plan of the Ministry of
Education, Taiwan, at the China Medical University. We also thank Dr.
Kuan-Teh Jeang and Willy W. L. Hong for their technical help and
99
Journal of Ethnopharmacology 213 (2018) 92–100
suggestions.
Author contributions
FJT, TML, YHY, WML, and YJL conceived and designed the ex-
periments. CFC, THL, CCL, and SMH performed the experiments. CFC
analyzed the data. TJH, XL, HT, JPL, JCL, and CCL contributed re-
agents/materials/analysis tools. WML and YJL wrote the manuscript.
All the authors have read and approved the final manuscript.
Conflict of interest statement
The authors have no conflict of interest to disclose.
Appendix A. Supplementary material
Supplementary data associated with this article can be found in the
online version at http://dx.doi.org/10.1016/j.jep.2017.10.031.
References
Al-Harbi, N.O., Imam, F., Al-Harbi, M.M., Ansari, M.A., Zoheir, K.M., Korashy, H.M.,
Sayed-Ahmed, M.M., Attia, S.M., Shabanah, O.A., Ahmad, S.F., 2016. Dexamethasone
attenuates LPS-induced acute lung injury through inhibition of NF-kappaB, COX-2,
and pro-inflammatory mediators. Immunol. Investig. 45 (4), 349–369.
Amitani, M., Amitani, H., Sloan, R.A., Suzuki, H., Sameshima, N., Asakawa, A., Nerome,
Y., Owaki, T., Inui, A., Hoshino, E., 2015. The translational aspect of complementary
and alternative medicine for cancer with particular emphasis on Kampo. Front.
Pharmacol. 6, 150.
Chang, H.K., Yang, H.Y., Lee, T.H., Shin, M.C., Lee, M.H., Shin, M.S., Kim, C.J., Kim, O.J.,
Hong, S.P., Cho, S., 2005. Armeniacae semen extract suppresses lipopolysaccharide-
induced expressions of cyclooxygenase [correction of cycloosygenase]−2 and in-
ducible nitric oxide synthase in mouse BV2 microglial cells. Biol. Pharm. Bull. 28 (3),
449–454.
Chen, H.Y., Lin, Y.H., Thien, P.F., Chang, S.C., Chen, Y.C., Lo, S.S., Yang, S.H., Chen, J.L.,
2013. Identifying core herbal treatments for children with asthma: implication from a
chinese herbal medicine database in taiwan. Evid. Based Complement. Altern. Med.
2013, 125943.
Chen, K.H., Yeh, M.H., Livneh, H., Chen, B.C., Lin, I.H., Lu, M.C., Tsai, T.Y., Yeh, C.C.,
2017. Association of traditional Chinese medicine therapy and the risk of dementia in
patients with hypertension: a nationwide population-based cohort study. BMC
Complement. Altern. Med. 17 (1), 178.
Chen, R., Moriya, J., Luo, X., Yamakawa, J., Takahashi, T., Sasaki, K., Yoshizaki, F., 2009.
Hochu-ekki-to combined with interferon-gamma moderately enhances daily activity
of chronic fatigue syndrome mice by increasing NK cell activity, but not neuropro-
tection. Immunopharmacol. Immunotoxicol. 31 (2), 238–245.
Chen, Y., Zhu, J., Zhang, W., 2014. Antitumor effect of traditional Chinese herbal med-
icines against lung cancer. Anticancer Drugs 25 (9), 983–991.
Chiang, C.J., Lo, W.C., Yang, Y.W., You, S.L., Chen, C.J., Lai, M.S., 2016. Incidence and
survival of adult cancer patients in Taiwan, 2002–2012. J. Formos. Med. Assoc. 115
(12), 1076–1088.
Collaborators, G.B.D.R.F., 2016. Global, regional, and national comparative risk assess-
ment of 79 behavioural, environmental and occupational, and metabolic risks or
clusters of risks, 1990–2015: a systematic analysis for the Global burden of disease
study 2015. Lancet 388 (10053), 1659–1724.
Feng, L.Y., 1992. Effects of xiang sha liu jun zi tang on gastric and intestinal functions in
animals. Zhongguo Zhong Xi Yi Jie He Za Zhi 12 (1), 35–37.
Gao, Z., Li, F.S., Upur, H., 2011. A study of the law of herbal administration in treating
lung-distension by TCM physicians through history using cluster analysis. J. Tradit.
Chin. Med. 31 (4), 303–307.
Hsu, W.L., Tsai, Y.T., Wu, C.T., Lai, J.N., 2015. The prescription pattern of Chinese herbal
products containing ginseng among tamoxifen-treated female breast cancer survivors
in Taiwan: a population-based study. Evid. Based Complement. Altern. Med. 2015,
385204.
Hu, Y.C., Wu, C.T., Lai, J.N., Tsai, Y.T., 2015. Detection of a negative correlation between
prescription of Chinese herbal products containing coumestrol, genistein or daidzein
and risk of subsequent endometrial cancer among tamoxifen-treated female breast
cancer survivors in Taiwan between 1998 and 2008: a population-based study. J.
Ethnopharmacol. 169, 356–362.
Huang, T.P., Liu, P.H., Lien, A.S., Yang, S.L., Chang, H.H., Yen, H.R., 2013. Characteristics
of traditional Chinese medicine use in children with asthma: a nationwide popula-
tion-based study. Allergy 68 (12), 1610–1613.
Hung, K.F., Hsu, C.P., Chiang, J.H., Lin, H.J., Kuo, Y.T., Sun, M.F., Yen, H.R., 2017.
Complementary Chinese herbal medicine therapy improves survival of patients with
gastric cancer in Taiwan: a nationwide retrospective matched-cohort study. J.
Ethnopharmacol. 199, 168–174.
Hung, Y.C., Tseng, Y.J., Hu, W.L., Chen, H.J., Li, T.C., Tsai, P.Y., Chen, H.P., Huang, M.H.,
Su, F.Y., 2015. Demographic and prescribing patterns of chinese herbal products for
individualized therapy for ischemic heart disease in Taiwan: population-based study.
T.-M. Li et al.
PLoS One 10 (8), e0137058.
Jeong, J.S., Ryu, B.H., Kim, J.S., Park, J.W., Choi, W.C., Yoon, S.W., 2010. Bojungikki-
tang for cancer-related fatigue: a pilot randomized clinical trial. Integr. Cancer Ther.
9 (4), 331–338.
Kuo, C.C., Chen, J.J., Tsai, J.Y., Hsueh, C.T., 2014. Effects of Chinese herbal medicine in
combination with mitomycin C on gastric cancer cells. Biomark. Res. 2 (1), 26.
Lai, Y.H., Yu, S.L., Chen, H.Y., Wang, C.C., Chen, H.W., Chen, J.J., 2013. The HLJ1-
targeting drug screening identified Chinese herb andrographolide that can suppress
tumour growth and invasion in non-small-cell lung cancer. Carcinogenesis 34 (5),
1069–1080.
Lee, A.J., Lee, H.J., Kim, J.D., Jung, H.J., Bae, S.H., Ryoo, H.M., Kim, S.G., 2014. Changes
of peripheral blood lymphocyte subtypes in patients with end stage cancer ad-
ministered localized radiotherapy and bojungikki-tang. Evid. Based Complement.
Altern. Med. 2014, 207613.
Lee, Y.C., Huang, Y.T., Tsai, Y.W., Huang, S.M., Kuo, K.N., McKee, M., Nolte, E., 2010.
The impact of universal National Health Insurance on population health: the ex-
perience of Taiwan. BMC Health Serv. Res. 10, 225.
Li, S.G., Chen, H.Y., Ou-Yang, C.S., Wang, X.X., Yang, Z.J., Tong, Y., Cho, W.C., 2013. The
efficacy of Chinese herbal medicine as an adjunctive therapy for advanced non-small
cell lung cancer: a systematic review and meta-analysis. PLoS One 8 (2), e57604.
Li, W., Chen, C., Saud, S.M., Geng, L., Zhang, G., Liu, R., Hua, B., 2014. Fei-Liu-Ping
ointment inhibits lung cancer growth and invasion by suppressing tumor in-
flammatory microenvironment. BMC Complement. Altern. Med. 14, 153.
Li, X., Wang, S., Zhu, R., Li, H., Han, Q., Zhao, R.C., 2016. Lung tumor exosomes induce a
pro-inflammatory phenotype in mesenchymal stem cells via NFkappaB-TLR signaling
pathway. J. Hematol. Oncol. 9, 42.
Liang, C.Z., Zhang, J.K., Shi, Z., Liu, B., Shen, C.Q., Tao, H.M., 2012. Matrine induces
caspase-dependent apoptosis in human osteosarcoma cells in vitro and in vivo
through the upregulation of Bax and Fas/FasL and downregulation of Bcl-2. Cancer
Chemother. Pharmacol. 69 (2), 317–331.
Liang, Y., Wang, X., Song, J., Wang, L., Chen, D., Yang, Y., Bai, X., Wang, J., Shi, Y., Chen,
S., Liu, J., Yang, C., Luo, H., Liu, G., Wu, X., 2017. Therapeutic effects of traditional
Chinese medicine Niubeixiaohe in mouse tuberculosis models. J. Ethnopharmacol.
195, 318–323.
Lin, Y.J., Ho, T.J., Yeh, Y.C., Cheng, C.F., Shiao, Y.T., Wang, C.B., Chien, W.K., Chen, J.H.,
Liu, X., Tsang, H., Lin, T.H., Liao, C.C., Huang, S.M., Li, J.P., Lin, C.W., Pang, H.Y.,
Lin, J.G., Lan, Y.C., Liu, Y.H., Chen, S.Y., Tsai, F.J., Liang, W.M., 2015. Chinese herbal
medicine treatment improves the overall survival rate of individuals with hyperten-
sion among Type 2 diabetes patients and modulates in vitro smooth muscle cell
contractility. PLoS One 10 (12), e0145109.
Liu, R., Zheng, H., Li, W., Guo, Q., He, S., Hirasaki, Y., Hou, W., Hua, B., Li, C., Bao, Y.,
Gao, Y., Qi, X., Pei, Y., Zhang, Y., 2015. Anti-tumor enhancement of Fei-Liu-Ping
ointment in combination with celecoxib via cyclooxygenase-2-mediated lung meta-
static inflammatory microenvironment in Lewis lung carcinoma xenograft mouse
model. J. Transl. Med. 13, 366.
Lu, P., 2016. Inhibitory effects of hyperoside on lung cancer by inducing apoptosis and
suppressing inflammatory response via caspase-3 and NF-kappaB signaling pathway.
Biomed. Pharmacother. 82, 216–225.
Minaiyan, M., Ghannadi, A., Asadi, M., Etemad, M., Mahzouni, P., 2014. Anti-in-
flammatory effect of Prunus armeniaca L. (apricot) extracts ameliorates TNBS-in-
duced ulcerative colitis in rats. Res. Pharm. Sci. 9 (4), 225–231.
Mori, K., Kido, T., Daikuhara, H., Sakakibara, I., Sakata, T., Shimizu, K., Amagaya, S.,
Sasaki, H., Komatsu, Y., 1999. Effect of Hochu-ekki-to (TJ-41), a Japanese herbal
medicine, on the survival of mice infected with influenza virus. Antivir. Res. 44 (2),
103–111.
Ni, L., Zhu, X., Gong, C., Luo, Y., Wang, L., Zhou, W., Zhu, S., Li, Y., 2015. Trichosanthes
kirilowii fruits inhibit non-small cell lung cancer cell growth through mitotic cell-
cycle arrest. Am. J. Chin. Med. 43 (2), 349–364.
Niu, H., Wang, J., Li, H., He, P., 2011. Rapamycin potentiates cytotoxicity by docetaxel
possibly through downregulation of Survivin in lung cancer cells. J. Exp. Clin. Cancer
Res. 30, 28.
Ohgitani, E., Kita, M., Mazda, O., Imanishi, J., 2014. Combined administration of osel-
tamivir and hochu-ekki-to (TJ-41) dramatically decreases the viral load in lungs of
senescence-accelerated mice during influenza virus infection. Arch. Virol. 159 (2),
267–275.
Ouyang, M., Liu, Y., Tan, W., Xiao, Y., Yu, K., Sun, X., Huang, Y., Cheng, J., Luo, R., Zhao,
X., 2014. Bu-Zhong-Yi-Qi pill alleviate the chemotherapy-related fatigue in 4 T1
murine breast cancer model. BMC Complement. Altern. Med. 14, 497.
Sato, T., Kita, K., Sato, C., Kaneda, A., 2015. Hochuekkito (Buzhongyiqitang), a herbal
medicine, enhances cisplatininduced apoptosis in HeLa cells. Mol. Med. Rep. 12 (4),
6215–6220.
Takanashi, K., Dan, K., Kanzaki, S., Hasegawa, H., Watanabe, K., Ogawa, K., 2017.
Hochuekkito, a Japanese herbal medicine, restores metabolic homeostasis between
100
Journal of Ethnopharmacology 213 (2018) 92–100
mitochondrial and glycolytic pathways impaired by Influenza A Virus infection.
Pharmacology 99 (5–6), 240–249.
Tang, H., Song, X., Ling, Y., Wang, X., Yang, P., Luo, T., Chen, A., 2017. Puerarin at-
tenuates myocardial hypoxia/reoxygenation injury by inhibiting autophagy via the
Akt signaling pathway. Mol. Med. Rep. 15 (6), 3747–3754.
Tsai, F.J., Ho, T.J., Cheng, C.F., Liu, X., Tsang, H., Lin, T.H., Liao, C.C., Huang, S.M., Li,
J.P., Lin, C.W., Lin, J.G., Lin, J.C., Lin, C.C., Liang, W.M., Lin, Y.J., 2017. Effect of
Chinese herbal medicine on stroke patients with type 2 diabetes. J. Ethnopharmacol.
200, 31–44.
Tsai, T.Y., Li, C.Y., Livneh, H., Lin, I.H., Lu, M.C., Yeh, C.C., 2016. Decreased risk of stroke
in patients receiving traditional Chinese medicine for vertigo: a population-based
cohort study. J. Ethnopharmacol. 184, 138–143.
Utsuyama, M., Seidlar, H., Kitagawa, M., Hirokawa, K., 2001. Immunological restoration
and anti-tumor effect by Japanese herbal medicine in aged mice. Mech. Ageing Dev.
122 (3), 341–352.
Wang, B.R., Chang, Y.L., Chen, T.J., Chiu, J.H., Wu, J.C., Wu, M.S., Chou, C.L., Chou,
Y.C., 2014. Coprescription of Chinese herbal medicine and Western medication
among female patients with breast cancer in Taiwan: analysis of national insurance
claims. Patient Prefer. Adherence 8, 671–682.
Wang, B.Y., Huang, J.Y., Cheng, C.Y., Lin, C.H., Ko, J., Liaw, Y.P., 2013. Lung cancer and
prognosis in taiwan: a population-based cancer registry. J. Thorac. Oncol. 8 (9),
1128–1135.
Wang, D., Yang, J., Du, Q., Li, H., Wang, S., 2016. The total alkaloid fraction of bulbs of
Fritillaria cirrhosa displays anti-inflammatory activity and attenuates acute lung in-
jury. J. Ethnopharmacol. 193, 150–158.
Wang, D., Zhu, J., Wang, S., Wang, X., Ou, Y., Wei, D., Li, X., 2011. Antitussive, ex-
pectorant and anti-inflammatory alkaloids from Bulbus Fritillariae Cirrhosae.
Fitoterapia 82 (8), 1290–1294.
Wang, D.D., Feng, Y., Li, Z., Zhang, L., Wang, S., Zhang, C.Y., Wang, X.X., Liu, Z.Y., 2014.
In vitro and in vivo antitumor activity of Bulbus Fritillariae Cirrhosae and pre-
liminary investigation of its mechanism. Nutr. Cancer 66 (3), 441–452.
Wu, C.T., Tsai, Y.T., Lai, J.N., 2017. Demographic and medication characteristics of
traditional Chinese medicine users among colorectal cancer survivors: a nationwide
database study in Taiwan. J. Tradit. Complement. Med. 7 (2), 188–194.
Xiao, Y., Liu, Y.Y., Yu, K.Q., Ouyang, M.Z., Luo, R., Zhao, X.S., 2012. Chinese herbal
medicine liu jun zi tang and xiang sha liu jun zi tang for functional dyspepsia: meta-
analysis of randomized controlled trials. Evid. Based Complement. Altern. Med. 2012,
936459.
Xie, J., Liu, J.H., Liu, H., Liao, X.Z., Chen, Y., Lin, M.G., Gu, Y.Y., Liu, T.L., Wang, D.M.,
Ge, H., Mo, S.L., 2016. Tanshinone IIA combined with adriamycin inhibited malig-
nant biological behaviors of NSCLC A549 cell line in a synergistic way. BMC Cancer
16 (1), 899.
Yang, S.H., Hong, C.Y., Yu, C.L., 2002. The stimulatory effects of nasal discharge from
patients with perennial allergic rhinitis on normal human neutrophils are normalized
after treatment with a new mixed formula of Chinese herbs. Int. Immunopharmacol.
2 (12), 1627–1639.
Yu, N., Xiong, Y., Wang, C., 2017. Bu-Zhong-Yi-Qi Decoction, the water extract of chinese
traditional herbal medicine, enhances cisplatin cytotoxicity in A549/DDP cells
through induction of apoptosis and autophagy. Biomed. Res. Int. 2017, 3692797.
Zhang, D., Gao, X., Wang, Q., Qin, M., Liu, K., Huang, F., Liu, B., 2013. Kakkalide ame-
liorates endothelial insulin resistance by suppressing reactive oxygen species-asso-
ciated inflammation. J. Diabetes 5 (1), 13–24.
Zhang, L., Wu, C., Zhang, Y., Liu, F., Wang, X., Zhao, M., Hoffman, R.M., 2014.
Comparison of efficacy and toxicity of traditional Chinese medicine (TCM) herbal
mixture LQ and conventional chemotherapy on lung cancer metastasis and survival in
mouse models. PLoS One 9 (10), e109814.
Zhang, S., Zhang, Y., Zhuang, Y., Wang, J., Ye, J., Zhang, S., Wu, J., Yu, K., Han, Y., 2012.
Matrine induces apoptosis in human acute myeloid leukemia cells via the mi-
tochondrial pathway and Akt inactivation. PLoS One 7 (10), e46853.
Zheng, H., He, S., Liu, R., Xu, X., Xu, T., Chen, S., Guo, Q., Gao, Y., Hua, B., 2017. Chinese
patent medicine Fei-Liu-Ping ointment as an adjunctive treatment for non-small cell
lung cancer: protocol for a systematic review. BMJ Open 7 (1), e015045.
Zhong, L.R., Chen, X., Wei, K.M., 2013. Radix tetrastigma hemsleyani flavone induces
apoptosis in human lung carcinoma a549 cells by modulating the MAPK pathway.
Asian Pac. J. Cancer Prev. 14 (10), 5983–5987.
Zhu, K., Fukasawa, I., Furuno, M., Inaba, F., Yamazaki, T., Kamemori, T., Kousaka, N.,
Ota, Y., Hayashi, M., Maehama, T., Inaba, N., 2005. Inhibitory effects of herbal drugs
on the growth of human ovarian cancer cell lines through the induction of apoptosis.
Gynecol. Oncol. 97 (2), 405–409.
Zhu, X., Xie, M., Wang, K., Zhang, K., Gao, Y., Zhu, L., Zhou, F., 2014. The effect of
puerarin against IL-1beta-mediated leukostasis and apoptosis in retinal capillary
endothelial cells (TR-iBRB2). Mol. Vis. 20, 1815–1823.