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, 19:551 | Cite as

“Yellow-dragon Wonderful-seed Formula” for hyperuricemia in gout patients with dampness-heat pouring downward pattern: a pilot randomized controlled trial

  • Xiao Ning Yu
  • Hai Yan Wu
  • Yuan Ping Deng
  • Guang Tong Zhuang
  • Bang Huan Tan
  • Yan Zhou Huang
  • Shi Yun Tang
  • Xiang Tu
  • James B Jordan
  • Sen Zhong
Open Access
Research
  • 80 Downloads

Abstract

Background

In Traditional Chinese Medicine (TCM) theories, the typical clinical manifestations of gout are attributed to the “dampness-heat pouring downward.” Therefore, TCM practitioners always consider prescribing the formulae which are believed to clear heat and drain dampness for the management of gout. This clinical trial aims: (1) to determine the hypouricemic effect of “Yellow-dragon Wonderful-seed Formula” (YWF) decoction in gout patients with dampness-heat pouring downward pattern and (2) to determine if gypsum could provide additional significant benefits to YWF.

Methods

A total of 72 hyperuricemic individuals with gout and dampness-heat pouring downward pattern were included with 62 of them completing the trial. Participants were randomly assigned to the YWF group, the YWF + gypsum group, or the allopurinol group. YWF and YWF + gypsum decoctions were orally administered for four weeks. Allopurinol was also orally administered for four weeks as the active control. Serum uric acid (sUA) level was the primary outcome measure. Urine urate level, scores on the SF-36 scale, erythrocyte sedimentation rate (ESR), X ray film, and C reactive protein (CRP) level were the secondary outcome measures.

Results

Compared with the values at week 0, YWF and YWF + gypsum did not significantly decrease the sUA level at each weekend reading. YWF, YWF + gypsum, and allopurinol decreased the urine urate levels and there were significant differences between the YWF group and the YWF + gypsum group. All the changes in the eight structures of SF-36 during the intervention period were not significantly different among the three groups and there was no significant difference in the CRP level among the three groups at each weekend reading.

Conclusions

YWM, which modified on the basis of Two Wonderful Herbs Powder (2WHP), does not show significant hypouricemic effect. There is a possibility that Gypsum Fibrosum may provide additional effects to YWF in decreasing the urine urate levels but cannot add benefits to YWF in other outcome measures.

Trial registration

Chinese Clinical Trial Registry, ChiCTR-TRC-12001933. Registered on 10 February 2012.

Keywords

Yellow-dragon Wonderful-seed formula Chinese herbal medicine formula Gout Hyperuricemia Randomized controlled trial Gypsum Fibrosum 

Abbreviations

2WHP

Two Wonderful Herbs Powder

3WHP

Three Wonderful Herbs Pill

4WHP

Four Wonderful Herbs Pill

ANOVA

Analysis of variance

BP

Bodily pain

CRP

C-reactive protein

ESR

Erythrocyte sedimentation rate

FAS

Full-analysis set

GCP

Good Clinical Practice

GH

General health

ITT

Intention-to-treat

mGLUT9

Mouse glucose transporter 9

MH

Mental health

mOAT1

Mouse organic anion transporter 1

mURAT1

Mouse urate transporter 1

PF

Physical functioning

PPS

Per-protocol set

RCT

Randomized controlled trial

RE

Role-emotional

RP

Role-physical

SF

Social functioning

sUA

Serum uric acid

TCM

Traditional Chinese Medicine

TKKD

Three Kinds of Kernels Decoction

VT

Vitality

XOD

Xanthine oxidase

YWF

Yellow-dragon Wonderful-seed Formula

Background

Epidemiological evidence from New Zealand, the USA, the UK, and China suggests that gout is becoming more prevalent [1]. The incidence of gout is approximately 1–2% in western countries, affecting > 3% of adults in the US [1, 2], which is very similar to that in China (1%) [3]. Gout is commonly characterized by hyperuricemia and acute arthritis, tophi, interstitial nephritis, and joint deformity resulting from deposition of sodium urate crystals.

At the beginning of the 21st century, according to the epidemiology of the eastern city of Nanjing (Jiangsu province), the mean concentration of serum uric acid (sUA) was 342.3 ± 87.3 μmol/L in Chinese men and 252.2 ± 77.8 μmol/L in Chinese women [4]. The incidence of hyperuricemia was 17.6% in men and 9.3% in women; gout occurred in 1.98% and 0.72%, respectively [4].

An investigation carried out in the northern province of Hebei in 2004 reported that the incidence of hyperuricemia was 15.8% in 1215 male individuals [5]. An article published in 2012 reported that the incidence of hyperuricemia was 24.73% in 1929 men and 10.79% in 686 women in Guizhou province, located in south China [6].

In Traditional Chinese Medicine (TCM) theories, the typical clinical manifestations of gout are attributed to the “dampness-heat pouring downward.” Both dampness and heat are the pathogenic factors and they have distinct characteristics: dampness is similar to water and heat is similar to fire. When heat invades gout patients, it results in a red, swollen joint. In the original Chinese medical text, the Huangdi Neijing says, “When dampness attacks the body, it first impairs the lower part of the body.” Dampness tends to move downward, like water. Therefore, the disease caused by dampness usually involves the lower part of the body. Dampness usually affects the lower extremities in gout patients, leading to attacks on the feet, ankle, or knees.

Therefore, TCM practitioners always consider prescribing the formulae which are believed to clear heat and drain dampness for the management of gout. Theoretically, dampness can be drained by diuretic TCM or dried by using TCM bitter in taste. Heat can be eliminated by TCM of cold property.

The typical diuretic TCM formula is Two Wonderful Herbs Powder (2WHP). In fact, there is a series of formulae developed from the 2WHP – the Three Wonderful Herbs Pill (3WHP) is modified from the 2WHP by adding one TCM (Cyathulae Radix) and the Four Wonderful Herbs Pill (4WHP) is also modified from the 2WHP by adding two TCM (Cyathulae Radix and Coix seeds).

Current reports demonstrated that the series formulae modified from 2WHP are effective for hyperuricemia in gout (see below).

2WHP:

The experiment in vivo by Kong et al. [7] demonstrated that the hypouricemic effect of 2WHP was “equal to that of the reference drug allopurinol” in hyperuricemic mice pretreated with oxonate.

In the article by Li [8], 98 individuals with gout received modified 2WHP for 14 days. The results showed that the levels of sUA decreased below normal values in 64 participants, accounting for 65.3%. Lv et al. [9] reported that the water extract of 2WHP could inhibit the production of hepatic urate and promote the excretion of urine urate in hyperuricemic rats induced by oxonic acid potassium salt. The underlying mechanisms may be related to the downregulation of the messenger RNA (mRNA) and protein levels of hepatic xanthine oxidase (XOD) and renal mouse urate transporter 1 (mURAT1) regulated by 2WHP.

3WHP:

When expanding 2WHP to 3WHP by adding Cyathulae Radix, some case reports showed positive results. Lu et al. [10] reported that modified 3WHP was given to 30 gout patients for ten days and the sUA values of 25 patients decreased below normal limits and were maintained for at least two years. Shan et al. [11] carried out an in vivo study to explore the mechanisms of 3WHP for inflammation of acute gouty arthritis. Their results showed that 3WHP could reduce the inflammation in the ankle of rats with acute gouty arthritis and this was related to the inhibition of TNF-α, IL-6, and IL-8 levels in the ankle synovial tissues of gout rats which were associated with the downregulation of NF-ΚB P65 protein expression by 3WHP.

4WHP:

Hu et al. [12] reported 4WHP could enhance the renal urate excretion by effectively reversing oxonate-induced alterations in renal mURAT1, mouse glucose transporter 9 (mGLUT9), and organic anion transporter 1 (mOAT1) mRNA and protein levels. The conclusion was that their findings “suggest that 4WHP processes uricosuric and nephroprotective actions by regulating renal organic ion transporters in hyperuricemic animals.”

In a randomized controlled trial (RCT), 178 participants were randomized to either the modified 4WHP group or the western medicine group. The treatment period was 14 days. The sUA level of the 4WHP group decreased from 585.93 ± 93.93 μmol/L to 319.13 ± 87.63 μmol/L. There was no significant difference between the 4WHP group and western medicine group. Two individuals suffered from slight diarrhea in the 4WHP group [13]. In another RCT, 120 participants were randomly assigned to either the modified 4WHP group (n = 60) or to the allopurinol group (n = 60). The UA and CRP levels were determined after a one-month intervention period. The authors concluded that modified 4WHP could “significantly improve the symptoms and signs of gouty arthritis and decrease the levels of UA and CRP. It is good for gouty arthritis” [14].

As mentioned above, modified 2WHP appears to be an excellent approach to hyperuricemia in gout patients. Published literature also suggested that gypsum (Pinyin Name: Shi Gao; Latin Name: Gypsum Fibrosum) played an important role for hyperuricemia in gout patients [15, 16, 17]. Generally, current clinical evidence concerning TCM for gout is methodologically problematic [8, 10, 13, 14]. We decided to put the 2WHP and other TCM together to create a new formula, i.e. YWF, and test its clinical efficacy with a RCT of desirable methodology.

Methods

Aims

We carried out a RCT to evaluate YWF for the treatment of hyperuricemia in gout patients with the specific TCM pattern, i.e. dampness-heat pouring downward pattern. This was also to determine whether Gypsum Fibrosum could provide significant additional benefits to YWF.

Design and setting of the study

The present clinical study was a pilot RCT where there were three arms and the allocation ratio among the three groups was 1:1:1. This pilot trial was neither a superiority test nor a non-inferiority test, it was an exploratory trial. The pilot RCT was conducted at six centers in Sichuan Province and Chongqing City, China.

Participants

Participants must have a physician diagnosis of gout [18] and hyperuricemia (sUA > 420 μmol/L) and be aged 18–70 years. If the patient had already received treatment for gout, he/she had to undergo a two-week washout period; only those whose sUA remained > 420 μmol/L after the washout period could be included. Only the patients differentiated as dampness-heat pouring downward pattern were included. The dampness-heat pouring downward pattern was confirmed by clinical symptoms and signs manifested as red, swollen, hot, and painful acute joint arthritis, red tongue, yellow and greasy tongue coating, and smooth pulse [19]. The pattern must be differentiated by at least two trained doctors of TCM. Patients were excluded if they had any of the following: pregnancy or lactation; allergic constitution, or an allergic history to test TCM or allopurinol; serum creatinine > 1.5 mg/dL; elevated values of ALT twice as high as the normal upper limit; severe deformity or stiffness of gouty arthropathy resulting in disability; arrhythmia of clinical significance; or a history of alcohol abuse. The patients were also excluded if they had severe cerebrovascular, kidney, liver, or hematopoietic system co-morbidities, cancer or mental disorders; taken concurrent hypouricemic medications, azathioprine, 6-mercaptopurine, medications containing aspirin (> 325 mg) or salicylate; or had participated in other clinical trials within the past three months.

Interventions

The typical TCM formula to clear heat and dry dampness is Three Kinds of Kernels Decoction (TKKD) and cardamom is the monarch herb of TKKD. We therefore, added cardamom to 4WHP to make the new formula become more appropriate for the dampness-heat pouring downward pattern. Because TCM experts believe that blood stasis plays an important role in gout, we added Pheretima to promote blood circulation and to dredge the collateral. The TCM ingredient of the new formula is shown in Table 1 and we call it “Yellow-dragon Wonderful-seed Formula” (YWF), a reference to Phellodendron bark in Chinese which is called “Yellow cypress” and Pheretima called “earth dragon.” As some TCM experts reported, gypsum plays a special role in the treatment of gout [16, 17]. We designed an independent arm with YWF + gypsum. The daily dose of gypsum was 15 g.
Table 1

Ingredients TCM of YWF

Pinyin name

Latin name

English name

Daily dose (g)

Di Long

Pheretima

Earthworm

10

Dou Kou

Amomum kravanh Pirre ex Gagnep.

Amomum, cardamon

6

Huang Bai

Cortex Phellodendri Chinensis

Cortex Phellodendri, Phellodendron bark

10

Cang Zhu

Atractylodes Lancea (Thunb.) DC.

Atractylodes, sword-like attractylodes rhizome, Chineseatractylodes rhizome

9

Yi Yi Ren

Coix lacryma-jobi L.var.ma-yuen(Roman.)Stapf(Yi Yi)

Coix seeds,Job’s tears

20

Chuan Niu Xi

Cyathula officinalis Kuan.

Cyathula, medicinal cyathula root

10

In this study, 72 individuals were randomly assigned to receive either YWF decoction, YWF + gypsum decoction, or allopurinol. All patients were advised not to consume purine-rich diets. TCM was purchased from Sichuan Rejuvenation Hall Pharmaceutical Co., Ltd., China. Professor HouLin Xia from the College Pharmacy, Chengdu University of TCM, confirmed that all TCM ingredients were the right herbal species recorded in the Chinese Pharmacopeia (2015 Edition) [20]. Suining (Sichuan, China) FDA assayed the quality standards of all ingredients TCM and provided quality reports which confirmed that their quality standards meet the Chinese Pharmacopeia (2015 Edition) requirements. All TCM ingredients were decocted together for 30 min at 120 °C with an automatic boiling and packaging machine, using three packages of decoction (100 mL/package). The TCM decoction was taken orally three times daily (100 mL each time) for four weeks. The starting dose of allopurinol was 100 mg day−1 in week 1 and increased to 200 mg during weeks 2–4.

Outcomes

The level of sUA was the primary outcome, which was measured by enzymatic method with a Beckman (USA, AU5400) automatic biochemical analyzer every four weeks. The assay agent was purchased from ZhongSheng Corporation, Beijing, China. The secondary outcome measures included the urine urate measured every four weeks by the same analyzer and agent for sUA, scores on SF-36 which were measured at week 0 and week 4, the ESR was measured by the Westergren method every four weeks, the CRP was measured with a CRP automatic analyzer (QUIKREAD GO, Finland) and its matched agent kits every four weeks, and the X ray film examined at week 0 and week 4. We recorded acute flares during the treatment period. We designed serum concentration of xanthine and hypoxanthine as the additional outcome measures in the study protocol, but they were not assayed due to the insufficiency of funding.

Sample size

As this study was a pilot trial, each arm of the RCT had 24 participants.

Randomization

Sequence allocation

The randomization sequence was generated with an SAS software.

Allocation concealment

The randomization sequence was concealed and disseminated with opaque envelopes.

Implementation

The Good Clinical Practice (GCP) center of the Teaching Hospital of Chengdu University of TCM provided the randomization sequence. TCM doctors at six collaborating centers enrolled patients and the assistant nurses disseminated the randomization envelopes.

Blinding

Blinding was not used due to the obvious difference between YWF decoction and allopurinol. However, the statisticians were blind to the study design.

Statistical methods

Intention-to-treat (ITT) analysis was used to analyze data and the primary population for assessing efficacy was the full-analysis set (FAS). Patients who took at least one dose of the study medications and had at least one value on treatment were included by the FAS. The last-observation-carried-forward method was used to impute the missing data, whereby missing values were replaced by the last non-missing value. The baseline characteristics among the three groups were analyzed by one-way analysis of variance (ANOVA). Repeated measures and multivariate analysis of variance of the general linear model were used to determine the changes in sUA, urine urate, and CRP. The scores on SF-36 scale were analyzed by analysis of covariance. SPSS software (version 18.0, SPSS Inc., Chicago, IL, USA) was used to analyze statistics and P < 0.05 was considered significant.

Results

Participant flow

A total of 72 male participants were involved in this study and ten dropped out during the study period (Fig. 1).
Fig. 1

Participant flow. A total of 72 patients were randomized to the three arms. All 72 participants received the allocated intervention and therefore all 72 were included in the FAS. Ten individuals dropped out and therefore 62 participants were included in the PPS

Recruitment

The recruitment period was from 1 March 2012 to 15 December 2014.

Baseline data

The baseline characteristics of the three groups of patients were comparable (P > 0.05) and shown in Table 2.
Table 2

The baseline characteristics of the FAS population of the three groups of patients

Characteristic

YWF

YWF + gypsum

Allopurinol

F value

Age (years)

45.33 ± 9.86

46.13 ± 10.75

49.21 ± 9.47

1.00

Gout history (months)

39.42 ± 29.00

55.25 ± 36.58

42.96 ± 32.38

1.54

sUA (μmol/L)

562.29 ± 108.29

585.46 ± 100.06

618.00 ± 114.27

1.62

Urine urate (mmol/24 h)

7.80 ± 0.37

7.79 ± 0.33

7.78 ± 0.31

0.01

CRP (mg/L)

13.13 ± 2.63

14.03 ± 3.40

13.15 ± 1.13

0.33

ESR (mm/h)

8.96 ± 4.99

8.79 ± 3.16

9.88 ± 6.96

0.29

SF-36 scale

BP

25.00 ± 14.52

31.71 ± 11.74

26.96 ± 9.54

1.95

RP

27.08 ± 23.22

22.92 ± 19.39

25.00 ± 23.31

0.21

PF

78.96 ± 7.07

81.04 ± 9.44

77.50 ± 10.11

0.95

VT

73.13 ± 7.91

75.83 ± 9.85

75.42 ± 9.20

0.63

SF

41.15 ± 22.87

43.23 ± 17.28

42.71 ± 20.16

0.07

RE

19.43 ± 21.79

26.38 ± 24.04

24.99 ± 22.52

0.95

GH

64.79 ± 13.95

66.04 ± 12.70

59.71 ± 14.43

1.44

MH

43.67 ± 15.78

46.17 ± 15.78

46.42 ± 16.23

0.22

Numbers analyzed

The per-protocol set (PPS) included 21 participants in the YWF arm, 20 in the YWF + gypsum arm, and 21 in the allopurinol arm. The FAS included 24 participants in each of the three arms.

Outcomes

The data analysis on the FAS was largely consistent with the PPS.

sUA

Compared with the values at week 0, YWF and YWF + gypsum did not significantly decrease the sUA levels at each weekend reading (Table 3, Fig. 2). There was no significant difference between YWF and YWF + gypsum at each reading (P > 0.05).
Table 3

Changes in sUA (mean ± SD, μmol/L)

  

Week 0

Week 1

Week 2

Week 3

Week 4

PPS

YWF arm

547.38 ± 97.32

539.24 ± 121.62

522.43 ± 143.97

516.29 ± 155.89

517.38 ± 157.96

YWF + gypsum arm

570.35 ± 93.61

572.90 ± 148.29

568.05 ± 140.46

548.75 ± 164.78

559.10 ± 202.94

Allopurinol arm

618.76 ± 115.64

517.43 ± 124.03*

482.10 ± 144.27*

476.24 ± 136.72*

466.81 ± 141.27*

FAS

YWF arm

562.29 ± 108.30

550.33 ± 120.16

530.71 ± 143.63

525.33 ± 154.39

526.29 ± 156.15

YWF + gypsum arm

585.46 ± 100.06

588.62 ± 144.79

574.50 ± 157.62

557.67 ± 176.13

566.29 ± 206.08

Allopurinol arm

618.00 ± 114.27

528.46 ± 125.58*

494.21 ± 145.64*

489.08 ± 139.65*

480.83 ± 144.34*

*In comparison with week 0, there was a statistically significant difference (P < 0.05)

Fig. 2

Changes in sUA of the three intervention groups. The sUA level of the YWF arm and YWF + gypsum arm did not significantly decrease at each reading, whereas allopurinol significantly reduced the sUA level. There was no significant change among the three arms at each reading

Urine urate

The levels of urine urate decreased in all three groups (P < 0.05). Analysis on FAS showed that there was a significant difference between the YWF group and the YWF + gypsum group at each reading (P < 0.05, Table 4, Fig. 3).
Table 4

Changes in urine urate (mean ± SD, mmol/24 h)

  

Week 0

Week 1

Week 2

Week 3

Week 4

PPS

YWF arm

7.77 ± 0.39

7.59 ± 0.28*

7.42 ± 0.32*

7.33 ± 0.32*

7.33 ± 0.35*

YWF + gypsum arm

7.82 ± 0.28

7.50 ± 0.33*

7.28 ± 0.44*

7.19 ± 0.45*

7.17 ± 0.48*

Allopurinol arm

7.80 ± 0.31

7.53 ± 0.27*

7.32 ± 0.36*

7.24 ± 0.39*

7.21 ± 0.41*

FAS

YWF arm

7.80 ± 0.37

7.65 ± 0.31*

7.50 ± 0.36*

7.43 ± 0.38*

7.43 ± 0.41*

YWF + gypsum arm

7.79 ± 0.33

7.48 ± 0.30*

7.28 ± 0.40*

7.21 ± 0.41*

7.19 ± 0.44*

Allopurinol arm

7.78 ± 0.31

7.53 ± 0.26*

7.33 ± 0.35*

7.25 ± 0.36*

7.23 ± 0.40*

*In comparison with value at week 0, there was statistically significant difference (P < 0.05)

In comparison with YWF arm at each reading, there was statistically significant difference (P < 0.05)

Fig. 3

Changes in urine urate of the three intervention groups. The level of urine urate of all three arms significantly decreased at each reading in comparison with the values at week 0. There was a significant difference between YWF arm and YWF + gypsum arm at each reading

SF-36

The items of the SF-36 scale can be summarized as eight structures including physical functioning (PF), role-physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role-emotional (RE), and mental health (MH). All the changes in the eight structures of SF-36 during the treatment period were not significantly different between the three groups (data not shown).

CRP

In comparison with the values at week 0, the CRP level of the YWF significantly decreased at week 4 (P < 0.05) and there was no significant difference among the three groups at each weekend reading (Table 5).
Table 5

Changes in CRP (mean ± SD, mg/L)

  

Week 0

Week 1

Week 2

Week 3

Week 4

PPS

YWF arm

14.43 ± 2.73

13.13 ± 1.82

13.34 ± 1.08

12.49 ± 0.64

10.09 ± 4.71*

YWF + gypsum arm

13.66 ± 1.63

13.26 ± 1.81

12.98 ± 0.75

12.55 ± 0.85

11.56 ± 5.06

Allopurinol arm

13.25 ± 1.32

12.99 ± 1.19

13.34 ± 1.15

12.56 ± 0.77*

11.03 ± 4.98

FAS

YWF arm

13.13 ± 2.63

12.87 ± 1.83

13.04 ± 1.30

12.33 ± 0.85

10.33 ± 4.34*

YWF + gypsum arm

14.03 ± 3.40

13.03 ± 1.81

12.81 ± 0.96

12.45 ± 0.97

11.64 ± 4.62

Allopurinol arm

13.15 ± 1.13

13.05 ± 1.31

13.20 ± 1.19

12.54 ± 0.76*

11.13 ± 4.77

*In comparison with value at week 0, there was a statistically significant difference (P < 0.05)

ESR

The ESR levels of the three arms fell in the scope of normal values and there was no significant change during treatment period (data not shown).

X-ray film

No individuals showed any significant changes on X-ray film digital image.

Acute flares

No acute flare was recorded in each group during treatment period.

Adverse events

No adverse events were reported.

Discussion

Limitations

The lack of blinding of the present clinical study could result in performance bias and detection bias. Another limitation is that we were not sure whether our negative results resulted from the YWF had not been modified as an appropriate formula for patients with long gout history. We notice that the gout history in our study is, on average, 39–55 months. We consider whether the dampness and heat might have evolved as a “toxin.” The toxin accumulated in the blood and joints, resulting in hyperuricemia and gout arthritis. Modifying YWF by adding some TCM with property of detoxification may produce better clinical benefits of YWF.

Generalizability

Our results of data analysis on FAS were largely consistent with those on PPS, which suggests that our results were sound. To our knowledge, in the field of TCM for gout, it is the first time that a clinical study was presented according to the CONSORT Extension for Chinese Herbal Medicine Formulas 2017 ([21], Additional file 1). Although the modification of 2WHP may vary greatly due to the large number of TCM, this study is of clinical importance to those many TCM professionals who want to prescribe or receive the formulae modified, based on 2WHP.

Interpretation

A large amount of literature has investigated the conventional urate lowering medications for hyperuricemia in gout, such as febuxostat, allopurinol, and benzbromarone [22]. Febuxostat, given its established efficacy and safety, has been recommended as a suitable pharmacological option for first-line treatment of gout [23]. However, controversies remain: a systematic review and meta-analysis concluded that “There was no evidence that febuxostat is superior to allopurinol for clinically relevant outcomes. Given its higher cost, febuxostat should not be routinely used for chronic gout” [24]. Chen et al. [25] reported a traditional Chinese medicine prescription: Quzhuotongbi decoction could significantly lower the sUA levels in hyperuricemia model rats. Kodithuwakku et al. [26] reported that Shuang Qi gout capsules might be a potent anti-hyperuricemic agent. A systematic review concluded that Chinese herbal decoction and traditional western medicine led to similar clinical efficacy including lowering sUA [27].

A number of animal experiments reported that TCM showed hypouricemic effects [28, 29] and 2WHP series formulae [14, 16, 17] lowered the uric acid levels by diverse mechanisms. In a systematic review published in 2013, “25 out of 41 trials, involving 23 different herbal prescriptions, Li, et al., found statistical significance in lowering the serum uric acid level.” However, the authors admitted that the evidence was not decent due to “low quality of included trials” [30]. Generally speaking, in humans, the current literature reports TCM shows at least similar, if not better, clinical efficacy in comparison with western medicine [27]. We have carried out a systematic review where 19 RCTs and 1646 participants were included to evaluate the clinical efficacy of 2WHP series formulae and the results show that, compared with western medicine, the TCM formulae based on the 2WHP series could significantly decrease the level of sUA and increase the cure rate [31]. However, unexpectedly, the results of the present pilot RCT were not consistent with our previous systematic review findings: YWF failed to significantly decrease the sUA levels.

A large number of published clinical studies did not have the control arm [13, 15]. Many published RCTs claimed randomization, but none of them provide the details with respect to randomization. Due to the poor methodology involved in proper randomization, it appears that the current clinical evidence is not sound.

Conclusions

The present clinical study, as a pilot trial, was exploratory rather than conclusive. We drew the following conclusions based on our research results: (1) YWM when modified on the basis of 2WHP does not show significant hypouricemic effect; (2) Gypsum Fibrosum could provide additional effects to YWF in decreasing the urine urate levels but cannot add benefits to YWF in other outcome measures. Generally speaking, our clinical study is of optimal methodology and our conclusions were of desirable reliability.

Notes

Acknowledgements

We thank all the people who have been involved in our study.

Funding

This clinical study is supported by Physician Investigator Foundation of National TCM Clinical Research Base for Diabetes Mellitus (CSZYJ2011010). The funding body played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors’ contributions

YXN, WHY, DYP, ZGT, JJB, TX, and ZS conceived this clinical study. TX and ZS named the formula. WHY, DYP, ZGT, TBH and TSY carried out this clinical study. HYZ and TX analyzed the data. YXN, WHY, DYP, ZGT, JJB, TX, and ZS drafted the manuscript. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

The protocol was approved by the ethics committee of the Teaching Hospital of Chengdu University of TCM and all patients provided a written informed consent.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary material

13063_2018_2917_MOESM1_ESM.docx (15 kb)
Additional file 1: CONSORT Herbal checklist. (DOCX 15 kb)

References

  1. 1.
    Roddy E, Doherty M. Epidemiology of gout. Arthritis Res Ther. 2010;12(6):223.CrossRefGoogle Scholar
  2. 2.
    Roddy E, Choi HK. Epidemiology of gout. Rheum Dis Clin N Am. 2014;40(2):155–75.CrossRefGoogle Scholar
  3. 3.
    Liu R, Han C, Wu D, Xia X, Gu J, Guan H, et al. Prevalence of hyperuricemia and gout in mainland China from 2000 to 2014: a systematic review and meta-analysis. Biomed Res Int. 2015;2015:762820.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Shao JH, Mo BQ, Yu RB, Zhong L, Hua L, Xu YC. Epidemiological study on hyperuricemia and gout in community of Nanjing. Chin J Dis Control Prev. 2003;7(4):305–8.Google Scholar
  5. 5.
    Sun LY, Niu XB, Li JB, Yu QJ. Analysis of blood uric acid and lipid and their relation to gout in 1215 males in Cangzhou in 2004. Chinese J Med Lab Technol. 2005;6(2):135–7.Google Scholar
  6. 6.
    Lu JJ, Qian L, Min W, et al. Study on the prevalence of hyperuricemia and metabolic syndrome in the senior of Guizhou. Guizhou Med J. 2012;36(2):115–8.Google Scholar
  7. 7.
    Kong LD, Yang C, Ge F, Wang HD, Guo YS. A Chinese herbal medicine Ermiao wan reduces serum uric acid level and inhibits liver xanthine dehydrogenase and xanthine oxidase in mice. J Ethnopharmacol. 2004;93(2–3):325–30.CrossRefGoogle Scholar
  8. 8.
    Li CM. Efficacy observation on 98 subjects with gouty arthritis treated with modified Ermiao Powder. Yunnan J Tradit Chinese Med Mater Med. 2012;33(4):47.Google Scholar
  9. 9.
    Lv YZ, Hu QH, Xing W, Zhen OY, Kong LD. Effects of Ermiao Pill water extracts on imbalance of urate levels and its related genes and protein levels in hyperuricemic mice. Chinese Tradit Herb Drugs. 2010;41(3):418–23.Google Scholar
  10. 10.
    Lu JZ, Wu M. Modified Sanmiao Pill in the treatment of 30 patients with gout. Jiangsu J Tradit Chinese Med. 1998;19(11):31.Google Scholar
  11. 11.
    Wei S, Jue HF. On action mechanism of Sanmiao Pill and Medicinal Cyathula Root for inflammatory reaction of acute gouty arthritis. World Chinese Med. 2013;8(2):189–93.Google Scholar
  12. 12.
    Hu QU, Jiao RQ, Wang X, Lv YZ, Kong LD. Simiao pill ameliorates urate underexcretion and renal dysfunction in hyperuricemic mice. J Ethnopharmacol. 2010;128(3):685–92.CrossRefGoogle Scholar
  13. 13.
    Wang HJ, Zhang GH, Jun Z, Fan XZ. A clinical study on modified Simiao Powder for acute gouty arthritis and hyperuricemia. J Emerg Tradit Chinese Med. 2009;18(10):1609–10 1626.Google Scholar
  14. 14.
    Qiu R, Shen R, Lin D, Chen Y, Ye H. Treatment of 60 cases of gouty arthritis with modified Simiao Tang. J Tradit Chin Med. 2008;28(2):94–7.CrossRefGoogle Scholar
  15. 15.
    Zhao F, Guochun L, Yang Y, Shi L, Xu L, Yin L. A network pharmacology approach to determine active ingredients and rationality of herb combinations of modified-Simiaowan for treatment of gout. J Ethnopharmacol. 2015;168:1–16.CrossRefGoogle Scholar
  16. 16.
    Wu JX. Gypsum and Sanmiao decoction for the treatment of acute gouty arthritis in 31 subjects. Jiangsu J Tradit Chinese Med. 2014;5:403.Google Scholar
  17. 17.
    Yuan Q. Heavy dose of gypsum for the treatment of acute gouty arthritis in 26 subjects. Yunnan J Tradit Chinese Med Mater Med. 2002;23(2):15–6.Google Scholar
  18. 18.
    Schlesinger N. Diagnosis of Gout: Clinical, Laboratory, and Radiologic Findings. Am J Manag Care. 2005;11:S443–50.PubMedGoogle Scholar
  19. 19.
    State Administration of Traditional Chinese Medicine of the People’s Republic of China. Criteria of Diagnosis and Therapeutic Effect of Internal Diseases and Syndromes in Traditional Chinese Medicine. ZY/T001.1–94.Google Scholar
  20. 20.
    Chinese National Committee of Pharmacopeia. Pharmacopeia of People’s Republic of China (2015 Edition). Beijing: China Medical Science Press; 2015.Google Scholar
  21. 21.
    Cheng CW, Wu TX, Shang HC, Li YP, Altman DG, Moher D, et al. CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration. Ann Intern Med. 2017;  https://doi.org/10.7326/M16-2977.CrossRefGoogle Scholar
  22. 22.
    Borghi C, Perez-Ruiz F. Urate lowering therapies in the treatment of gout: a systematic review and meta-analysis. Eur Rev Med Pharmacol Sci. 2016;20(5):983–92.PubMedGoogle Scholar
  23. 23.
    Frampton JE. Febuxostat: a review of its use in the treatment of hyperuricaemia in patients with gout. Drugs. 2015;75(4):427–38  https://doi.org/10.1007/s40265-015-0360-7.CrossRefGoogle Scholar
  24. 24.
    Faruque LI, Ehteshami-Afshar A, Wiebe N, Tjosvold L, Homik J, Tonelli M. A systematic review and meta-analysis on the safety and efficacy of febuxostat versus allopurinol in chronic gout. Semin Arthritis Rheum. 2013;43(3):367–375. https://doi.org/ https://doi.org/10.1016/j.semarthrit.2013.05.004.CrossRefGoogle Scholar
  25. 25.
    Chen J, Zhou J, Wei S, Xie Z, Wen C, Xu G. Effect of a traditional Chinese medicine prescription Quzhuotongbi decoction on hyperuricemia model rats studied by using serum metabolomics based on gas chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2016;1026:272–8  https://doi.org/10.1016/j.jchromb.2015.10.031.CrossRefGoogle Scholar
  26. 26.
    Kodithuwakku ND, Feng YD, Zhang YY, Pan M, Fang WR, Li YM. The molecular insight into the antihyperuricemic and renoprotective effect of Shuang Qi gout capsule in mice. J Ethnopharmacol. 2015;163:278–89  https://doi.org/10.1016/j.jep.2015.01.013.CrossRefGoogle Scholar
  27. 27.
    Zhou L, Liu L, Liu X, Chen P, Liu L, Zhang Y, et al. Systematic review and meta-analysis of the clinical efficacy and adverse effects of Chinese herbal decoction for the treatment of gout. PLoS One. 2014;9(1):e85008  https://doi.org/10.1371/journal.pone.0085008.CrossRefGoogle Scholar
  28. 28.
    Sun WF, Zhu MM, Li J, Zhang XX, Liu YW, Wu XR, et al. Effects of Xie-Zhuo-Chu-Bi-Fang on miR-34a and URAT1 and their relationship in hyperuricemic mice. J Ethnopharmacol. 2015;161:163–9.CrossRefGoogle Scholar
  29. 29.
    Chen J, Zhou J, Wei S, Xie Z, Wen C, Xu G. Effect of traditional Chinese medicine prescription Quzhuotongbi decoction on hyperuricemia model rats studied by using serum metabolomics based on gas chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2016;1026:272–8.CrossRefGoogle Scholar
  30. 30.
    Li XX, Han M, Wang YY, Liu JP. Chinese herbal medicine for gout: a systematic review of randomized clinical trials. Clin Rheumatol. 2013;32(7):943–59.CrossRefGoogle Scholar
  31. 31.
    Tang SY, Wan XM, Qin J, Bo P, Xiang T, Sen Z. Effectiveness of Ermiao San series of prescriptions for gout: a systematic review. Pharmacol Clin Chinese Mater Med. 2014;30(6):198–202.Google Scholar

Copyright information

© The Author(s). 2018

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors and Affiliations

  • Xiao Ning Yu
    • 1
  • Hai Yan Wu
    • 2
  • Yuan Ping Deng
    • 3
  • Guang Tong Zhuang
    • 4
  • Bang Huan Tan
    • 5
  • Yan Zhou Huang
    • 5
  • Shi Yun Tang
    • 6
  • Xiang Tu
    • 7
  • James B Jordan
    • 7
  • Sen Zhong
    • 8
  1. 1.Basic Medical College of Chengdu University of Traditional Chinese MedicineChengduChina
  2. 2.Department of GerontologySichuan Academy of Medical Sciences & Sichuan Provincial People’s HospitalChengduChina
  3. 3.Department of Internal MedicineTraditional Chinese Medicine Hospital of Fushun CountyFushunChina
  4. 4.Department of Internal MedicineTraditional Chinese Medicine Hospital of Pidu DistrictChengduChina
  5. 5.Department of Internal MedicineTraditional Chinese Medicine Hospital of Kaizhou DistrictChongqing CityChina
  6. 6.College of Clinical MedicineChengdu University of Traditional Chinese MedicineChengduChina
  7. 7.National Traditional Chinese Medicine Clinical Research Base for Diabetes Mellitus/Teaching Hospital of Chengdu University of Traditional Chinese MedicineChengduChina
  8. 8.Administration Committee of Affiliated Hospitals of Chengdu University of Traditional Chinese MedicineChengduChina

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