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Uric acid lowering effect of Tibetan Medicine RuPeng15 powder in
animal models of hyperuricemia
Kou Yiying, Li Yongfang, Ma Husai, Li Wangyu, Li Ruilian, Dang Zhancui
aa
Kou Yiying, Li Yongfang, Li Ruilian, Department of Phar-
macology, Medical College of Qinghai University, Xining
810001, China
Dang Zhancui, Public Health Department of Medical Col-
lege of Qinghai University, Xining 810001, China
Ma Husai, Department of Surgery, Qinghai Red Cross Hospi-
tal, Xining 810000, China
Li Wangyu, Gastroenterology Department of Qinghai Red
Cross Hospital, Xining 810001, China
Supported by the National Natural Sciences Foundation of
China (A Study on the Anti-gout Effects and Related Mecha-
nisms of Tibetan Medicine Rupeng15 Powder, No. 81160410)
Correspondence to: Kou Yiying, Pharmacology Depart-
ment of Medical College of Qinghai University, Xining
810001, China. sainaerkyy@163.com
Telephone: +86-971-6104046
Accepted: June 6, 2015
Abstract
OBJECTIVE: To evaluate the influence of the Tibet-
an medicine RuPeng15 powder (RPP15) on uric ac-
id levels, and explore its possible mechanisms of ac-
tion in hyperuricemic animal models.
METHODS: Hyperuricemic mice were generated
by orally administering yeast extract paste twice
daily (30 g/kg) for 8 days, to mimic human hyperuri-
cemia induced by high-protein diets. Hyperurice-
mic rats were generated by intraperitoneal injec-
tion of 250 mg/kg potassium oxonate to each ani-
mal 1 h before the last oral administration of test
compounds, which raised the serum uric acid level
by inhibiting the decomposition of uric acid. Levels
of uric acid and creatinine in serum and urine were
detected by the phosphotungstic acid and picric
acid methods respectively, and the activity of xan-
JTCM | www. journaltcm. com
ISSN 0255-2922
© 2016 JTCM. All rights reserved.
EXPERIMENTAL STUDY
TOPIC
thine oxidase (XOD) was assayed using a commer-
cial test kit.
RESULTS: RPP15 (0.4, 0.8, 1.2 g/kg) significantly de-
creased the level of serum uric acid in healthy rats
(P < 0.05). Furthermore, hyperuricemic rats treated
with RPP15 (0.4, 0.8, 1.2 g/kg) had lower serum uric
acid levels (P < 0.05), accompanied by lower urine
uric acid (P < 0.05). For the hyperuricemic mice, the
levels of uric acid in the serum decreased signifi-
cantly (P < 0.05) and the activity of XOD in the liver
was restored to normal levels after treatment with
RPP15 (P < 0.05).
CONCLUSION: RPP15 (0.4, 0.8, 1.2 g/kg) demon-
strated an anti-hyperuricemic effect on both
healthy and hyperuricemic animals, and the mecha-
nism is most likely associated with inhibiting the ac-
tivity of XOD.
© 2016 JTCM. All rights reserved.
Key words: RuPeng15 powder; Hyperuricemia;
Gout; Uric Acid; Xanthine Oxidase
INTRODUCTION
Hyperuricemia is characterized by abnormally high lev-
els of uric acid in the blood. In general, the upper end
of the normal range is 360 µmol/L (6 mg/dL) for wom-
en and 416 µmol/L (7.0 mg/dL) for men.1 Hyperurice-
mia has also emerged as a metabolic disease which
threatens human health, and is considered as an impor-
tant risk factor for gout and may be associated with
metabolic syndromes, stroke incidence, chronic kidney
disease and cardiovascular disease.2-4 Current anti-hy-
peruricemic agents in use include: xanthine oxidase
205 April 15, 2016 | Volume 36 | Issue 21 |
 Kou YY et al. / Experimental Study
(XOD) inhibitors, which inhibit the activity of XOD,
an enzyme involved in purine metabolism, of which al-
lopurinol is the most often prescribed; uricosuric
agents, which act on the proximal tubules in the kid-
neys to interfere with the absorption of uric acid from
the urine back into the blood, and include probenecid,
benzbromarone and sulfinpyrazone; and the enzyme
urate oxidase, including the recombinant form rasburi-
case, which catalyzes the oxidation of uric acid to the
more soluble allantoin which is more readily excreted
via the kidneys. However, these existing anti-hyperuri-
cemic agents possess undesirable effects. For example,
allopurinol, which is the drug of choice, has side effects
including gastrointestinal irritation, bone marrow sup-
pression, hypersensitivity syndromes, hepatitis and
worsening renal function, which are unable to be toler-
ated by approximately 5% of patients. Uricosuric
agents are used in patients with allopurinol-allergic syn-
dromes as well as in under excreters with normal renal
function and no history of urolithiasis. However, urico-
suric agents, such as benzbromarone, also have issues.
Though benzbromarone is still marketed in several
countries by other drug companies, it was withdrawn
by Sanofi-Synthélabo in 2003 after reports of serious
hepatotoxicity. Similarly, the uricosuric agents probene-
cid and sulfinpyrazone have been reported to be neph-
rotoxic when used to treat hyperuricemia associated
with moderate chronic renal insufficiency.5-11 Enzyme
therapy using urate oxidase is only for treating severe
hyperuricemia and is not widely used. Thus, anti-hyper-
uricemic agents have been limited in their clinical use
due to their severe side effects. Therefore, it is impor-
tant to search for alternative anti-hyperuricemic agents
with more favorable toxicological profiles, and in par-
ticular from natural sources.
Tibetan medicine, which has historic connections to
Traditional Chinese Medicine, is an integral part of Ti-
betan culture and has been developed over many centu-
ries. It is beneficial for chronic diseases such as diges-
tive problems, arthritis, gout, asthma, and problems re-
lated to the liver, kidneys and heart.12 RuPeng15 pow-
der (RPP15) is a herbal multi-compound remedy com-
prised of 15 specific herbs that originate from tradition-
al Tibetan medicine. It is produced by combining the
Ten Tastes Frankincense powder with the Five Musks
pill as detailed in the classical recipe recorded in "The
Four Medical Tantras," compiled by Yuthok Yönten
Gönpo in the ninth century. Both recipes have been
continually improved by Tibetan doctors over the cen-
turies. In 1813, according to Tibetan Notes, the two
recipes were combined together to comprise what is
now called RPP15. RPP15 has been described to have
anti-gout, anti-inflammatory and anti-hyperuricemic
effects.13-15 Although RPP15 has been seen to be an ef-
fective and safe prescription in the treatment of hyper-
uricemia and gout for centuries, Tibetan populations
have used it primarily based on classical records and
clinical experience.16,17 Its functional roles in the treat-
JTCM | www. journaltcm. com
ment of hyperuricemia and gout have not been com-
pletely elucidated. Thus, the aim of the present study is
to evaluate the anti-hyperuricemic effect of this com-
pound and identify the possible underlying mecha-
nisms in animal models of hyperuricemia.
MATERIALS AND METHODS
Reagents
Potassium oxonate (PO) was purchased from Adamas
Reagent Co., Ltd. (Shanghai, China). Yeast was ob-
tained from Oxoid (Basingstoke, Hampshire, Eng-
land), and allopurinol tablets from the Haizhen phar-
maceutical company (Zhejiang, China). Benzbroma-
rone capsules were from the Huashen pharmaceutical
company (Chengdu, China). Uric acid test kits (phos-
photungstic acid method), creatinine assay kits (picric
acid method) and XOD test kits (colorimetric) were
purchased from Jiancheng Biotech (Nanjing, China).
All assays were carried out according to the manufac-
turer's instructions. The total protein assay kit (BCA)
was from Pierce (Rockford, IL, USA).
Plant material and preparation
The RPP15, a herbal mixture comprised of 15 ingredi-
ents: Ruxiang (Olibanum), Kuanjinteng (Caulis
Tinosporae Sinesis), Juemingzi (Semen Cassiae Obtusifoli-
ae), Zhaxungao (Brag zhun), Huangkuizi (Semen Abel-
moschi), Tibetan Changpu (Bhizoma Acori Calami),
Baxiaga (Adhatoda vasica Nees), Ercha (Catechu), Hezi
(Fructus Chebulae), Anxixiang (Benzoinum), Maohezi
(Fructus Terminaliae Billericae), Tiebangchui (Radix
Aconiti Penduli), Muxiang (Radix Aucklandiae),
Shexiang (Moschus), Yuganzi (Fructus Phyllanthi Embli-
cae) was procured from the Qinghai Provincial Tibetan
Medical Hospital, the authority in the area on Tibetan
medicine. According to Tibetan doctors, the recom-
mended dosage of RPP15 for adults is 2.4 g (total raw
materials/day). In rats and mice, equivalent doses are
approximately 7 and 10 times the human dose, respec-
tively.18 Based on clinical observations of the safety of
the drug, we chose 10, 20 and 30 times the human
dose as lower, middle and high dosage, respectively.
Three doses of RPP15 were used at 0.4, 0.8 and 1.2 g/
kg suspended in distilled water and administered by
oral gavage for 6-10 days in the study. Allopurinol and
benzbromarone were used as positive controls and simi-
larly prepared in distilled water.
Animals
Fifty six male Sprague-Dawley rats (8-10 weeks of age,
weighing 180-200 g) and 72 male Kun-Ming strain
mice (24-27 g) were obtained from The Medical Col-
lege Experimental Animal Center of Lanzhou Universi-
ty, China (Certificate of Quality: SCXK-2009-0004).
Both rats and mice were fed a commercial laboratory
diet (Beijing Keao Xieli Feed Co., Ltd., China) and al-
206 April 15, 2016 | Volume 36 | Issue 21 |
 Kou YY et al. / Experimental Study
lowed ad libitum access to food and water. All animals
were maintained on a 12 h day-night cycle and the
temperature and humidity were kept at 22-24 ℃ and
50% , respectively. They were handled gently as much
as possible to minimize animal suffering and the num-
ber of animals used was reduced according to the rec-
ommendation of the local and national ethics commit-
tees. All experimental protocols described in this study
were conducted in accordance with The Medical Col-
lege Experimental Animal Center of Lanzhou University.
Induction of hyperuricemia and experimental
protocol
Hyperuricemic rats were generated by intraperitoneal
injection of 250 mg/kg PO dissolved in 0.9% saline so-
lution 1 h before the last administration of the test
compound.19,20 Rats were randomly allocated to seven
groups using a random number table method, with
eight rats in each group. Group Ⅰ served as a healthy
control treated with vehicle. In group Ⅱ, hyperurice-
mia was induced in rats by PO and treated with vehicle
(hyperuricemic model group). Groups Ⅲ-Ⅴ were
comprised of PO-induced hyperuricemia treated with
RPP15 (0.4, 0.8, 1.2 g/kg). Groups Ⅵ and Ⅶ hyper-
uricemic rats were treated with allopurinol (5 mg/kg)
and benzbromarone (10 mg/kg) respectively, which
served as the positive controls. RPP15 (0.4, 0.8, 1.2 g/
kg), allopurinol (5 mg/kg) and benzbromarone (10 mg/
kg) were administered orally once a day for 8 days. On
the seventh day, 2 h after administration, blood sam-
ples were taken from the healthy control group and the
groups treated with RPP15 (0.4, 0.8, 1.2 g/kg) by cut-
ting the tail tips to detect the serum uric acid levels af-
ter centrifuging blood samples at 3500 rpm for 10 min,
at 4 ℃ for plasma separation. Animals were required to
fast for 12 h before such measurements, but had free
access to water. Then, on the eighth day, 250 mg/kg
PO suspended in 0.9% saline solution was adminis-
tered intraperitoneally to each animal at 1 h before the
oral administration. Before the injection, the suspen-
sions were sonicated at 4 ℃ for 20 min and vortexed
vigorously. Blood samples were taken as previously de-
scribed at 3 h after the injection of PO to measure se-
rum uric acid and creatinine level, and then the rats
were anesthetized using an intraperitoneal injection of
urethane (1.0 g/kg). Then, 5 h after hyperuricemia was
induced by PO, urine was taken from the bladder to
measure uric acid and creatinine.
For the mouse experiments, mice were randomly divid-
ed into six groups with twelve mice per group: Group
I, healthy control group treated with vehicle; Group II,
hyperuricemia group, in which hyperuricemic mice
were generated by orally administering yeast extract
paste (30 g/kg), twice daily for 8 days.21,22 Groups
Ⅲ-Ⅵ, mice were given RPP15 (0.4, 0.8, 1.2 g/kg) and
allopurinol (5 mg/kg) on the third day after hyperurice-
mia induction. The freshly prepared compounds were
administered to the respective groups for six consecu-
JTCM | www. journaltcm. com
tive days by oral gavage 2 h after hyperuricemia induc-
tion. Blood samples were obtained by removing the
eyeballs at 2 h after the last administration. This proto-
col was performed on the mice only under anesthesia.
Samples were then centrifuged and the serum uric acid
and creatinine levels determined. Before the measure-
ment, mice were also required to fast for 12 h, but had
free access to water. After the animals were sacrificed,
the liver was removed, weighed, cut into pieces, and
the XOD activity determined using a commercially
available kit.
Statistical analysis
The data are expressed as the mean ± standard devia-
tion ( xˉ ± s). The analyses were conducted using SPSS
Statistic17.0 software (SPSS, Inc., Chicago, IL, USA).
The statistical comparison of healthy controls with hy-
peruricemic controls was performed by independent
sample t test and each experimental group with hyper-
uricemic controls analyzed using one-way analysis of
variance followed by Dunnett's multiple comparison
test to determine the level of significance. A P-value of
P < 0.05 was considered statistically significant.
RESULTS
Effect of RPP15 on serum uric acid levels in healthy
rats
The serum uric acid levels after treatment with RPP15
in comparison with healthy controls is depicted in Ta-
ble 1. As shown, statistically significant differences
were observed in average serum uric acid levels be-
tween rats fed with RPP15 and the healthy control
group. Serum uric acid levels in groups treated with
RPP15 (0.4, 0.8, 1.2 g/kg) were significantly lowered
compared with the healthy control group (P = 0.04,
P = 0.02, and P < 0.0001 respectively).
Table 1 Effect of RPP15 on serum uric acid in healthy rats
(μmol/L, xˉ ± s)
Group n SUA
Healthy control 8 75±16
Healthy-0.4 g/kg RPP15-treated 8 57±9a
Healthy-0.8 g/kg RPP15-treated 8 48±13a
Healthy-1.2 g/kg RPP15-treated 8 37±8b
Notes: healthy rats were treated with vehicle, 0.4 g/kg RPP15,
0.8 g/kg RPP15, or 1.2 g/kg RPP15 orally daily at 8:00 am.
RPP15: RuPeng15 powder; SUA: serum uric acid. aP < 0.05,
b
P < 0.01, versus healthy control group.
Effect of RPP15 on levels of uric acid and creatinine
in serum and urine of rats with hyperuricemia
induced by potassium oxonate
Table 2 shows that rats treated with PO had serum uric
acid levels significantly higher than that of the healthy
control group (P < 0.0001). In addition, the allopuri-
nol positive control group demonstrated significantly
207 April 15, 2016 | Volume 36 | Issue 21 |
 Kou YY et al. / Experimental Study

lower levels of both serum and urine uric acid (P <
0.0001, P = 0.001 respectively) in this model. Howev-
er, the benzbromarone-treated group did not show sta-
tistically significant changes in the level of either serum
or urine uric acid (P = 0.082, P = 0.484). The
RPP15-treated groups demonstrated decreased serum
uric acid levels at low, middle and high dosages (all P <
0.0001), as well as significantly reduced urine uric acid
(P = 0.020, P = 0.002, and P = 0.002 respectively)
compared with the hyperuricemic control. The creati-
nine level in both serum and urine were not significant-
ly different in RPP15 treated rats compared with the
hyperuricemic control (all P > 0.05).
Effect of RPP15 on uric acid and creatinine levels in
serum and activity of XOD in the liver in yeast
extract paste-induced hyperuricemia in mice
After 30 g/kg yeast extract paste was administered daily
for 8 days, the serum uric acid and XOD activity in
the liver was significantly increased in the model group

Table 2 Effect of RPP15 on levels of uric acid and creatinine in the serum and urine in potassium oxonate-induced hyperuricemia
in rats (μmol/L, xˉ ± s)
Group n SUA UUA SCr UCr
Healthy control 8 60±11 908±314 50±8 1600±610
Hyperuricemic control 8 179±22 a
838±206 49±6 1759±283
Hyperuricemic-0.4 g/kg RPP15-treated 7 117±32c 432±158b 46±5 1229±272
Hyperuricemic-0.8 g/kg RPP15-treated 7 127±25 c
297±103 c
53±3 1220±246
Hyperuricemic-1.2 g/kg RPP15-treated 7 105±22 c
222±52 c
44±9 1173±358
Hyperuricemic-allopurinol-treated 7 64±27 c
148±77 c
51±4 2092±455
Hyperuricemic-benzbromarone-treated 7 155±23 1077±234 51±6 1731±898
Notes: healthy rats were only treated with vehicle, rats with hyperuricemia induced by intraperitoneal injection of 250 mg/kg PO one hour
before the last test compound administration were treated with vehicle, 0.4 g/kg RPP15, 0.8 g/kg RPP15, 1.2 g/kg RPP15, 5 mg/kg allo-
purinol, 10 mg/kg benzbromarone for 8 days. RPP15: RuPeng15 powder; PO: potassium oxonate; SUA: serum uric acid; UUA: urine uric
acid; SCr: serum creatinine; Ucr: urine creatinine. aP < 0.01 versus healthy control group; bP < 0.05, cP < 0.01 versus hyperuricemia control
group. Some Blood Samples had hemolysis that happened when taking blood that could interfere with plasma uric acid,and we removed
the hemolysis samples, so the number of animals had been reduced.

Table 3 Effect of RPP15 on uric acid and creatinine levels in serum in yeast extract paste-induced hyperuricemia in mice (μmol/L,
xˉ ± s)
Group n SUA SCr
Healthy control 9 77±11 36±5
Hyperuricemic control 10 118±23a 38±4
Hyperuricemic-0.4 g/kg RPP15-treated 11 96±15b 38±7
Hyperuricemic-0.8 g/kg RPP15-treated 11 75±14 b
40±6
Hyperuricemic-1.2 g/kg RPP15-treated 11 45±22 b
39±5
Hyperuricemic-allopurinol-treated 9 53±12b 42±6
Notes: healthy mice treated only with vehicle, hyperuricemic mice generated by orally administering yeast extract paste (30 g/kg) twice daily
for 8 days were treated with vehicle, 0.4 g/kg RPP15, 0.8 g/kg RPP15, 1.2 g/kg RPP15, 5 mg/kg allopurinol administrated on the third day
after hyperuricemia induction for six consecutive days. RPP15: RuPeng15 powder; SUA: serum uric acid; SCrL: serum creatinine. aP <
0.05, versus healthy control group; bP < 0.01, versus hyperuricemia control group induced by yeast. Some Blood Samples had hemolysis
that happened when taking blood that could interfere with plasma uric acid, and we removed the hemolysis samples, so the number of ani-
mals had been reduced.
Table 4 Effect of RPP15 on XOD activity in the liver in yeast extract paste-induced hyperuricemia in mice (U/g protein, xˉ ± s)
Group n XOD Activity
Healthy control 12 0.61±0.23
Hyperuricemic control 12 1.51±0.49a
Hyperuricemic-0.4 g/kg RPP15-treated 12 0.72±0.17b
Hyperuricemic-0.8 g/kg RPP15-treated 12 0.76±0.11b
Hyperuricemic-1.2 g/kg RPP15-treated 12 0.55±0.15b
Hyperuricemic-allopurinol-treated 12 0.49±0.23c
Notes: when the mice were sacrificed under anesthesia, activity of XOD in the liver was measured by test kits in the six groups that includ-
ed the healthy control group, hyperuricemic model group induced by yeast, and hyperuricemic groups receiving 0.4 g/kg RPP15, 0.8 g/kg
RPP15, 1.2 g/kg RPP15 and 5 mg/kg allopurinol by intragastric administration. RPP15: RuPeng15 powder; XOD: xanthine oxidase. aP <
0.01, versus healthy control group; bP < 0.05, cP < 0.01, versus hyperuricemia control group.

JTCM | www. journaltcm. com 208 April 15, 2016 | Volume 36 | Issue 21 |
 Kou YY et al. / Experimental Study
(P = 0.028, P < 0.0001) compared with the healthy
control. The level of serum uric acid in the RPP15
(0.4, 0.8, 1.2 g/kg) and allopurinol-treated groups
were all significantly decreased (P = 0.008, P < 0.0001,
P < 0.0001, P < 0.0001 ) in a dose-dependent manner
(Table 3). The level of XOD activity in the liver was al-
so shown to be reduced compared with the hyperurice-
mic mice (P = 0.037, P = 0.048, P = 0.013, P =
0.008) (Table 4).
DISCUSSION
Uric acid is the fi nal oxidation product of purine me-
tabolism and is excreted in urine in humans, who have
lost hepatic uricase activity during evolution. As a con-
sequence, humans have higher serum uric acid levels
compared with most mammals. Several factors includ-
ing high-protein diet, alcohol consumption, high cell
turnover, and renal failure, can result in elevated uric
acid levels. In recent decades, hyperuricemia has re-
ceived increasing attention as a major public health
problem because of its high prevalence and the associat-
ed increases in the risk of hypertension, cardiovascular
disease, diabetes and chronic kidney disease.23-25 Patho-
genic mechanisms of hyperuricemia include uric acid
overproduction or under-excretion caused by aberra-
tions in renal uric acid handling, thus XOD and urate
transporters play important roles in urate homeostasis.
XOD is mostly expressed in the liver and is an impor-
tant enzyme in humans that plays a crucial role in me-
diating purine metabolism. The major function of
XOD is to convert hypoxanthine to xanthine and xan-
thine to uric acid, with 70% of the daily output of uric
acid being excreted through the kidneys.26-29
Our animal models of hyperuricemia were induced by
yeast and PO administration. Yeast, containing abun-
dant protein, nucleic acids, vitamin B constituents,
and so forth, can be completely hydrolyzed into organ-
ic alkalis (including purine and pyrimidine) and phos-
phoric acid in vivo. Therefore, after yeast administra-
tion, normal purine metabolism can be disturbed by in-
creased XOD activity and the acceleration of uric acid
production, so that large quantities of uric acid will be
generated. This model is similar to human hyperurice-
mia induced by high-protein diets due to purine and
nucleic acid metabolic disturbances.21,22 In contrast, PO
is an inhibitor of uricase, and an intraperitoneal injec-
tion of oxonate partially blocks the conversion of uric
acid to allantoin and hence artificially elevates serum
uric acid levels in rats to provide a hyperuricemic ani-
mal model.19,20
The present study demonstrated that allopurinol signif-
icantly decreased levels of serum and urine uric acid
consistent with its XOD inhibitory activity in hyperuri-
cemia models. In hyperuricemic rats, benzbromarone,
which acts on the urate anion transport pathway and
inhibits renal proximal tubule urate reabsorption,
showed a trend towards an uric acid lowering effect,
JTCM | www. journaltcm. com
but this was not statistically significant，it might be the
reason elevated serum uric acid induced by potassium
oxonate exceeded the antihyperuricemic effects of benz-
bromarone. Our test compound RPP15 exerted a uric
acid lowering effect in both yeast-induced hyperurice-
mia in mice and PO-induced hyperuricemia in rats. It
was also shown that RPP15 (0.4, 0.8, 1.2 g/kg) re-
duced serum uric acid levels in healthy rats. Excretion
of urine uric acid was also demonstrated to be less in
the RPP15 (0.4, 0.8, 1.2 g/kg) treated hyperuricemic
rats when compared with the hyperuricemic controls
where the further metabolism of uric acid was inhibit-
ed by oxonate. Therefore, we could conclude that
RPP15 primarily inhibited uric acid synthesis. In addi-
tion, in the RPP15 treated hyperuricemic mice, attenu-
ation of serum uric acid levels was consistent with
XOD inhibitory activity in the liver. Therefore, the
uric acid lowering mechanism of action of RPP15
might be due to its XOD-inhibitory activity, thus hin-
dering the enzymes involved in uric acid synthesis and
reducing the formation of uric acid.
In conclusion, the present study demonstrates that
RPP15 has a uric acid lowering effects in healthy and
hyperuricemic animals, and its mechanism of action
may be related to inhibiting the activity of XOD. How-
ever, further studies are required to confirm this in hu-
man subjects and to investigate the underlying mecha-
nisms involved in greater detail. These data would pro-
vide a scientific basis for the clinical application of
RPP15 in hyperuricemic patients.
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