Toxicology 198 (2004) 195–201

Studies on the toxicity of Aristolochia

manshuriensis (Guanmuton)夽
Shi-Lin Hu a,∗ , Hong-Qi Zhang b , Kelvin Chan b , Quan-Xi Mei c
a Institute of Chinese Material Medica, China Academy of Traditional Chinese Medicine, Beijing 100700, China
b School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
c Zhongshan Hospital of Traditional Chinese Medicine, Zhongshan, Guangdong Province, China

Abstract

Aims: (1) To study the acute and chronic toxicity of stem of Aristolochia manshuriensis (AMA Guanmuton) which is a Chinese
medicinal herb in order to provide basis for safe clinical use. (2) To investigate the possibility of reducing toxicity of the herb
combined with Rhizoma Coptidis (Huanglian). Methods: The 70% ethanol extract of the herb was fed to mice via gastric tube
for 8 weeks. The blood was collected to assess liver and renal functions. The tissue samples of the liver, kidney and bladder
were collected from executed animals for pathology examination. Results: The LD50 with a 95% average trustable probability
(P = 0.95) of AMA from Hanzhong (HZ) is 29.2 ± 3.71 g/kg. The weight of animals in the treatment group at a dose of
4 g/kg raw drug, equivalent to 40 times of normal human dose in clinical prescription, remained the same as the control group
(P > 0.05). On pathological examination, there were no morphological changes under light microscope in the liver and bladder.
For the kidney, the renal toxicity was significantly reduced after using ethanol extract of R. coptidis to process HZ AMA in that
there were no interstitial inflammation, formation of hyaline cast or regeneration of renal tubules.
© 2004 Published by Elsevier Ireland Ltd.

Keywords: Herbal safety; Arisolochic acid; Aristolochia manshuriensis

1. Introduction per day with a 10 day course, there would be about

The stem of Aristolochia manshuriensis Kom.
(AMA, Guanmuton) is a traditional Chinese medicinal
herb mainly harvested from the Northeast of China.
It has been used widely for thousands years in China
and other countries. In 1983, as an example from a
survey conducted 20 years ago, the domestic sale of
Guanmuton was 320 t. This implied that, based on 6 g
夽
Supported by Hong Kong Baptist University FRG/00-01/II-81.
∗ Corresponding author. Tel.: +86-10-64012317;
fax: +86-10-64012317.
E-mail address: h5horse5@163.com (S.-L. Hu).
5.3 million people using it. It could imply, based on
this account, that there would be 6400 t of Guanmuton
consumed over the last 20 years involving 1 billion
patients. The export of the herb to Japan and South-
east Asia countries was about 20 t per year (CMM,
1995). Despite this large consumption, however, the
incidence of renal carcinoma that might not be related
to Guanmuton in China is 3.5% within all cancers,
lower than that of the 4% world-wide average and
most Western countries (Li, 2001). From the epidemi-
ological point of view, there is no evidence for the
association between the use of Guanmuton (AMA)
and carcinogenesis in the urinary tract in China.

0300-483X/$ – see front matter © 2004 Published by Elsevier Ireland Ltd.

doi:10.1016/j.tox.2004.01.026
196 S.-L. Hu et al. / Toxicology 198 (2004) 195–201
There was very little research on the toxicity and
side-effects of AMA until 1990s when the Belgian-
reported cases of side-effects of aristolochic acid (AA)
containing herbs such as roots of Aristolochia fangchi
used in weight-reductioncontrol formulae were made
known. Research on long term toxicity of AMA in rats
was started (Hu, 1998, 1991; Hu and Zhang, 2003;
Huang and Jiang, 2001; Qiu and Liu, 1999, 2001).
However, there have been no reports so far on the
comparison of AMA from different sources and af-
ter different processing procedures. In some of these
reported experiments the AA content was not mea-
sured and some drew conclusion from experiments
on 5–8 rats for a few days, while others used ex-
tremely high does, 600 times the normal clinical dose
that made these experimental results meaningless clin-
ically. Thus, we set out to investigate the toxicity and
side-effects of AMA from different sources in order
to provide a scientific base for safe use of the herb.
Because of the limitation of the water boiling method,
we used 70% ethanol reflux methods for the extrac-
tion of fat-soluble AA in order to get the maximum
extraction. Since in the practice AMA is often used in
combination with the roots and rhizomes of Rhizoma
Coptidis (Huanglian), we also processed AMA with
ethanol R. coptidis (Huanglian), solution in order to
find out whether this process may reduce the toxicity
of AMA.
2. Material and methods
2.1. Animal model
NIH mice of both sexes and body weight of 18–22 g
were provided by Guangzhou Animal Center. SD rats
with mixed both sexes and body weight of 180–200 g
were provided by Guangdong Animal Center for Med-
ical Research. The animals were kept in the animal
holding facilities with light–dark cycle, 20–26 ◦ C and
40–60 ◦ C humidity. The room was regularly disin-
fected by UV light.
2.2. The herb preparation
The AMA was collected from various representa-
tive areas in China: Hanzhong (HZ), Shanxi Province;
Changbai county, Jilin (JL) Province; Yuanqu county
(YQ), Shanxi Province. Since HZ is the main source
of AMA from Han Dynasty, we focused on the AMA
from this source. After grinding the dried herb to pass
20 mess filters, the following steps were taken for pro-
ducing the herb extracts:
HZ AMA: The herb was refluxed with ethanol twice
(1 h each) and condensed to fluid extract, stored in the
fridge before use. A range of solutions were diluted
with distill water to make up concentrations equivalent
to raw herb 0.4, 0.2, 0.1 g/ml for high (HZH), medial
(HZM) and low (HZL) dose, respectively.
HZ AMA processed with ethanol R. coptidis (HZP):
The HZ herb was extracted in ethanol R. coptidis and
then refluxed twice (1 h each) with 70% ethanol, con-
densed to make extract and kept in fridge before use.
It was diluted to cover the concentration equivalent to
raw herb of 0.2 g/ml for testing.
JLL and SXL were processed with the same
method: they were refluxed with ethanol twice (1 h
each) and then concentrated to produce the extracts
which were kept in fridge before use when it was
diluted with distill water to raw herb 0.1 g/ml.
HZ AMA compound (HZC): A formula with equal
proportions of HZ AMA, Ruhmannia dried root and
Licorice root was refluxed with 70% ethanol twice (1 h
each), the extract was concentrated and kept in fridge
and diluted before use to equivalent to raw AMA
0.2 g/ml. The concentrated extracts were measured by
HPLC, HZ AMA, JL AMA and YQ AMA contained
AA 1.06, 0.53, 0.45%, respectively of raw herbs.
2.3. Grouping
2.3.1. LD50
Each group consisting of 16 NIH mice were ran-
domly divided into groups with both gender. The
ethanol extract of AMA was diluted and introduced
into the mice stomach, and the standard test was
carried out to derive the oral LD50 .
2.3.2. Chronic toxicity test
Eight groups of mice were used, each containing 16
animals with both gender. They were fed (1 ml/100 g)
with the following herb preparations:
(1) HZH, raw drug dose 4 g/kg per day (i.e. 0.4 g/1 ml/
100 g per day);
(2) HZM, 2 g/kg per day (i.e. 0.2 g/1 ml/100 g per
day);
 S.-L. Hu et al. / Toxicology 198 (2004) 195–201 197

(3) HZL, 1 g/kg per day (i.e. 0.1 g/1 ml/100 g per day);
(4) HZP, 2 g/kg per day;
(5) JLL, 1 g/kg per day;
(6) SXL, 1 g/kg per day;
(7) HZC, 2 g/kg per day;
(8) Control group (CON), distill water 1 ml/100 g per
day.
At the first and the eighth weeks, blood samples
were collected from retroocular venous plexus (1–
2 ml) for biochemical examinations. At week 8, 10
rats from each group were sacrificed and their organs
(liver, kidney and bladder) were collected for patho-
logical examination. The remaining mice stopped to
take the herbal medicines from week 9, and were sac-
rificed at week 10 for collection of blood and organ
samples.
Blood tests including ALT, AST, total bilirubin, al-
bumin, creatinine (Cr) and BUN were performed. The
collected tissue samples were prepared routinely, and
cut into 2 ␮m slides and stained with H-E. Statistical
analysis was carried out by means of Dunnet t-test on
average ± standard deviation (x̄ ± S.D.). P < 0.05 is
considered as significant and P < 0.01 highly signifi-
cant.
3. Results
3.1. Acute toxicity test
LD50 results are shown in Table 1.
3.2. Chronic toxicity test
General conditions: There was no significant differ-
ence between the groups in body weight (P > 0.05).
At early stage there were casualties that were shown
by autopsy to be caused by technical errors in tube
feeding instead of by drug toxicity. At late stage, the

Table 1
LD50 of Aristolochia manshuriensis (HZ)
Group N Dose (g/kg) Lgd (x) Death Mortality (p) P2

1 10 160 2.204 (d1 , xm) 10 1

2 10 112 2.049 (d2 ) 10 1
3 10 78 1.892 (d3 ) 10 1
4 10 55 1.740 (d4 ) 10 1 1
5 10 38 1.580 (d5 ) 9 0.9 0.81
6 10 27 1.431 (d5 ) 3 0.3 0.09
Note: LD50 from the last three groups is 29.2 g/kg with a 95% trustable limit 29.2 ± 3.71 g/kg.

Table 2
ALT changes (U/l)
Time n CON HZC HZP YQL JLL HZL HZM HZH

0 n = 16 57.9 ± 12.7 61.9 ± 13.1 56.6 ± 9.6 57.9 ± 12.2 48.9 ± 8.9 55.2 ± 8.5 58.5 ± 9.5 49.6 ± 15.1
8 n = 12 40.5 ± 8.7 59.2 ± 16.3∗∗ 42.0 ± 12.3 40.7 ± 7.8 36.6 ± 7.3 34.3 ± 7.8 37.9 ± 8.6 53.8 ± 14.0∗
10 n =6 37.7 ± 3.9 44.7 ± 8.4 39.6 ± 13.6 42.8 ± 16.7 55.8 ± 31.7 43.9 ± 11.1 39.0 ± 6.6 45.2 ± 9.3
Note: comparing with the control group (CON).
∗ P < 0.05.
∗∗ P < 0.01.

Table 3
AST changes (U/l)
Week n CON HZC HZP YQL JLL HZL HZM HZH
0 16 201.6 ± 43.1 192.3 ± 39.5 226.8 ± 51.2 225.8 ± 40.5 201.4 ± 44.3 191.7 ± 30.6 191.5 ± 24.6 163.1 ± 22.8
8 12 237.7 ± 46.6 220.6 ± 27.2 213.1 ± 32.3 219.5 ± 28.2 196.7 ± 34.1∗ 173.4 ± 23.9∗ 154.9 ± 29.0∗ 138.7 ± 18.3∗
10 6 211.3 ± 36.3 247.8 ± 35.9 224.2 ± 31.9 214.7 ± 26.0 294.7 ± 97.8 231.5 ± 37.5 250.6 ± 49.8 301.5 ± 44.1
∗ P < 0.05.
198 S.-L. Hu et al. / Toxicology 198 (2004) 195–201

Table 4
Albumin level change (g/l)
Week n CON HZC HZP YQL JLL HZL HZM HZH

0 16 31.0 ± 3.4 30.0 ± 3.1 29.9 ± 1.7 29.2 ± 3.0 30.0 ± 3.4 30.3 ± 2.7 30.4 ± 1.4 31.0 ± 2.2
8 12 32.7 ± 3.1 32.9 ± 2.0 32.5 ± 2.7 33.3 ± 1.9 32.9 ± 3.0 37.1 ± 13.5 32.8 ± 2.9 31.7 ± 1.6
10 6 31.2 ± 2.2 32.2 ± 1.3 33.7 ± 2.1 32.8 ± 2.2 33.8 ± 2.0 33.5 ± 3.1 32.8 ± 2.2 33.7 ± 1.5

Table 5
Total bilirubin change (␮mol/l)
Week n CON HZC HZP YQL JLL HZL HZM HZ

0 16 1.0 ± 0.4 1.1 ± 0.9 1.0 ± 0.8 1.0 ± 0.5 1.1 ± 0.6 1.2 ± 0.6 1.3 ± 0.6 1.1 ± 0.7
8 12 1.1 ± 0.6 1.2 ± 0.5 1.2 ± 0.3 1.3 ± 0.4 1.1 ± 0.5 1.4 ± 0.4 0.9 ± 0.5 1.1 ± 0.6
10 6 1.1 ± 0.1 1.3 ± 0.4 1.1 ± 0.2 1.8 ± 1.5 2.4 ± 1.9 1.2 ± 0.8 1.1 ± 0.3 1.1 ± 0.2

animals showed hair erecting and sitting with head
up position, particularly in the middle and high dose
groups. It was observed that the HZC group had more
urine output than other groups.
Serum tests results are shown in the following
Tables 2–7. It was demonstrated from the ALT result
that after taking the medicine for 8 weeks, there was a
significant increase in ALT level in HZH (P < 0.05)
and HZC (P < 0.01) groups, although the level de-
clined at week 10. The other groups did not show
significant changes.
The results in Table 3 demonstrate that after tak-
ing the medicine for 8 weeks, there was a significant
decrease of AST level in JLL, HZL, HZM and HZH
groups in comparison with the control group.
The results in Table 4 show that there were no sig-
nificant changes in albumin level in all groups in com-
parison with the control.
The results in Table 5 indicate that there were no
significant differences between the testing groups and
the control, and between week 8 and the start of the
experiment.
As shown by Tables 6 and 7, the renal function was
not affected by the herbal extracts, as there were no
significant differences between the testing groups and
the control, and between week 8 and the start of the
experiment.
3.3. Pathological examination
As only one sample in HZ Guanmuton group with
the medial dose showed band-like necrosis in the liver
tissue, the toxic effect of the drug on the liver is in-
conclusive (see Table 8).
The renal tubular hydropic changes were not only
observed in the treatment groups but also in the control

Table 6
BUN changes (mmol/l)
Week n CON HZC HZP YQL JLL HZL HZM HZH

0 16 8.1 ± 2.5 7.7 ± 1.8 6.7 ± 0.8 6.9 ± 0.9 6.3 ± 1.0 6.0 ± 0.7 7.0 ± 1.0 6.1 ± 0.8
8 12 7.8 ± 1.3 8.6 ± 2.4 7.7 ± 1.0 7.7 ± 1.2 7.5 ± 0.7 7.7 ± 1.0 8.1 ± 1.9 8.5 ± 3.8
10 6 7.4 ± 0.4 6.7 ± 0.7 7.1 ± 1.0 6.7 ± 1.3 6.1 ± 0.3 6.7 ± 1.0 7.3 ± 1.0 7.3 ± 1.1

Table 7
Creatinine changes (␮mol/l)
Week n CON HZC HZP YQL JLL HZL HZM HZH
0 16 85.1 ± 8.6 79.3 ± 4.6 79.9 ± 5.8 81.2 ± 5.7 78.2 ± 2.3 82.2 ± 7.0 81.2 ± 2.9 83.0 ± 6.8
8 12 75.4 ± 11.4 78.8 ± 9.9 72.9 ± 5.7 74.8 ± 6.3 70.2 ± 7.2 69.8 ± 5.0 73.6 ± 8.8 79.0 ± 17.0
10 6 74.5 ± 9.2 72.5 ± 5.9 70.4 ± 3.9 73.7 ± 5.4 69.2 ± 8.5 71.0 ± 6.1 72.4 ± 8.3 76.5 ± 4.0
 S.-L. Hu et al. / Toxicology 198 (2004) 195–201 199

Table 8
Liver pathological changes
Week n CON HZH HZM HZL HZP HZC YQL JLL

8 10 no no 1/10a no no no no no
2 after stop 4–6 no no no no no no no no
a One in 10 samples showed band necrosis.

Table 9
Renal pathological changes
Week n CON HZH HZM HZL HZP HZC YQL JLL

8 10 5/10RTE-M 3/10RTE-M 5/10RTE-M 9/10RTE-M 3/10RTE-M 8/10RTE-M 3/10RTE-M 5/10RTE-M

5/10RTE-L 7/10RTE-L 5/10RTE-L 1/10RTE-L 7/10RTE-L 2/10RTE-L 7/10RTE-L 5/10RTE-L
1/10RII-L 3/10RII-L 6/10RII-L 2/10RII-L 1/10RII-L 3/10RII-L 1/10RII-M 2/10RII-L
2/10RTR 2/10RTR 1/10RTR 1/10RTR 1/10RTR
1/10RHC
2 after stop 4–8 4/4RTE-L 4/4RTE-L 4/5RTE-L 8/8RTE-L 5/5RTE-L 6/6RTE-L 6/6RTE-L 5/6RTE-L
1/4RII-L 3/4RII-L 1/5RTE-M 3/8RII-L 1/6RII-L 2/6RII-L 1/6RTE-M
1/5RII-L 1/6RII-L
Note: RTE, renal tubular edema; RII, renal interstitial inflammation; RHC, renal hyaline casts; RTR, renal tubular regeneration; L, light;
M, medial.

Table 10
Pathological changes in urinary bladder
Week n CON HZH HZM HZL HZP HZC YQL JLL

8 10 no no 1/10* no no no no no
2 after stop 4–6 no no no no no no no no
Note: there was one in 10 samples in HZM group shown epithelial papilloma-like proliferation.

group. It might be due to the technical problem dur-
ing tissue processing. The renal interstitial inflamma-
tion, hyaline casts and tubular regeneration were ob-
served pathological changes, but the renal interstitial
inflammation was less severe in HZP group than in
the non-processed HZ group with the equivalent dose
(HZM) (see Tables 9 and 10).
4. Discussion
The AA contents of AMA were measured and the
results were 1.06, 0.53 and 0.45% in samples of HZ
(from most southern part of China), Changbai County
of Jilin Province (from more northern part of China)
and Yuanqu County of Shanxi Province (from middle
of China), respectively, indicating that there existed
no much difference among them with respects to the
contents of AA. In the LD50 test, we found that for
YQ AMA, the lethality rate was 25% with the dosage
of 150 g/kg (there were no data of 100% non lethal-
ity rate). The lethality rate was up to 100% with the
dosage of 33 g/kg. Likewise, the toxicity of HZ AMA
is stronger than that of YQ AMA. In the maximum
tolerance dose of YQ AMA, 200 g/kg, there was not
any death of mouse in the first 3 days; But for JL
AMA with the maximum tolerance dose of 195 g/kg,
the majority of mice died in 2 h after the adminis-
tration. Therefore, we conclude that that the toxic-
ity of JL AMA is stronger than that of YQ AMA.
However, there was no correlation between LD50 and
AA contents. There could be other components in
the extracts dominating the toxicity intensity and ac-
tion speed. It was recorded (Lou, 1996) that the LD50
of A. manshuriensis from Liuhe, Jilin Province was
15.5 ± 0.60 g/kg. All these data suggested that there
existed close relationship between LD50 toxicity of
AMA and their habitats. This should arouse the high
200 S.-L. Hu et al. / Toxicology 198 (2004) 195–201
attention on the influence of geographic distribution
factors and biodiversity of subspecies populations to
herbal safety, efficacy and quality (Hu, 1998, 1999).
The use of HZ AMA together with Huanglian (R.
coptidis) might remarkably reduce the occurrence rate
of interstitial nephritis, showing similar tendency with
that of Radix Aristolochiae Fangchi (Hu and Zhang,
2003) combining with R. coptidis in the long term tox-
icity test of the former. In the rats of the compound
powder group (Dao Chi San), it was observed that
the wood scraps were often wetter than that of other
groups. This suggested that such combination of herbs
promote the function of diuresis and clearance of heat.
These phenomena and clues need further investigation
in order to better understand the scientific significance
of mixing herbs in compound prescriptions and com-
patibilities and this is at least beneficial according to
the basic theory development of Chinese herbal pre-
scriptions.
In the long-term test, the toxicity of Aristolochiae
fangchi, A. manshuriensis from Ningan, Heilongjiang
Province (AA content 0.61%, 7.5 g/kg per day) was
used to perform for the comparison. From the sev-
enth day of drug administration, 12 of 16 rats died
consecutively. The rats had the characteristics such
as extreme emaciation, unwillingness of movement,
staggering gait and foul odour. Both Ningan County
and Changbai County are situated in Changbai Moun-
tain area and the AA contents in AMA of both ori-
gins are nearly equal. The key reason covering such
great difference of toxicity was their dosages. Other re-
searchers (Cui and Wang, 2000; Zhang, 1989) also ob-
served that there were no pathological and biochemical
changes in 1–4 g/kg and produced qualitative change
with dramatic increase of toxicity over 4 g/kg.
It is time to abandon the term ‘Chinese herbs
nephropathy’ (CHN). This was labelled unfortunately
for all Chinese medicinal materials because of the
incidence of miss use of Chinese medicines in the
Belgian slimming regime, which consisted of ortho-
dox medicines such as amphetamine-like and diuretic
western drugs. The term ‘Chinese herbs nephropathy’
was produced by Belgian practitioners (Martinez and
Nortier, 2002) and is a very prejudicial term. First of
all, they used root of A. fangchi for weight control
in long-term administration. In traditional Chinese
medicine (TCM), AA-containing herbals such as A.
fangchi should not be used for weight-control, and
they are not allowed for a long use. Secondly, many
hundreds of Chinese medicinal herbs are safely used
in China and throughout the world. The term Chi-
nese Herbs Nephropathy may wrongly imply that
Chinese herbs in general cause renal impairment.
Thirdly, AA-containing species are not only growing
in China and not only used by TCM. In fact, they are
widely distributed in Asia, (Aristolochia india and
A. canadense), Africa (Aristolochia bracteata Retz.),
Europe (Aristolochia acuminata Lam.) and Amer-
ica (Aristolochia serpentaria L. and Aristolochia
argentina Griseb.), and used by local practitioners.
Fourthly, the nomenclature of medical terms involved
a nation needs to be carefully scrutinised. For in-
stance, mongolism has been replaced by Down’s
syndrome and ’Malta fever’ by Brucellosis. Australia
antigen was changed to hepatitis B surface antigen.
Any medical terms and statements tending to encour-
age prejudice or of ethnic origin should be abandoned.
Therefore, the term ‘Chinese herbs nephropathy’ is
etiologically misleading and politically harmful, and
should be changed. We suggest that Chinese herbal
nephropathy be replaced by AA-associated nephropa-
thy (AAN).
According to our study, we suggest to pay more
attention to biodiversity of subspecies (among the
geo-populations); multi-chemicals markers for qual-
ity control and safety evaluation, and chemico-
pharmaceutical methods for quality control and safety
evaluation. Although A. fangchi, Aristolochia het-
erophylla, A. manshuriensis, Aristolochia debilis and
other species of the Aristolochiaceae all contain AA,
their AA levels are very different. If used correctly,
they may benefit patients without adverse effects.
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