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Effects of Chinese herbal cataplasm Xiaozhang Tie on cirrhotic ascites
Journal of Ethnopharmacology 139 (2012) 343–349
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Effects of Chinese herbal cataplasm Xiaozhang Tie on cirrhotic ascites Feng Xing a,b,1 , Ye Tan a,b,1 , Guang-Jun Yan c , Jian-Jun Zhang d , Zhao-Hong Shi e , Shan-Zhong Tan f , Nian-Ping Feng g , Cheng-Hai Liu a,b,∗ a
Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai 201203, China Department of Infectious Diseases, Hubei Jingzhou Hospital of Traditional Chinese Medicine, Jingzhou 434000, China d Department of Infectious Diseases, Hubei Zhongshan Hospital, Wuhan 430033, China e Department of Gastroenterology, Wuhan No. 1 Hospital, Wuhan 430030, China f Department of Integrated Medicine, The Second Hospital of Nanjing, Nanjing 211103, China g Department of Pharmaceutics, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China b c
a r t i c l e
i n f o
Article history: Received 6 April 2011 Received in revised form 12 October 2011 Accepted 15 October 2011 Available online 17 November 2011 Keywords: Xiaozhang Tie Cataplasm Cirrhotic ascites Traditional Chinese medicine
a b s t r a c t Background: Conventional methods of treating cirrhotic ascites are inadequate. We sought to identify a novel, effective approach to relieve the suffering of patients with cirrhotic ascites. Aim of the study: To investigate the efficacy of Xiaozhang Tie, a traditional Chinese herbal cataplasm composed of dahuang (Rheum palmatum L.), laifuzi (Raphanus sativus L.), concocted gansui (Euphorbia kansui T.N. Liou ex T.P. Wang), chenxiang [Aquilaria sinensis (Lour.) Gilg], dingxiang (Eugenia caryophyllata Thunb.), bingpian (Borneolum syntheticum) and shexiang (artificial Moschus), as an adjuvant in treating cirrhotic ascites. Materials and methods: A multicenter, randomized, placebo-controlled trial was conducted. One hundred patients with cirrhotic ascites were divided into two groups of equal size. The test group took an umbilical compress with Xiaozhang Tie for 30 days while the control group was administered an umbilical compress with placebo, in addition to primary therapy. Efficacy was evaluated according to the criteria including ascites volume, urine 24-h volume, abdominal circumference, body weight, abdominal distention, appetite, flatus and defecation. Results: Ninety-two patients completed the study, 7 were withdrawn and 1 was excluded. The effective rate of grades I and II was 63.3% for the test group (n = 49) and 38.0% for the control one (n = 50). Both groups showed decreased body weight and abdominal circumference, increased urine volume and improved symptoms after treatment. However, the differences between pre-treatment and post-treatment in body weight, abdominal circumference and urine volume were 8.7 ± 5.8 kg, 12.4 ± 8.3 cm and 683 ± 644 ml respectively in the test group, noticeably higher than those in the control group, which were 5.3 ± 4.6 kg, 8.0 ± 6.5 cm and 372 ± 697 ml, respectively. The ranking orders of the symptoms of the test group were significantly lower than those of the control group after treatment. No severe adverse reactions were seen. Conclusion: Xiaozhang Tie as an adjuvant to primary therapy of cirrhotic ascites is safe and shows a remarkable efficacy on relieving abdominal distention. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Abbreviations: Alb, albumin; ALT, alanine aminotransferase; GCP, good clinical practice; ITT, intention to treat; RCT, randomized, controlled clinical trial; SBP, spontaneous bacterial peritonitis; SD, standard deviation; TBil, total billirubin; TCM, traditional Chinese medicine. ∗ Corresponding author at: 528 Zhangheng Road, Pudong New Area, Shanghai 201203, China. Tel.: +86 21 20256521; fax: +86 21 20256521. E-mail address: Chenghai [email protected] (C.-H. Liu). 1 These authors made equal contributions. 0378-8741/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jep.2011.10.040
Liver cirrhosis is the end stage of many chronic liver diseases. It has been showed that 10 years after diagnosis, the probability of developing decompensated cirrhosis is about 60%, and ascites is the most frequent complication (about 50%) (Ginés et al., 1987). Ascites, manifested by the accumulation of fluid in the peritoneal cavity, is the most common complication and cause of hospitalization of patients with cirrhosis. Ascites usually results from portal hypertension, albumin synthesis reduction and sodium retention, etc. (Planas et al., 2006). Cirrhotic ascites is associated with poor quality of life and a high risk of developing complications such
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as hepatorenal syndrome, spontaneous bacterial peritonitis (SBP), with increased morbidity and mortality (Rimola et al., 2000). Therefore, there is a clear rationale for better management of cirrhotic ascites that accompany cirrhosis. The management of cirrhotic ascites usually needs comprehensive measures: the primary treatment includes sodium-restricted diet, diuretics application and albumin infusion. (European Association for the Study of the Liver, 2010). These measures usually work for moderate ascites without any effects on refractory ascites (Santos et al., 2003), and diuretics could cause electrolyte disorders, renal failure, hepatic encephalopathy and other problems (Ferenci, 1991). The surgical methods, including large-volume paracentesis, transjugular intrahepatic portosystemic shunting, peritoneal venous shunting and liver transplantation, are very helpful for refractory ascites. Apart from the problems that most of these procedures involve high costs and expertise that is only available at certain facilities, there are the complications of post-operative infections, electrolyte disorders and circulatory dysfunction. Liver transplantation is further limited by the scarcity of suitable donors (Schuppan and Afdhal, 2008). More importantly, patients with ascites suffer from abdominal distension, caused by fluid retention or excess gas in stomach and intestine due to impaired gastrointestinal motility. The measures mentioned above cannot relieve abdominal distension effectively. Therefore, there remains a need to develop effective approaches to relieve the suffering of patients with cirrhotic ascites. Traditional Chinese medicine (TCM) has a long history and rich experiences in treating cirrhotic ascites and nowadays is widely applied in clinical practice as a complementary and alternative approach (Pan et al., 2004). Chinese herbal decoction is the common way of treating ascites, however, the fact that the patients with cirrhotic ascites have difficulty taking in food and water because of their abdominal distention and reduced gastric capacity can get in the way of the therapeutic efficacy of this approach. TCM external therapy, pasting the herbal mixture to the umbilicus, could overcome the difficulty of oral herbal decoction and may be directly effective on ascites. The umbilical compress with herbs is an ancient method in TCM practice with the advantages of convenience and economy. One example was firstly recorded 2000 years ago in the Wu Shi Er Bing Fang (Prescriptions for 52 Types of Diseases) in the pre-Qin Dynasty (Review group of Mawangdui silk texts, 1979). The Ben Cao Gang Mu (Compendium of Materia Medica) written by Li Shizhen in the Ming Dynasty described how to use umbilical compress against ascites in detail (Li, 1998). Over the past 10 years, our research group has tried to take advantage of the umbilical compress to treat cirrhotic ascites. Firstly we designed 2 formulae, shizhang recipe consisting of dahuang (Rheum palmatum L.), laifuzi (Raphanus sativus L.), gansui (Euphorbia kansui T.N. Liou ex T.P. Wang), chenxiang (Aquilaria sinensis (Lour.) Gilg), dingxiang (Eugenia caryophyllata Thunb.), bingpian (Borneolum syntheticum), shexiang (artificial Moschus), and xuzhang recipe consisting of huangqi (Astragalus membranaceus (Fisch.), Bge), fuzi (Aconitum carmichaeli Debx.), rougui (Cinnamomum cassia Presl), xiangfu (Cyperus rotundus L.), dingxiang (Eugenia caryophyllata Thunb.), bingpian (Borneolum syntheticum) and shexiang (artificial Moschus). Then we made them into cataplasms and observed the efficacy of shizhang and xuzhang cataplasms on cirrhotic ascites by umbilical compress for shi-syndrome and xu-syndrome patients, respectively. In this previous study, 242 patients were enrolled and divided into 4 groups: the shi-syndrome control and shi-syndrome test, xusyndrome control and xu-syndrome test. In addition to primary treatment with limited diuretics and sodium-restricted diet, the shi-syndrome and xu-syndrome test groups received the compress with shizhang cataplasm or xuzhang cataplasm on the umbilicus, respectively, while the control groups got placebo of cataplasm
without any herbs. Efficacy was evaluated according to the patient’s symptoms, body weight, abdominal circumference, urinary 24h volume, and ascites detected by ultrasound. Effective grading criteria are explained in Section 2.3. The herbal cataplasms were changed every 2 days and the treatment course was 30 days. At last 220 patients completed the full course, with 22 withdrawn. The results showed that compared to their respective controls, patients in both test groups had a decreased body weight, abdomen circumference and amount of ascites accompanying with increased urinary volume and flatus. The effective rates of grades I and II in the control and test groups were 37.5% and 72.2% in the xu-syndrome group and 39.5% and 75.0% in the shi-syndrome group (Liu et al., 2006 and author’s data not published). These results indicate that both herbal cataplasms have adjuvant effects in relieving abdominal distention by not only reducing ascites but also increasing gas passage, and the shizhang cataplasm is superior to the xuzhang cataplasm. Therefore, in the subsequent study, we focused on the shizhang cataplasm, further optimized the formula, fixed its manufacturing procedure with stringent quality control, and re-named it Xiaozhang Tie. Xiaozhang Tie was chosen to signify the cataplasm’s function of eliminating distension. In this study, we set up a randomized double-blind controlled clinical trial to evaluate the efficacy of Xiaozhang Tie as an adjuvant in treating cirrhotic ascites and to identify its characters in order to develop a helpful and reliable external therapy for cirrhotic ascites.
2. Materials and methods 2.1. Design, setting and participants A multicenter, double-blind, randomized, placebo-controlled clinical trial of 100 patients was conducted from November 2008 to September 2009. All patients came from the inpatient department of Shuguang Hospital Affiliated to Shanghai University of TCM, Wuhan No. 1 Hospital, Hubei Zhongshan Hospital, Hubei Jingzhou Hospital of TCM, and the Second Hospital of Nanjing. We recruited volunteers from inpatients. All practitioners committed adequate time to explaining the compositions, effects and adverse reactions of Xiaozhang Tie and our hypothesis about umbilical compress therapy and the primary treatment including diuretics and albumin. This study was conducted in accordance with the guidelines for human experimentation outlined in the Declaration of Helsinki and Declaration of Tokyo. The protocol of this study was approved by Ethics Committee of Shuguang Hospital Affiliated to Shanghai University of TCM and supported by State Administration of TCM. The purpose and protocol of this trial were explained to eligible patients. Patients entered into the protocol therapy after giving both oral and written informed consent before the study commenced. The participants were volunteers and received no pay. They were permitted to refuse treatment or quit any time on their own without penalty. Patients aged from 18 to 80 years, were diagnosed with cirrhotic ascites based on criterion established by the Chinese Medical Association Society of Infectious and Parasitic Diseases and Society of Liver Diseases in 2000 (Society of Infectious and Parasitic Diseases and Society of Liver Diseases, Chinese Medical Association, 2000). They all suffered from cirrhosis of decompensated stage (B/C grade of Child-Pugh classification) and their ascites was certified by abdominal ultrasound. All patients had no prior treatment for ascites. Laboratory assessment of liver function, renal function and electrolytes was also performed. Patients with psychosis, cancer (including liver tumors without hemorrhagic ascites), renal
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Table 1 The formula of Xiaozhang Tie (one dose). Drug name
Plant sources
Medicinal parts
Dosage (g)
Dahuang Laifuzi Gansui Chenxiang Dingxiang Borneolum syntheticum Artificial moschus
Rheum palmatum L. Raphanus sativus L. Euphorbia kansui T.N. Liou ex T.P. Wang Aquilaria sinensis (Lour.) Gilg Eugenia caryophyllata Thunb.
Rhizoma Seed Root Stem Flower bud
1 1 1 0.2 1 0.04 0.004
insufficiency, diabetes with unstable blood glucose or any serious diseases of the cardiovascular, respiratory, nervous or hematologic systems were not eligible. Lactation and pregnant women were also excluded. The participants were considered withdrawn from the study when the following situations occurred: patients quitted the treatment on their own but still had ascites; experienced serious complications including hepatic encephalopathy, hepatorenal syndrome, and gastrointestinal hemorrhage; took surgical methods for ascites such as large volume paracentesis and ascites ultrafiltration and reinfusion. All withdrawal cases received intention to treat (ITT) analysis. A randomized schedule was generated prior to the initiation of the study. Following signed informed consent, successful completion of screening evaluations, and satisfaction of all eligibility criteria, subjects were randomized in a 1:1 ratio to either the test or control group.
2.2. Intervention The formula of Xiaozhang Tie (one cataplasm, daily dosage) is presented in Table 1 and the manufacturing procedure was as follows: The mixture of powder preparations of dahuang (Rheum palmatum L.), laifuzi (Raphanus sativus L.) and gansui (Euphorbia kansui T.N. Liou ex T.P. Wang) was extracted successively two times with 10 folds of 75% ethanol under reflux. The 75% ethanol extract was then filtered through absorbent gauze, and the filtrate was concentrated under reduced pressure to remove ethanol and then dried to produce the extract powder. The volatile oil was exacted from the dingxiang (Eugenia caryophyllata Thunb.) by steam distillation. Finally, the extract powder, volatile oil, borneolum syntheticum and artificial moschus were made into cream with the excipients, such as plasdone K-90, viscomate NP700, polyplasdone XL-10. The cream was coated onto rubberized fabric and the resulting plaster was cut into small pieces (7 cm × 7 cm). Each cataplasm contained at least 0.42 mg emodin and 18.0 mg borneol, according to the requirements of medicinal paste detailed in the Pharmacopoeia of the People’s Republic of China. These values roughly correspond to pharmaceutical quality standards currently under investigation by pharmaceutical
experts from Department of Pharmaceutics, Shanghai University of TCM. The manufacturing procedure of placebo cataplasm was the same as that of Xiaozhang Tie, and the placebo contained all of the excipients that were used in Xiaozhang Tie without herbs. All participants received the primary therapies as follows: (1) Diuretics: Spironolactone was administered orally at a dose of no more than 100 mg per day and Furosemide was administered orally at a dose of no more than 40 mg per day. (2) Hepatoprotectives: Silymarin (140 mg bid) or Fuzhenghuayu capsules (1.5 g tid) were available as an option. (3) Human serum albumin was administered intravenously at a dose of 10 g biw to patients whose serum albumin was less than 25 g/L. (4) Intravenous antibiotics (Cefotaxime 2 g q12 h or Ceftriaxone 2 g q12 h for 7 days) were used in patients who were diagnosed with SBP. The patients in the test group or the control group were treated with primary therapies plus Xiaozhang Tie or placebo. Umbilical compress therapy was performed as follows: After cleaning and disinfecting the umbilical region of patients, the Xiaozhang Tie (7 cm × 7 cm) or placebo was compressed directly on the umbilicus and changed once a day. The research staff who administered the cataplasms applied good clinical practices (GCP). The course of treatment lasted 30 days. If ascites were eliminated before the full course was complete, the treatment was terminated in advance. Xiaozhang Tie and placebo cataplasms were revealed to the research staff only after statistical analysis was completed. The research staff was prepared to take therapeutic measures in the case of any allergic or other adverse reactions. The participants will be early terminated if severe adverse reactions occurred. All adverse reactions were recorded.
2.3. Measurements of outcome Clinical symptoms including abdominal distention, appetite, flatus and defecation were observed and recorded daily according to the symptom scale table (Table 2). Physical and instrumental examinations were performed as follows: (1) Ascites: Ascites was examined by ultrasound under the same anthropometric position pre-treatment, during the second week of treatment, and post-treatment (3 times totally) with the
Table 2 Symptom scale table. Grade I
Grade II
Grade III
Grade IV
Abdominal distension
None
Relieved while lying supine, affects daily living and diet
Continuous and unbearable
Appetite Flatus
Normal >4 times per day
Bearable, does not affect daily living or diet Reduced <1/3 2–3 times per day
Defecation
1–2 times per day, unobstructed and formed
1 time per day, a little hard or shapeless
Reduced >1/3 ≤1 time per day, tympanitic note upon abdominal percussion 1 time every 2–3 days and dry or 2 times per day and shapeless
Reduced >1/2 Little, obvious tympanitic note upon abdominal percussion <1 time every 3 days or 3 times per day and shapeless
The scale table was formulated by practitioners from 5 hospitals. Symptom scores were estimated using information supplied by patients or their dependents and the variations in symptoms were recorded daily.
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same apparatus and by the same practitioner. (2) Urine volume: Urine 24-h volume was measured using the same graduated cylinder and recorded every day. (3) Abdominal circumference: Maximum abdominal circumference was measured with the patient supine using the same ruler and recorded every morning. (4) Body weight: Body weight was measured using the same scale every morning. Laboratory tests including liver function, renal function and electrolyte were performed by an automatic biochemical analyzer pre-treatment, during the 2nd week of treatment and posttreatment (3 times totally). Efficacy was evaluated according to the modified grading criterion established in 2004 by the China Association of Integrated Medicine’s Society of Digestive Disease (Society of Digestive Disease and China Association of Integrated Medicine, 2004): (1) Effective grade I: Ascites was undetectable by ultrasound. Clinical symptoms were improved as grade I. Body weight returned to normal. (2) Effective grade II: Ascites was mostly eliminated, appearing ≥50% reduced by ultrasound. Clinical symptoms were improved to grade II. Body weight was reduced ≥2 kg or the abdominal circumference was reduced ≥5 cm. (3) Effective grade III: Ascites was partially eliminated, appearing <50% reduced by ultrasound. Clinical symptoms were improved to grade III. Body weight was reduced <2 kg or abdominal circumference was reduced <5 cm. (4) Ineffective grade: Ascites was not reduced. Clinical symptoms were not clearly improved. There was no obvious change in body weight or abdominal circumference. 2.4. Statistical analysis Quantitative data are expressed as mean ± SD. The differences in quantitative variables within each group and between two groups such as age, urine volume, abdominal circumference, body weight and liver function were compared with paired t-test or independent t-test. Rank-sum test was used to compare the symptom scores between the two groups before or after treatment, and the
difference of symptom scores between pre-treatment and posttreatment. The chi-square test and ridit analysis were used for categorical variables, such as sex distribution and the gradations of curative effect. p < 0.05 was considered statistically significant. The ITT principle was employed in comparing efficacy rates. All statistical analyses were performed with the SPSS software package.
3. Results 3.1. Participant profiles Of the 100 patients enrolled, 7 withdrew. After enrollment, another patient was excluded from the test group after being diagnosed with tuberculosis peritonitis. Eventually, 92 patients including 47 patients in the test group and 45 patients in the control one completed the study. The baseline characteristics of the patients are shown in Table 3. The 92 patients included in the analysis, 57 men and 35 women, had an average age of 58 (range: 37–80). The two groups were comparable at entry with regard to age, gender, clinical features, vital signs, hematological data, seriousness of illness and number of days hospitalized.
3.2. Treatment outcomes 3.2.1. Clinical symptoms Patients in the control group were treated with placebo and primary therapy, such as diuretic and hepatoprotective agents, while patients in the test group were treated with primary therapy and Xiaozhang Tie. Before treatment, there were no statistical differences in abdominal distention, appetite, flatus and defecation between the two groups. After treatment, patients in both groups showed improvement in all symptoms (Table 4). However, the statistical rank orders of the symptoms in the test group were significantly lower than those of the control group after treatment, which suggests that primary therapy combined with Xiaozhang Tie is superior to primary therapy plus placebo (Table 5).
Table 3 Patient characteristics.
General data
Etiology
Biochemical
Cases (enrolled/completed/withdrawn/excluded) Sex (M/F) Average age (range) Average number of days hospitalized (range) Chronic hepatitis B Schistosomiasis Alcohol Primary biliary cirrhosis Chronic hepatitis C Drug use Autoimmune hepatitis Chronic hepatitis B and schistosomiasis Chronic hepatitis B and alcohol Chronic hepatitis B and drug use Cryptogenic ALT (U/L) (range) Alb (g/L) (range) TBil (mol/L) (range)
Test
Control
50/47 /2/1 27/20♦ 58.5 ± 9.9 (37–80) 18.8 ± 7.8 (6–30) 33 4 3 3 1 0 0 1 1 0 1 53.1 ± 64.7夽 (10.2–439.9) 27.6 ± 6.0 (17.0–40.1) 44.4 ± 29.9# (7.3–138.0)
50/45/5/0 30/15 58.3 ± 9.8 (39–79) 19.0 ± 7.4 (7–30) 30 3 3 1 1 1 1 3 0 1 1 75.0 ± 121.9 (12.3–668.8) 27.0 ± 6.3 (15.0–42.7) 57.9 ± 59.8 (7.0–348.3)
Quantitative data are expressed as mean ± SD. Chi-square testing was used in comparisons of case number and sex. Independent t-test was used in comparisons of age, TBil, ALT, Alb, and number of hospitalization days. p = 0.57 vs. the control group. ♦ p = 0.34 vs. the control group. p = 0.89 vs. the control group. p = 0.87 vs. the control group. 夽 p = 0.28 vs. the control group. p = 0.65 vs. the control group. # p = 0.17 vs. the control group.
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Table 4 Effects of Xiaozhang Tie on differences of clinical symptom scores between pre-treatment and post-treatment in patients with cirrhotic ascites. Group
n
Abdominal distension
Appetite
Flatus
Defecation
Test p Control p
47
−5.65* 0.00 −3.66* 0.00
−5.69* 0.00 −3.53* 0.00
−5.61* 0.00 −3.23* 0.00
−5.69* 0.00 −3.08* 0.00
45
Values are expressed as the pre-treatment score subtracted from the post-treatment score. The rank-sum test used to evaluate single symptoms within each group. * p < 0.01 within each group before and after treatment. Table 5 Effects of Xiaozhang Tie on clinical symptom scores of patients with cirrhotic ascites (rank orders). Group
Test Control p
n
Before treatment
47 45 –
After treatment
Abdominal distension
Appetite
Flatus
Defecation
Abdominal distension
Appetite
Flatus
Defecation
45.16 47.90 0.56
46.36 46.64 0.95
47.67 45.28 0.61
46.74 46.24 0.91
40.44* 52.83 0.02
40.18* 53.10 0.01
39.97* 53.32 0.01
39.99* 53.30 0.01
Values are expressed as rank order before and after treatment. Rank-sum testing was used to evaluate rank order of single symptoms between the two groups. * p < 0.05 between the two groups after treatment. Table 6 Effects of Xiaozhang Tie on body weight, abdominal circumference, and urine volume in patients with cirrhotic ascites. Group
n
Test
47
p
–
Control
45
p
–
Before treatment After treatment – Before treatment After treatment –
Body weight (kg)
Abdominal circumference (cm)
Urine volume (ml)
70.9 ± 12.2 62.2 ± 11.2* 0.00 69.4 ± 11.3 64.1 ± 10.6* 0.00
94.8 ± 11.4 82.6 ± 7.5* 0.00 93.3 ± 10.4 85.2 ± 10.3* 0.00
1207 ± 525 1890 ± 532* 0.00 1359 ± 639 1730 ± 569* 0.00
Quantitative data are expressed as mean ± SD. Paired t-test was used to evaluate single signs within each group. * p < 0.01 within each group before and after treatment.
3.2.2. Physical and instrumental examinations Body weight, abdominal circumference and 24-h urine volume were significantly reduced in both test and control groups (Table 6). However, differential values in body weight, abdominal circumference and urine volume between pre-treatment and post-treatment of the test group were greater than those of the control group (Table 7).
3.2.4. Ultrasound After treatment, in 47 patients of the test group, ascites was undetectable in 17 patients, mostly eliminated in 14 patients, partially decreased in 15 patients and barely reduced in 1 patient. In 45 patients of the control group, the numbers of the patients with different ascites volume are 9, 10, 16 and 10, respectively.
3.2.3. Laboratory tests Before treatment, there were no statistically significant differences in serum total bilirubin (TBil), serum albumin (Alb), or serum alanine aminotransferase activity (ALT) between the two groups. After treatment, participants in test group showed lower TBil and higher Alb, and there was no statistically significant difference in ALT. Patients in control group showed lower ALT, higher Alb but no statistically significant difference in TBil after treatment. There was no statistically significant difference in Alb or ALT between the two groups, but TBil was lower in the test group than in the control group (Table 8). For differential values of TBil, ALT and Alb between pre-treatment and post-treatment, the test group was not superior to the control one (Table 9), which indicated Xiaozhang Tie had a limited efficacy in promoting liver functions.
3.3. Efficacy evaluation Taking into account symptoms, signs and ultrasound, the efficacy in the test group was significantly superior to that in the control group with the rate of effective grades I and II of 63.3% and 38.0% in the test group and control group, respectively (Table 10). 3.4. Adverse reactions Skin rashes occurred in 4 patients, 2 in each group. The rashes disappeared 2 days after cataplasm treatment was paused and did not reappear during subsequent cataplasm treatment. General side reactions such as nausea or dizziness were not reported.
Table 7 Effects of Xiaozhang Tie on differences in body weight, abdominal circumference, and urine volume between pre-treatment and post-treatment in patients with cirrhotic ascites. Group Test Control p
n 47 45 –
Body weight (kg)
Abdominal circumference (cm)
Urine volume (ml)
8.7 ± 5.8** 5.3 ± 4.6 0.002
12.4 ± 8.3** 8.0 ± 6.5 0.006
683 ± 644* 372 ± 697 0.029
The quantitative data were expressed as the mean ± SD. Independent t-test was used to evaluate differential value between two groups. * p < 0.05 vs. the control group. ** p < 0.01 vs. the control group.
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Table 8 Effects of Xiaozhang Tie on liver function in patients with cirrhotic ascites. Group
n
Test
47
Before treatment After treatment
45
Before treatment After treatment
p (within the test group) Control p (within the control group) p (between two groups before treatment) p (between two groups after treatment)
TBil (mol/L)
ALT (U/L)
Alb (g/L)
44.4 ± 29.9 33.6 ± 29.4* , # 0.02 57.9 ± 59.8 55.8 ± 56.6 0.57 0.17 0.03
53.1 ± 64.7 40.2 ± 30.0 0.08 75.0 ± 121.9 43.5 ± 37.4* 0.03 0.28 0.65
27.6 ± 6.0 31.2 ± 5.2* 0.00 27.0 ± 6.3 29.2 ± 5.5* 0.00 0.65 0.08
The quantitative data were expressed as the mean ± SD. Paired t-test were adopted to compare single liver function parameter within each group and independent t-test to that between the test and control group. * p < 0.05 within each group before and after treatment. # p < 0.05 vs. the control group after treatment. Table 9 Effects of Xiaozhang Tie on differences of liver function between pre-treatment and post-treatment in patients with cirrhotic ascites. Group
n
TBil (mol/L)
ALT (IU/L)
Alb (g/L)
Test Control p
47 45
9.2 ± 25.1 3.7 ± 30.1 0.35
14.1 ± 53.2 32.3 ± 95.2 0.27
3.6 ± 4.3 2.1 ± 4.1 0.11
The quantitative data were expressed as the mean ± SD. Independent t-test was used to compare differences of liver function between pre-treatment and post-treatment in two groups.
4. Discussion In the study, the decreases in body weight, abdominal circumference and increases in urine output were greater in the test group than in the control one, as determined by differential values analysis. These data confirm that Xiaozhang Tie has therapeutic action in assisting the excretion of fluids and relieving abdominal distension, when used as adjuvant in reducing cirrhotic ascites volume and relieving patient symptoms. There is a long history in the search for effective management strategies against cirrhotic ascites. Among these explorations, many techniques and measures were invented and utilized clinically. For example, “head-out water immersion” was used in Europe and Asia in ancient times (Rim et al., 1997). Tapping of ascites was used in China more than 2000 years ago (Nanjing University of Chinese Medicine, 2006). Although current medications, including diuretics and albumin, are well developed, they cannot work in all situations. TCM has rich experiences in treating cirrhotic ascites, with oral administration or external treatment according to individualized principles. The oral decoctions are usually effective, but not acceptable by patients with large-volume ascites. The TCM external therapy, mainly with umbilical compress, has been used for a long time. In the famous work of the Ming Dynasty, Compendium of Materia Medica (Li, 1998), it is recorded that “edema and abdominal distension can be treated as follows: mash shanglugen [radix phytolaccae] firstly, add shexiang into the mash, then put the mixed mashes to the umbilicus and finally bind up with silk cloth.” In recent years, several herbal formulae for umbilical compress have been developed and put into practice to cure cirrhotic ascites, and the positive effects have been reported (Tong et al., 2003; Pan et al., 2004). Although these formulae use the common herbs such as shexiang (Moschus), mangxiao (Natrii sulfas), gansui
(Euphorbia kansui T.N. Liou ex T.P. Wang) and shanglugen (Radix phytolaccae), they are not fixed and manufactured with stringent quality control, and lack the evidence evaluated by randomized, controlled clinical trial (RCT). In particular, there is no patch or cataplasm product for clinical practice conveniently and consistently. Through more than 10 years of investigations, our research group developed a fixed formula (Xiaozhang Tie) as an external treatment for cirrhotic ascites, and made it into cataplasm with regular quality control. In this study, we conducted a RCT in order to evaluate the efficacy and safety of Xiaozhang Tie as an adjuvant in treating cirrhotic ascites and explore its characteristics. Skin rashes appeared in 4 patients, disappearing 2 days after pause of treatment. These rashes did not reappear when the umbilical compress therapy resumed. There were no negative side reactions such as nausea or dizziness in either test or placebo group, suggesting that Xiaozhang Tie is safe. Moreover, the efficacy of Xiaozhang Tie on cirrhotic ascites was confirmed by objective parameters such as reductions in ascites volume and body weight, as well as improvements in subjective symptoms like abdominal distention, etc. The mechanisms of action of Xiaozhang Tie remain to be determined. In the study, Xiaozhang Tie had no influence on the serum liver functions including albumin level, so the cataplasm may not act through increasing serum albumin, one of determining factors for ascites formation. However, we found that patients receiving the cataplasm compress had more flatus, especially in the earlier stage of treatment; patients passed more gases and showed less abdominal distension as well as better appetite. In our animal study (data not shown), Xiaozhang Tie showed better effect compared to placebo in reducing ascites and promoting gastrointestinal motility in carbon–tetrachloride-induced cirrhotic rats. It suggests that Xiaozhang Tie can promote gastrointestinal motility. In liver cirrhosis, the gastrointestinal motility disorders exist
Table 10 Efficacy of Xiaozhang Tie on patients with cirrhotic ascites. Group
n
Test Control
49 50
Effective grade I 17 8
Effective grade II
Effective grade III
Ineffective grade
Withdrawal
Rate of effective grades I and II
14 11
15 16
1 10
2 5
63.3%* 38.0%
ITT principle was employed and withdrawal cases were considered invalid. Ridit analysis was adopted. * p = 0.002 vs. the control group after treatment.
F. Xing et al. / Journal of Ethnopharmacology 139 (2012) 343–349
(Isobe et al., 1994), which can cause intestinal bacterial overgrowth and bacterial translocation, induce endotoxemia and activate the renin–angiotensin–aldosterone system, then contributing to the ˜ et al., formation of ascites (Morales-Ruiz et al., 1996; García-Estan 2002; Zong et al., 2003; Garcia-Tsao and Wiest, 2004). Therefore, we speculate that promoting the dispersal of ascites and relieving abdominal distension may be associated with improving gastrointestinal motility in cirrhotic patients. TCM theory recognizes that Qi is the commander of the body fluid and blood, and can promote the transportation of water ( ). Xiaozhang Tie is mainly composed of herbs with functions of motivating Qi, such as dahuang, laifuzi and shexiang. Therefore, the mechanism of Xiaozhang Tie can be explained as regulating the movement of Qi followed by excreting urine and dispelling excess water in the abdomen. Briefly, this study confirms that Xiaozhang Tie can decrease ascites and attenuate abdominal distention. The herbal cataplasm provides an adjuvant approach as an external treatment for cirrhotic ascites. Xiaozhang Tie could become a promising cataplasm product of herbal medicine, and be widely used in the comprehensive management of ascites due to cirrhosis and maybe other etiologies such as liver cancer. In the further investigations, we will study the efficacy of Xiaozhang Tie on uncomplicated and refractory cirrhotic ascites, so as to optimize its indications, and elucidate its precise mechanisms of action through more animal experiments and clinical studies. 5. Conclusion When applied as an adjuvant to primary therapy of cirrhotic ascites, Xiaozhang Tie is safe and shows remarkable efficacy in relieving abdominal distention through promoting the passage of gas and excretion of urine. Its mechanism of action may be related to regulating gastrointestinal motility. Acknowledgements This work was supported by Science and Technology Commission of Shanghai Municipality (07DZ19718), Program for Outstanding Medical Academic Leader of Shanghai Municipality (LJ10005), the Innovative Research Team in Universities of Shanghai Municipal Education Commission and the E-institute of Shanghai Municipal Education Commission (E03008). Leading Academic Discipline of Hepatology of State Administration of TCM China (No: 2010sh). References European Association for the Study of the Liver, 2010. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. Journal of Hepatology 53, 397–417.
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Ferenci, P., 1991. Hepatic encephalopathy. In: McIntyre, N., Benhamou, J.P., Bircher, J., Rizzetto, M., Rodés, J. (Eds.), Oxford Textbook of Clinical Hepatology, vol. 1. Oxford University Press, Oxford, pp. 473–483. ˜ J., Ortiz, M.C., Lee, S.S., 2002. Nitric oxide and renal and cardiac dysGarcía-Estan, function in cirrhosis. Clinical Science 102, 213–222. Garcia-Tsao, G., Wiest, R., 2004. Gut microflora in the pathogenesis of the complications of cirrhosis. Best Practice and Research: Clinical Gastroenterology 18, 353–372. Ginés, P., Quintero, E., Arroyo, V., Terés, J., Bruguera, M., Rimola, A., Caballería, J., Rodés, J., Rozman, C., 1987. Compensated cirrhosis: natural history and prognostic factors. Hepatology 7, 122–128. Isobe, H., Sakai, H., Satoh, M., Sakamoto, S., Nawata, H., 1994. Delayed gastric emptying in patients with liver cirrhosis. Digestive Diseases Sciences 39, 983–987. Li, S., 1998. Bencao Gangmu (Compendium of Materia Medica). China Press of Chinese Medicine, Beijing, p. 486 (Chinese). Liu, C., Zhang, Y., Feng, N., Cai, J., Xue, H., Shi, M., Chen, J., 2006. Effects of syndrome dependent umbilical sticking with Shizhang cataplasm and Xuzhang cataplasm in treating liver cirrhosis caused ascites. Chinese Journal of Integrated Traditional and Western Medicine 26, 411– 414 (Chinese). Morales-Ruiz, M., Jiménez, W., Pérez-Sala, D., Ros, J., Leivas, A., Lamas, S., Rivera, F., Arroyo, V., 1996. Increased nitric oxide synthase expression in arterial vessels of cirrhotic rats with ascites. Hepatology 24, 1481– 1486. Nanjing University of Chinese Medicine, 2006. Translation and Interpretation of the Lingshu Huangdi Neijing, 2nd ed. Shanghai Scientific and Technical Publisher, Shanghai (Translation and Interpretation of Spiritual Pivot, The Inner Canon of Huangdi/Yellow Emperor’s Inner Canon.). Pan, C., Zhang, Y., Cai, J., Liu, C., 2004. Umbilical sticking therapy of ascites due to cirrhosis. Chinese Journal of Integrated Traditional and Western Medicine on Liver Diseases 14, 126–128 (Chinese). Planas, R., Montoliu, S., Ballesté, B., Rivera, M., Miquel, M., Masnou, H., Galeras, J.A., Giménez, M.D., Santos, J., Cirera, I., Morillas, R.M., Coll, S., Solà, R., 2006. Natural history of patients hospitalized for management of cirrhotic ascites. Clinical Gastroenterology and Hepatology 4, 1385–1394. Review Group of Mawangdui Silk Texts, 1979. 52 Bingfang (Mawangdui Silk Texts Recipes for Fifty-Two Ailments). Cultural Relics Press, Beijing. Rim, H., Yun, Y.M., Lee, K.M., Kwak, J.T., Ahn, D.W., Choi, J.K., Kim, K.R., Joh, Y.D., Kim, J.Y., Park, Y.S., 1997. Effect of physical exercise on renal response to head-out water immersion. Applied Human Science 16, 35–43. Rimola, A., García-Tsao, G., Navasa, M., Piddock, L.J., Planas, R., Bernard, B., Inadomi, J.M., 2000. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club, Journal of Hepatology 32, 142–153. Santos, J., Planas, R., Pardo, A., Durández, R., Cabré, E., Morillas, R.M., Granada, M.L., Jiménez, J.A., Quintero, E., Gassull, M.A., 2003. Spironolactone alone or in combination with furosemide in the treatment of moderate ascites in nonazotemic cirrhosis. A randomized comparative study of efficacy and safety. Journal of Hepatology 39, 187–192. Schuppan, D., Afdhal, N.H., 2008. Liver cirrhosis. The Lancet 371, 838–851. Society of Digestive Disease, China Association of Integrated Medicine, 2004. Guidelines for diagnosis and treatment of cirrhosis in integrative medicine. Chinese Journal of Integrated Traditional and Western Medicine 24, 869–871 (Chinese). Society of Infectious Parasitic Diseases and Society of Liver Diseases, Chinese Medical Association, 2000. Guidelines for prevention and treatment of viral hepatitis. Chinese Journal of Hepatology 8, 324–329 (Chinese). Tong, G., Zhou, D., He, J., 2003. Clinical study of Shehuang paste paved on the umbilicus in the treatment of refractory ascites due to cirrhosis. Chinese Journal of Integrated Traditional and Western Medicine on Digestion 11, 290–292 (Chinese). Zong, Y., Wang, H., Li, C., Huai, Y., 2003. Abnormal gastric and small intestinal transition in patients with liver cirrhosis. Chinese Journal of Digestion 23, 352–354 (Chinese).
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Journal of Ethnopharmacology journal homepage: www.elsevier.com/locate/jethpharm
Effects of Chinese herbal cataplasm Xiaozhang Tie on cirrhotic ascites Feng Xing a,b,1 , Ye Tan a,b,1 , Guang-Jun Yan c , Jian-Jun Zhang d , Zhao-Hong Shi e , Shan-Zhong Tan f , Nian-Ping Feng g , Cheng-Hai Liu a,b,∗ a
Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai 201203, China Department of Infectious Diseases, Hubei Jingzhou Hospital of Traditional Chinese Medicine, Jingzhou 434000, China d Department of Infectious Diseases, Hubei Zhongshan Hospital, Wuhan 430033, China e Department of Gastroenterology, Wuhan No. 1 Hospital, Wuhan 430030, China f Department of Integrated Medicine, The Second Hospital of Nanjing, Nanjing 211103, China g Department of Pharmaceutics, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China b c
a r t i c l e
i n f o
Article history: Received 6 April 2011 Received in revised form 12 October 2011 Accepted 15 October 2011 Available online 17 November 2011 Keywords: Xiaozhang Tie Cataplasm Cirrhotic ascites Traditional Chinese medicine
a b s t r a c t Background: Conventional methods of treating cirrhotic ascites are inadequate. We sought to identify a novel, effective approach to relieve the suffering of patients with cirrhotic ascites. Aim of the study: To investigate the efficacy of Xiaozhang Tie, a traditional Chinese herbal cataplasm composed of dahuang (Rheum palmatum L.), laifuzi (Raphanus sativus L.), concocted gansui (Euphorbia kansui T.N. Liou ex T.P. Wang), chenxiang [Aquilaria sinensis (Lour.) Gilg], dingxiang (Eugenia caryophyllata Thunb.), bingpian (Borneolum syntheticum) and shexiang (artificial Moschus), as an adjuvant in treating cirrhotic ascites. Materials and methods: A multicenter, randomized, placebo-controlled trial was conducted. One hundred patients with cirrhotic ascites were divided into two groups of equal size. The test group took an umbilical compress with Xiaozhang Tie for 30 days while the control group was administered an umbilical compress with placebo, in addition to primary therapy. Efficacy was evaluated according to the criteria including ascites volume, urine 24-h volume, abdominal circumference, body weight, abdominal distention, appetite, flatus and defecation. Results: Ninety-two patients completed the study, 7 were withdrawn and 1 was excluded. The effective rate of grades I and II was 63.3% for the test group (n = 49) and 38.0% for the control one (n = 50). Both groups showed decreased body weight and abdominal circumference, increased urine volume and improved symptoms after treatment. However, the differences between pre-treatment and post-treatment in body weight, abdominal circumference and urine volume were 8.7 ± 5.8 kg, 12.4 ± 8.3 cm and 683 ± 644 ml respectively in the test group, noticeably higher than those in the control group, which were 5.3 ± 4.6 kg, 8.0 ± 6.5 cm and 372 ± 697 ml, respectively. The ranking orders of the symptoms of the test group were significantly lower than those of the control group after treatment. No severe adverse reactions were seen. Conclusion: Xiaozhang Tie as an adjuvant to primary therapy of cirrhotic ascites is safe and shows a remarkable efficacy on relieving abdominal distention. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Abbreviations: Alb, albumin; ALT, alanine aminotransferase; GCP, good clinical practice; ITT, intention to treat; RCT, randomized, controlled clinical trial; SBP, spontaneous bacterial peritonitis; SD, standard deviation; TBil, total billirubin; TCM, traditional Chinese medicine. ∗ Corresponding author at: 528 Zhangheng Road, Pudong New Area, Shanghai 201203, China. Tel.: +86 21 20256521; fax: +86 21 20256521. E-mail address: Chenghai [email protected] (C.-H. Liu). 1 These authors made equal contributions. 0378-8741/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jep.2011.10.040
Liver cirrhosis is the end stage of many chronic liver diseases. It has been showed that 10 years after diagnosis, the probability of developing decompensated cirrhosis is about 60%, and ascites is the most frequent complication (about 50%) (Ginés et al., 1987). Ascites, manifested by the accumulation of fluid in the peritoneal cavity, is the most common complication and cause of hospitalization of patients with cirrhosis. Ascites usually results from portal hypertension, albumin synthesis reduction and sodium retention, etc. (Planas et al., 2006). Cirrhotic ascites is associated with poor quality of life and a high risk of developing complications such
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as hepatorenal syndrome, spontaneous bacterial peritonitis (SBP), with increased morbidity and mortality (Rimola et al., 2000). Therefore, there is a clear rationale for better management of cirrhotic ascites that accompany cirrhosis. The management of cirrhotic ascites usually needs comprehensive measures: the primary treatment includes sodium-restricted diet, diuretics application and albumin infusion. (European Association for the Study of the Liver, 2010). These measures usually work for moderate ascites without any effects on refractory ascites (Santos et al., 2003), and diuretics could cause electrolyte disorders, renal failure, hepatic encephalopathy and other problems (Ferenci, 1991). The surgical methods, including large-volume paracentesis, transjugular intrahepatic portosystemic shunting, peritoneal venous shunting and liver transplantation, are very helpful for refractory ascites. Apart from the problems that most of these procedures involve high costs and expertise that is only available at certain facilities, there are the complications of post-operative infections, electrolyte disorders and circulatory dysfunction. Liver transplantation is further limited by the scarcity of suitable donors (Schuppan and Afdhal, 2008). More importantly, patients with ascites suffer from abdominal distension, caused by fluid retention or excess gas in stomach and intestine due to impaired gastrointestinal motility. The measures mentioned above cannot relieve abdominal distension effectively. Therefore, there remains a need to develop effective approaches to relieve the suffering of patients with cirrhotic ascites. Traditional Chinese medicine (TCM) has a long history and rich experiences in treating cirrhotic ascites and nowadays is widely applied in clinical practice as a complementary and alternative approach (Pan et al., 2004). Chinese herbal decoction is the common way of treating ascites, however, the fact that the patients with cirrhotic ascites have difficulty taking in food and water because of their abdominal distention and reduced gastric capacity can get in the way of the therapeutic efficacy of this approach. TCM external therapy, pasting the herbal mixture to the umbilicus, could overcome the difficulty of oral herbal decoction and may be directly effective on ascites. The umbilical compress with herbs is an ancient method in TCM practice with the advantages of convenience and economy. One example was firstly recorded 2000 years ago in the Wu Shi Er Bing Fang (Prescriptions for 52 Types of Diseases) in the pre-Qin Dynasty (Review group of Mawangdui silk texts, 1979). The Ben Cao Gang Mu (Compendium of Materia Medica) written by Li Shizhen in the Ming Dynasty described how to use umbilical compress against ascites in detail (Li, 1998). Over the past 10 years, our research group has tried to take advantage of the umbilical compress to treat cirrhotic ascites. Firstly we designed 2 formulae, shizhang recipe consisting of dahuang (Rheum palmatum L.), laifuzi (Raphanus sativus L.), gansui (Euphorbia kansui T.N. Liou ex T.P. Wang), chenxiang (Aquilaria sinensis (Lour.) Gilg), dingxiang (Eugenia caryophyllata Thunb.), bingpian (Borneolum syntheticum), shexiang (artificial Moschus), and xuzhang recipe consisting of huangqi (Astragalus membranaceus (Fisch.), Bge), fuzi (Aconitum carmichaeli Debx.), rougui (Cinnamomum cassia Presl), xiangfu (Cyperus rotundus L.), dingxiang (Eugenia caryophyllata Thunb.), bingpian (Borneolum syntheticum) and shexiang (artificial Moschus). Then we made them into cataplasms and observed the efficacy of shizhang and xuzhang cataplasms on cirrhotic ascites by umbilical compress for shi-syndrome and xu-syndrome patients, respectively. In this previous study, 242 patients were enrolled and divided into 4 groups: the shi-syndrome control and shi-syndrome test, xusyndrome control and xu-syndrome test. In addition to primary treatment with limited diuretics and sodium-restricted diet, the shi-syndrome and xu-syndrome test groups received the compress with shizhang cataplasm or xuzhang cataplasm on the umbilicus, respectively, while the control groups got placebo of cataplasm
without any herbs. Efficacy was evaluated according to the patient’s symptoms, body weight, abdominal circumference, urinary 24h volume, and ascites detected by ultrasound. Effective grading criteria are explained in Section 2.3. The herbal cataplasms were changed every 2 days and the treatment course was 30 days. At last 220 patients completed the full course, with 22 withdrawn. The results showed that compared to their respective controls, patients in both test groups had a decreased body weight, abdomen circumference and amount of ascites accompanying with increased urinary volume and flatus. The effective rates of grades I and II in the control and test groups were 37.5% and 72.2% in the xu-syndrome group and 39.5% and 75.0% in the shi-syndrome group (Liu et al., 2006 and author’s data not published). These results indicate that both herbal cataplasms have adjuvant effects in relieving abdominal distention by not only reducing ascites but also increasing gas passage, and the shizhang cataplasm is superior to the xuzhang cataplasm. Therefore, in the subsequent study, we focused on the shizhang cataplasm, further optimized the formula, fixed its manufacturing procedure with stringent quality control, and re-named it Xiaozhang Tie. Xiaozhang Tie was chosen to signify the cataplasm’s function of eliminating distension. In this study, we set up a randomized double-blind controlled clinical trial to evaluate the efficacy of Xiaozhang Tie as an adjuvant in treating cirrhotic ascites and to identify its characters in order to develop a helpful and reliable external therapy for cirrhotic ascites.
2. Materials and methods 2.1. Design, setting and participants A multicenter, double-blind, randomized, placebo-controlled clinical trial of 100 patients was conducted from November 2008 to September 2009. All patients came from the inpatient department of Shuguang Hospital Affiliated to Shanghai University of TCM, Wuhan No. 1 Hospital, Hubei Zhongshan Hospital, Hubei Jingzhou Hospital of TCM, and the Second Hospital of Nanjing. We recruited volunteers from inpatients. All practitioners committed adequate time to explaining the compositions, effects and adverse reactions of Xiaozhang Tie and our hypothesis about umbilical compress therapy and the primary treatment including diuretics and albumin. This study was conducted in accordance with the guidelines for human experimentation outlined in the Declaration of Helsinki and Declaration of Tokyo. The protocol of this study was approved by Ethics Committee of Shuguang Hospital Affiliated to Shanghai University of TCM and supported by State Administration of TCM. The purpose and protocol of this trial were explained to eligible patients. Patients entered into the protocol therapy after giving both oral and written informed consent before the study commenced. The participants were volunteers and received no pay. They were permitted to refuse treatment or quit any time on their own without penalty. Patients aged from 18 to 80 years, were diagnosed with cirrhotic ascites based on criterion established by the Chinese Medical Association Society of Infectious and Parasitic Diseases and Society of Liver Diseases in 2000 (Society of Infectious and Parasitic Diseases and Society of Liver Diseases, Chinese Medical Association, 2000). They all suffered from cirrhosis of decompensated stage (B/C grade of Child-Pugh classification) and their ascites was certified by abdominal ultrasound. All patients had no prior treatment for ascites. Laboratory assessment of liver function, renal function and electrolytes was also performed. Patients with psychosis, cancer (including liver tumors without hemorrhagic ascites), renal
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Table 1 The formula of Xiaozhang Tie (one dose). Drug name
Plant sources
Medicinal parts
Dosage (g)
Dahuang Laifuzi Gansui Chenxiang Dingxiang Borneolum syntheticum Artificial moschus
Rheum palmatum L. Raphanus sativus L. Euphorbia kansui T.N. Liou ex T.P. Wang Aquilaria sinensis (Lour.) Gilg Eugenia caryophyllata Thunb.
Rhizoma Seed Root Stem Flower bud
1 1 1 0.2 1 0.04 0.004
insufficiency, diabetes with unstable blood glucose or any serious diseases of the cardiovascular, respiratory, nervous or hematologic systems were not eligible. Lactation and pregnant women were also excluded. The participants were considered withdrawn from the study when the following situations occurred: patients quitted the treatment on their own but still had ascites; experienced serious complications including hepatic encephalopathy, hepatorenal syndrome, and gastrointestinal hemorrhage; took surgical methods for ascites such as large volume paracentesis and ascites ultrafiltration and reinfusion. All withdrawal cases received intention to treat (ITT) analysis. A randomized schedule was generated prior to the initiation of the study. Following signed informed consent, successful completion of screening evaluations, and satisfaction of all eligibility criteria, subjects were randomized in a 1:1 ratio to either the test or control group.
2.2. Intervention The formula of Xiaozhang Tie (one cataplasm, daily dosage) is presented in Table 1 and the manufacturing procedure was as follows: The mixture of powder preparations of dahuang (Rheum palmatum L.), laifuzi (Raphanus sativus L.) and gansui (Euphorbia kansui T.N. Liou ex T.P. Wang) was extracted successively two times with 10 folds of 75% ethanol under reflux. The 75% ethanol extract was then filtered through absorbent gauze, and the filtrate was concentrated under reduced pressure to remove ethanol and then dried to produce the extract powder. The volatile oil was exacted from the dingxiang (Eugenia caryophyllata Thunb.) by steam distillation. Finally, the extract powder, volatile oil, borneolum syntheticum and artificial moschus were made into cream with the excipients, such as plasdone K-90, viscomate NP700, polyplasdone XL-10. The cream was coated onto rubberized fabric and the resulting plaster was cut into small pieces (7 cm × 7 cm). Each cataplasm contained at least 0.42 mg emodin and 18.0 mg borneol, according to the requirements of medicinal paste detailed in the Pharmacopoeia of the People’s Republic of China. These values roughly correspond to pharmaceutical quality standards currently under investigation by pharmaceutical
experts from Department of Pharmaceutics, Shanghai University of TCM. The manufacturing procedure of placebo cataplasm was the same as that of Xiaozhang Tie, and the placebo contained all of the excipients that were used in Xiaozhang Tie without herbs. All participants received the primary therapies as follows: (1) Diuretics: Spironolactone was administered orally at a dose of no more than 100 mg per day and Furosemide was administered orally at a dose of no more than 40 mg per day. (2) Hepatoprotectives: Silymarin (140 mg bid) or Fuzhenghuayu capsules (1.5 g tid) were available as an option. (3) Human serum albumin was administered intravenously at a dose of 10 g biw to patients whose serum albumin was less than 25 g/L. (4) Intravenous antibiotics (Cefotaxime 2 g q12 h or Ceftriaxone 2 g q12 h for 7 days) were used in patients who were diagnosed with SBP. The patients in the test group or the control group were treated with primary therapies plus Xiaozhang Tie or placebo. Umbilical compress therapy was performed as follows: After cleaning and disinfecting the umbilical region of patients, the Xiaozhang Tie (7 cm × 7 cm) or placebo was compressed directly on the umbilicus and changed once a day. The research staff who administered the cataplasms applied good clinical practices (GCP). The course of treatment lasted 30 days. If ascites were eliminated before the full course was complete, the treatment was terminated in advance. Xiaozhang Tie and placebo cataplasms were revealed to the research staff only after statistical analysis was completed. The research staff was prepared to take therapeutic measures in the case of any allergic or other adverse reactions. The participants will be early terminated if severe adverse reactions occurred. All adverse reactions were recorded.
2.3. Measurements of outcome Clinical symptoms including abdominal distention, appetite, flatus and defecation were observed and recorded daily according to the symptom scale table (Table 2). Physical and instrumental examinations were performed as follows: (1) Ascites: Ascites was examined by ultrasound under the same anthropometric position pre-treatment, during the second week of treatment, and post-treatment (3 times totally) with the
Table 2 Symptom scale table. Grade I
Grade II
Grade III
Grade IV
Abdominal distension
None
Relieved while lying supine, affects daily living and diet
Continuous and unbearable
Appetite Flatus
Normal >4 times per day
Bearable, does not affect daily living or diet Reduced <1/3 2–3 times per day
Defecation
1–2 times per day, unobstructed and formed
1 time per day, a little hard or shapeless
Reduced >1/3 ≤1 time per day, tympanitic note upon abdominal percussion 1 time every 2–3 days and dry or 2 times per day and shapeless
Reduced >1/2 Little, obvious tympanitic note upon abdominal percussion <1 time every 3 days or 3 times per day and shapeless
The scale table was formulated by practitioners from 5 hospitals. Symptom scores were estimated using information supplied by patients or their dependents and the variations in symptoms were recorded daily.
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same apparatus and by the same practitioner. (2) Urine volume: Urine 24-h volume was measured using the same graduated cylinder and recorded every day. (3) Abdominal circumference: Maximum abdominal circumference was measured with the patient supine using the same ruler and recorded every morning. (4) Body weight: Body weight was measured using the same scale every morning. Laboratory tests including liver function, renal function and electrolyte were performed by an automatic biochemical analyzer pre-treatment, during the 2nd week of treatment and posttreatment (3 times totally). Efficacy was evaluated according to the modified grading criterion established in 2004 by the China Association of Integrated Medicine’s Society of Digestive Disease (Society of Digestive Disease and China Association of Integrated Medicine, 2004): (1) Effective grade I: Ascites was undetectable by ultrasound. Clinical symptoms were improved as grade I. Body weight returned to normal. (2) Effective grade II: Ascites was mostly eliminated, appearing ≥50% reduced by ultrasound. Clinical symptoms were improved to grade II. Body weight was reduced ≥2 kg or the abdominal circumference was reduced ≥5 cm. (3) Effective grade III: Ascites was partially eliminated, appearing <50% reduced by ultrasound. Clinical symptoms were improved to grade III. Body weight was reduced <2 kg or abdominal circumference was reduced <5 cm. (4) Ineffective grade: Ascites was not reduced. Clinical symptoms were not clearly improved. There was no obvious change in body weight or abdominal circumference. 2.4. Statistical analysis Quantitative data are expressed as mean ± SD. The differences in quantitative variables within each group and between two groups such as age, urine volume, abdominal circumference, body weight and liver function were compared with paired t-test or independent t-test. Rank-sum test was used to compare the symptom scores between the two groups before or after treatment, and the
difference of symptom scores between pre-treatment and posttreatment. The chi-square test and ridit analysis were used for categorical variables, such as sex distribution and the gradations of curative effect. p < 0.05 was considered statistically significant. The ITT principle was employed in comparing efficacy rates. All statistical analyses were performed with the SPSS software package.
3. Results 3.1. Participant profiles Of the 100 patients enrolled, 7 withdrew. After enrollment, another patient was excluded from the test group after being diagnosed with tuberculosis peritonitis. Eventually, 92 patients including 47 patients in the test group and 45 patients in the control one completed the study. The baseline characteristics of the patients are shown in Table 3. The 92 patients included in the analysis, 57 men and 35 women, had an average age of 58 (range: 37–80). The two groups were comparable at entry with regard to age, gender, clinical features, vital signs, hematological data, seriousness of illness and number of days hospitalized.
3.2. Treatment outcomes 3.2.1. Clinical symptoms Patients in the control group were treated with placebo and primary therapy, such as diuretic and hepatoprotective agents, while patients in the test group were treated with primary therapy and Xiaozhang Tie. Before treatment, there were no statistical differences in abdominal distention, appetite, flatus and defecation between the two groups. After treatment, patients in both groups showed improvement in all symptoms (Table 4). However, the statistical rank orders of the symptoms in the test group were significantly lower than those of the control group after treatment, which suggests that primary therapy combined with Xiaozhang Tie is superior to primary therapy plus placebo (Table 5).
Table 3 Patient characteristics.
General data
Etiology
Biochemical
Cases (enrolled/completed/withdrawn/excluded) Sex (M/F) Average age (range) Average number of days hospitalized (range) Chronic hepatitis B Schistosomiasis Alcohol Primary biliary cirrhosis Chronic hepatitis C Drug use Autoimmune hepatitis Chronic hepatitis B and schistosomiasis Chronic hepatitis B and alcohol Chronic hepatitis B and drug use Cryptogenic ALT (U/L) (range) Alb (g/L) (range) TBil (mol/L) (range)
Test
Control
50/47 /2/1 27/20♦ 58.5 ± 9.9 (37–80) 18.8 ± 7.8 (6–30) 33 4 3 3 1 0 0 1 1 0 1 53.1 ± 64.7夽 (10.2–439.9) 27.6 ± 6.0 (17.0–40.1) 44.4 ± 29.9# (7.3–138.0)
50/45/5/0 30/15 58.3 ± 9.8 (39–79) 19.0 ± 7.4 (7–30) 30 3 3 1 1 1 1 3 0 1 1 75.0 ± 121.9 (12.3–668.8) 27.0 ± 6.3 (15.0–42.7) 57.9 ± 59.8 (7.0–348.3)
Quantitative data are expressed as mean ± SD. Chi-square testing was used in comparisons of case number and sex. Independent t-test was used in comparisons of age, TBil, ALT, Alb, and number of hospitalization days. p = 0.57 vs. the control group. ♦ p = 0.34 vs. the control group. p = 0.89 vs. the control group. p = 0.87 vs. the control group. 夽 p = 0.28 vs. the control group. p = 0.65 vs. the control group. # p = 0.17 vs. the control group.
F. Xing et al. / Journal of Ethnopharmacology 139 (2012) 343–349
347
Table 4 Effects of Xiaozhang Tie on differences of clinical symptom scores between pre-treatment and post-treatment in patients with cirrhotic ascites. Group
n
Abdominal distension
Appetite
Flatus
Defecation
Test p Control p
47
−5.65* 0.00 −3.66* 0.00
−5.69* 0.00 −3.53* 0.00
−5.61* 0.00 −3.23* 0.00
−5.69* 0.00 −3.08* 0.00
45
Values are expressed as the pre-treatment score subtracted from the post-treatment score. The rank-sum test used to evaluate single symptoms within each group. * p < 0.01 within each group before and after treatment. Table 5 Effects of Xiaozhang Tie on clinical symptom scores of patients with cirrhotic ascites (rank orders). Group
Test Control p
n
Before treatment
47 45 –
After treatment
Abdominal distension
Appetite
Flatus
Defecation
Abdominal distension
Appetite
Flatus
Defecation
45.16 47.90 0.56
46.36 46.64 0.95
47.67 45.28 0.61
46.74 46.24 0.91
40.44* 52.83 0.02
40.18* 53.10 0.01
39.97* 53.32 0.01
39.99* 53.30 0.01
Values are expressed as rank order before and after treatment. Rank-sum testing was used to evaluate rank order of single symptoms between the two groups. * p < 0.05 between the two groups after treatment. Table 6 Effects of Xiaozhang Tie on body weight, abdominal circumference, and urine volume in patients with cirrhotic ascites. Group
n
Test
47
p
–
Control
45
p
–
Before treatment After treatment – Before treatment After treatment –
Body weight (kg)
Abdominal circumference (cm)
Urine volume (ml)
70.9 ± 12.2 62.2 ± 11.2* 0.00 69.4 ± 11.3 64.1 ± 10.6* 0.00
94.8 ± 11.4 82.6 ± 7.5* 0.00 93.3 ± 10.4 85.2 ± 10.3* 0.00
1207 ± 525 1890 ± 532* 0.00 1359 ± 639 1730 ± 569* 0.00
Quantitative data are expressed as mean ± SD. Paired t-test was used to evaluate single signs within each group. * p < 0.01 within each group before and after treatment.
3.2.2. Physical and instrumental examinations Body weight, abdominal circumference and 24-h urine volume were significantly reduced in both test and control groups (Table 6). However, differential values in body weight, abdominal circumference and urine volume between pre-treatment and post-treatment of the test group were greater than those of the control group (Table 7).
3.2.4. Ultrasound After treatment, in 47 patients of the test group, ascites was undetectable in 17 patients, mostly eliminated in 14 patients, partially decreased in 15 patients and barely reduced in 1 patient. In 45 patients of the control group, the numbers of the patients with different ascites volume are 9, 10, 16 and 10, respectively.
3.2.3. Laboratory tests Before treatment, there were no statistically significant differences in serum total bilirubin (TBil), serum albumin (Alb), or serum alanine aminotransferase activity (ALT) between the two groups. After treatment, participants in test group showed lower TBil and higher Alb, and there was no statistically significant difference in ALT. Patients in control group showed lower ALT, higher Alb but no statistically significant difference in TBil after treatment. There was no statistically significant difference in Alb or ALT between the two groups, but TBil was lower in the test group than in the control group (Table 8). For differential values of TBil, ALT and Alb between pre-treatment and post-treatment, the test group was not superior to the control one (Table 9), which indicated Xiaozhang Tie had a limited efficacy in promoting liver functions.
3.3. Efficacy evaluation Taking into account symptoms, signs and ultrasound, the efficacy in the test group was significantly superior to that in the control group with the rate of effective grades I and II of 63.3% and 38.0% in the test group and control group, respectively (Table 10). 3.4. Adverse reactions Skin rashes occurred in 4 patients, 2 in each group. The rashes disappeared 2 days after cataplasm treatment was paused and did not reappear during subsequent cataplasm treatment. General side reactions such as nausea or dizziness were not reported.
Table 7 Effects of Xiaozhang Tie on differences in body weight, abdominal circumference, and urine volume between pre-treatment and post-treatment in patients with cirrhotic ascites. Group Test Control p
n 47 45 –
Body weight (kg)
Abdominal circumference (cm)
Urine volume (ml)
8.7 ± 5.8** 5.3 ± 4.6 0.002
12.4 ± 8.3** 8.0 ± 6.5 0.006
683 ± 644* 372 ± 697 0.029
The quantitative data were expressed as the mean ± SD. Independent t-test was used to evaluate differential value between two groups. * p < 0.05 vs. the control group. ** p < 0.01 vs. the control group.
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F. Xing et al. / Journal of Ethnopharmacology 139 (2012) 343–349
Table 8 Effects of Xiaozhang Tie on liver function in patients with cirrhotic ascites. Group
n
Test
47
Before treatment After treatment
45
Before treatment After treatment
p (within the test group) Control p (within the control group) p (between two groups before treatment) p (between two groups after treatment)
TBil (mol/L)
ALT (U/L)
Alb (g/L)
44.4 ± 29.9 33.6 ± 29.4* , # 0.02 57.9 ± 59.8 55.8 ± 56.6 0.57 0.17 0.03
53.1 ± 64.7 40.2 ± 30.0 0.08 75.0 ± 121.9 43.5 ± 37.4* 0.03 0.28 0.65
27.6 ± 6.0 31.2 ± 5.2* 0.00 27.0 ± 6.3 29.2 ± 5.5* 0.00 0.65 0.08
The quantitative data were expressed as the mean ± SD. Paired t-test were adopted to compare single liver function parameter within each group and independent t-test to that between the test and control group. * p < 0.05 within each group before and after treatment. # p < 0.05 vs. the control group after treatment. Table 9 Effects of Xiaozhang Tie on differences of liver function between pre-treatment and post-treatment in patients with cirrhotic ascites. Group
n
TBil (mol/L)
ALT (IU/L)
Alb (g/L)
Test Control p
47 45
9.2 ± 25.1 3.7 ± 30.1 0.35
14.1 ± 53.2 32.3 ± 95.2 0.27
3.6 ± 4.3 2.1 ± 4.1 0.11
The quantitative data were expressed as the mean ± SD. Independent t-test was used to compare differences of liver function between pre-treatment and post-treatment in two groups.
4. Discussion In the study, the decreases in body weight, abdominal circumference and increases in urine output were greater in the test group than in the control one, as determined by differential values analysis. These data confirm that Xiaozhang Tie has therapeutic action in assisting the excretion of fluids and relieving abdominal distension, when used as adjuvant in reducing cirrhotic ascites volume and relieving patient symptoms. There is a long history in the search for effective management strategies against cirrhotic ascites. Among these explorations, many techniques and measures were invented and utilized clinically. For example, “head-out water immersion” was used in Europe and Asia in ancient times (Rim et al., 1997). Tapping of ascites was used in China more than 2000 years ago (Nanjing University of Chinese Medicine, 2006). Although current medications, including diuretics and albumin, are well developed, they cannot work in all situations. TCM has rich experiences in treating cirrhotic ascites, with oral administration or external treatment according to individualized principles. The oral decoctions are usually effective, but not acceptable by patients with large-volume ascites. The TCM external therapy, mainly with umbilical compress, has been used for a long time. In the famous work of the Ming Dynasty, Compendium of Materia Medica (Li, 1998), it is recorded that “edema and abdominal distension can be treated as follows: mash shanglugen [radix phytolaccae] firstly, add shexiang into the mash, then put the mixed mashes to the umbilicus and finally bind up with silk cloth.” In recent years, several herbal formulae for umbilical compress have been developed and put into practice to cure cirrhotic ascites, and the positive effects have been reported (Tong et al., 2003; Pan et al., 2004). Although these formulae use the common herbs such as shexiang (Moschus), mangxiao (Natrii sulfas), gansui
(Euphorbia kansui T.N. Liou ex T.P. Wang) and shanglugen (Radix phytolaccae), they are not fixed and manufactured with stringent quality control, and lack the evidence evaluated by randomized, controlled clinical trial (RCT). In particular, there is no patch or cataplasm product for clinical practice conveniently and consistently. Through more than 10 years of investigations, our research group developed a fixed formula (Xiaozhang Tie) as an external treatment for cirrhotic ascites, and made it into cataplasm with regular quality control. In this study, we conducted a RCT in order to evaluate the efficacy and safety of Xiaozhang Tie as an adjuvant in treating cirrhotic ascites and explore its characteristics. Skin rashes appeared in 4 patients, disappearing 2 days after pause of treatment. These rashes did not reappear when the umbilical compress therapy resumed. There were no negative side reactions such as nausea or dizziness in either test or placebo group, suggesting that Xiaozhang Tie is safe. Moreover, the efficacy of Xiaozhang Tie on cirrhotic ascites was confirmed by objective parameters such as reductions in ascites volume and body weight, as well as improvements in subjective symptoms like abdominal distention, etc. The mechanisms of action of Xiaozhang Tie remain to be determined. In the study, Xiaozhang Tie had no influence on the serum liver functions including albumin level, so the cataplasm may not act through increasing serum albumin, one of determining factors for ascites formation. However, we found that patients receiving the cataplasm compress had more flatus, especially in the earlier stage of treatment; patients passed more gases and showed less abdominal distension as well as better appetite. In our animal study (data not shown), Xiaozhang Tie showed better effect compared to placebo in reducing ascites and promoting gastrointestinal motility in carbon–tetrachloride-induced cirrhotic rats. It suggests that Xiaozhang Tie can promote gastrointestinal motility. In liver cirrhosis, the gastrointestinal motility disorders exist
Table 10 Efficacy of Xiaozhang Tie on patients with cirrhotic ascites. Group
n
Test Control
49 50
Effective grade I 17 8
Effective grade II
Effective grade III
Ineffective grade
Withdrawal
Rate of effective grades I and II
14 11
15 16
1 10
2 5
63.3%* 38.0%
ITT principle was employed and withdrawal cases were considered invalid. Ridit analysis was adopted. * p = 0.002 vs. the control group after treatment.
F. Xing et al. / Journal of Ethnopharmacology 139 (2012) 343–349
(Isobe et al., 1994), which can cause intestinal bacterial overgrowth and bacterial translocation, induce endotoxemia and activate the renin–angiotensin–aldosterone system, then contributing to the ˜ et al., formation of ascites (Morales-Ruiz et al., 1996; García-Estan 2002; Zong et al., 2003; Garcia-Tsao and Wiest, 2004). Therefore, we speculate that promoting the dispersal of ascites and relieving abdominal distension may be associated with improving gastrointestinal motility in cirrhotic patients. TCM theory recognizes that Qi is the commander of the body fluid and blood, and can promote the transportation of water ( ). Xiaozhang Tie is mainly composed of herbs with functions of motivating Qi, such as dahuang, laifuzi and shexiang. Therefore, the mechanism of Xiaozhang Tie can be explained as regulating the movement of Qi followed by excreting urine and dispelling excess water in the abdomen. Briefly, this study confirms that Xiaozhang Tie can decrease ascites and attenuate abdominal distention. The herbal cataplasm provides an adjuvant approach as an external treatment for cirrhotic ascites. Xiaozhang Tie could become a promising cataplasm product of herbal medicine, and be widely used in the comprehensive management of ascites due to cirrhosis and maybe other etiologies such as liver cancer. In the further investigations, we will study the efficacy of Xiaozhang Tie on uncomplicated and refractory cirrhotic ascites, so as to optimize its indications, and elucidate its precise mechanisms of action through more animal experiments and clinical studies. 5. Conclusion When applied as an adjuvant to primary therapy of cirrhotic ascites, Xiaozhang Tie is safe and shows remarkable efficacy in relieving abdominal distention through promoting the passage of gas and excretion of urine. Its mechanism of action may be related to regulating gastrointestinal motility. Acknowledgements This work was supported by Science and Technology Commission of Shanghai Municipality (07DZ19718), Program for Outstanding Medical Academic Leader of Shanghai Municipality (LJ10005), the Innovative Research Team in Universities of Shanghai Municipal Education Commission and the E-institute of Shanghai Municipal Education Commission (E03008). Leading Academic Discipline of Hepatology of State Administration of TCM China (No: 2010sh). References European Association for the Study of the Liver, 2010. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. Journal of Hepatology 53, 397–417.
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