Résumé
This study combined the herbal pair Platycodonis Radix-Curcumae Rhizoma(PR-CR) possessing an inhibitory effect on tumor cell proliferation and metastasis with the active component of traditional Chinese medicine(TCM) silibinin-loaded nanoparticles(NPs) with a regulatory effect on tumor microenvironment based on the joint effect on tumor cells and tumor microenvironment to inhi-bit cell metastasis. The effects of PR-CR on the cellular uptake of NPs and in vitro inhibition against breast cancer proliferation and metastasis were investigated to provide an experimental basis for improving nanoparticle absorption and enhancing therapeutic effects. Silibinin-loaded lipid-polymer nanoparticles(LPNs) were prepared by the nanoprecipitation method and characterized by transmission electron microscopy. The NPs were spherical or quasi-spherical in shape with obvious core-shell structure. The mean particle size was 107.4 nm, Zeta potential was-27.53 mV. The cellular uptake assay was performed by in vitro Caco-2/E12 coculture cell model and confocal laser scanning microscopy(CLSM), and the results indicated that PR-CR could promote the uptake of NPs. Further, in situ intestinal absorption assay by the CLSM vertical scanning approach showed that PR-CR could promote the absorption of NPs in the enterocytes of mice. The inhibitory effect of NPs on the proliferation and migration of 4T1 cells was analyzed using 4T1 breast cancer cells and co-cultured 4T1/WML2 cells, respectively. The results of the CCK8 assay showed that PR-CR-containing NPs could enhance the inhibition against the proliferation of 4T1 breast cancer cells. The wound healing assay indicated that PR-CR-containing NPs enhanced the inhibition against the migration of 4T1 breast cancer cells. This study enriches the research on oral absorption of TCM NPs and also provides a new idea for utilizing the advantages of TCM to inhibit breast cancer metastasis.
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Humains , Souris , Animaux , Femelle , Silymarine/usage thérapeutique , Cellules Caco-2 , Polymères/composition chimique , Nanoparticules/composition chimique , Lignée cellulaire tumorale , Tumeurs du sein/anatomopathologie , Microenvironnement tumoralRésumé
The purpose of this study was to explore the effect and mechanism of Xihuang Pills on rats with precancerous lesions of the breast. Of 48 healthy female rats, 8 were randomly selected as blank group, and the other 40 were treated with 7,12-dimethylbenzanthracene(DMBA) combined with estrogen and progestin to establish a model of precancerous lesions of the breast. The successfully modeled rats were randomly divided into a model group, a tamoxifen group(1.8 mg·kg~(-1)·d~(-1)), a Xihuang Pills low-dose group(0.3 g·kg~(-1)·d~(-1)), a medium-dose group(0.6 g·kg~(-1)·d~(-1)) and a high-dose group(1.2 g·kg~(-1)·d~(-1)). After 30 days of admi-nistration, the histopathological changes of viscera and breast were observed by haematoxylin and eosin(HE) staining, and the visceral index was calculated. Enzyme linked immunosorbent assay(ELISA) was used to detect the contents of estradiol(E_2) and progesterone(P) in serum. The protein expressions of vascular endothelial growth factor(VEGF) and fibroblast growth factor 2(FGF2) were detected by immunohistochemistry. The protein expressions of VEGF, vascular endothelial growth factor receptor 2(VEGFR2), phosphorylated-vascular endothelial growth factor receptor 2(p-VEGFR2), B-cell lymphoma-2(Bcl-2), and Bcl-2 associated X protein(Bax) were detected by Western blot and the mRNA expressions of VEGF, FGF2, CXC-chemokine receptor 4(CXCR4), cysteine aspartic acid-specific protease(caspase-3), and stromal cell-derived factor 1(SDF-1) were detected by real-time polymerase chain reaction(RT-PCR). HE staining revealed that the model group had some liver and kidney damages and severe hyperplastic mammary tissue, while the Xihuang Pills high-dose group had mild hyperplasia. Compared with the model group, the Xihuang Pills groups had lo-wer ovarian coefficient(P<0.05 or P<0.01) and Xihuang Pills high-dose group had lower uterine coefficient(P<0.01). ELISA results showed that compared with the model group, expressions of E_2 and P in Xihuang Pills high-dose group were significantly decreased(P<0.05 or P<0.01). Immunohistochemistry, Western blot and RT-PCR indicated that compared with the conditions in the model group, the protein and mRNA expressions of VEGF and FGF2 in the Xihuang Pills groups were down-regulated(P<0.05 or P<0.01), and the protein expression of Bcl-2 was lowered(P<0.01); there was a decrease in the protein expressions of VEGFR2 and p-VEGFR2(P<0.01), a down-regulation in the mRNA expressions of CXCR4 and SDF-1(P<0.01), while an increase in the mRNA expression of caspase-3(P<0.01) in both Xihuang Pills medium-dose and high-dose groups; the protein expression of Bax in Xihuang Pills high-dose group was increased(P<0.01). The above results indicated that Xihuang Pills can effectively intervene in precance-rous lesions of the breast, and the mechanism may be related to the regulation of E_2 and P secretion as well as the inhibition of angiogenesis and chemokine receptor expression, thus controlling the occurrence of precancerous lesions of the breast in rats.
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Rats , Femelle , Animaux , Rat Sprague-Dawley , Protéine Bax , Facteur de croissance endothéliale vasculaire de type A/métabolisme , Caspase-3 , Récepteur-2 au facteur croissance endothéliale vasculaire , Facteur de croissance fibroblastique de type 2 , Protéines proto-oncogènes c-bcl-2 , 7,12-Diméthyl-benzo[a]anthracène/toxicité , États précancéreux , Hyperplasie , Récepteurs aux chimiokines , ARN messagerRésumé
The UPLC-MS/MS was established for the determination of acetyl-11-keto-beta-boswellic acid(AKBA) and β-boswellic acid(β-BA), the main active components of Olibanum and Myrrha extracts in Xihuang Formula, in rat plasma and urine. The effects of compatibility on the pharmacokinetic behaviors of AKBA and β-BA in rats were investigated, and the differences in pharmacokinetic behaviors between healthy rats and rats with precancerous lesions of breast cancer were compared. The results showed that compared with RM-NH and RM-SH groups, the AUC_(0-t) and AUC_(0-∞) of β-BA increased(P<0.05 or P<0.01), T_(max) decreased(P<0.05 or P<0.01), and C_(max) increased(P<0.01) after compatibility. The trends of AKBA and β-BA were the same. Compared with RM-SH group, the T_(max) decreased(P<0.05), C_(max) increased(P<0.01), and the absorption rate increased in the normal group of Xihuang Formula. The results of urinary excretion showed that there was a decreasing trend in the urinary excretion rate and total urinary excretion of β-BA and AKBA after compatibility, but there was no statistical difference. Compared with normal group of Xihuang Formula, the AUC_(0-t) and AUC_(0-∞) of β-BA increased(P<0.05), T_(max) increased(P<0.05), and the clearance rate decreased in the breast precancerous lesion group. AUC_(0-t) and AUC_(0-∞) of AKBA showed an increasing trend, the in vivo retention time was prolonged, and the clearance rate was reduced, but there was no significant difference compared with the normal group. The cumulative urinary excretion and urinary excretion rate of β-BA and AKBA decreased under pathological conditions, indicating that pathological conditions could affect the in vivo process of β-BA and AKBA, and reduce their excretion in the form of prototype drugs, showing different pharmacokine-tic characteristics from normal physiological conditions. In this study, UPLC-MS/MS analysis method was established, which was sui-table for in vivo pharmacokinetic analysis of β-BA and AKBA. This study laid a foundation for the development of new dosage forms of Xihuang Formula.
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Rats , Animaux , Chromatographie en phase liquide , Spectrométrie de masse en tandem , Médicaments issus de plantes chinoises , États précancéreux , Triterpènes/pharmacologieRésumé
We used metabolomics technology to identify and understand the biomarkers and therapeutic mechanisms of umbilical compress therapy based on Xiaozhang Tie (XT) to provide scientific evidence for its clinical application. A total of 10 patients with cirrhotic ascites and gastrointestinal motility disorders who were hospitalized in the Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from November 2017 to June 2018 were divided into a placebo group (4 cases) or an XT group (5 cases), and 10 healthy volunteers were included as controls. This clinical trial was approved according to the Ethics Committee of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (2017-528-11-01). The patients in the XT group were given umbilical compress therapy with Xiaozhang Tie, and patients in the placebo group were administered a plaster patch in which the drug content was less than 5%, receiving one patch per day for three consecutive days. Non-targeted metabolomics technology and UPLC-Q/Orbitrap-MS/MS analysis technology were utilized to investigate the fluctuations in endogenous metabolic profiles in the patient's urine prior to and after administration of XT. By analyzing and comparing the urine metabolic profiles of patients with cirrhotic ascites to those of healthy volunteers, a total of 31 biomarkers were identified, 14 of which were significantly decreased by the intervention with Xiaozhang Tie (P <0.05). Pathway enrichment analysis revealed that phenylalanine metabolism and tryptophan metabolism are key pathways affected by XT treatment. The results suggest that XT can alleviate cirrhotic ascites by modulating abnormalities in amino acid metabolism.
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In this paper, co-processed lactose SuperTab 40 LL was selected as fillers to study the preparation of musk sustained-release mini-tablets in the Xihuang multiple-unit drug release system. Musk sustained-release tablets containing different proportions of SuperTab 40 LL and MCC were prepared under various pressures, and then the compressibility and compactibility of these prescriptions were evaluated by Walker, Heckel and Ryshkewitch-Duckworth equations. In addition, the fluidity of the prescriptions was evaluated by parameters of Kawakita equation. There was a comprehensive analysis of the effect of SuperTab 40 LL on musk sustained-release mini-tablets combined with the appearance of SuperTab 40 LL and their tensile strength. The results shown that SuperTab 40 LL had better compression process through the Heckel equation, and the direct compression process of drug powders with excipients can be analyzed by the Kawakita and Ryshkewitch-Duckworth equations. As a new type of co-processed lactose, SuperTab 40 LL had a good fluidity and compactibility. SuperTab 40 LL may undergo particle crushing and plastic deformation during the compression process, which increased the contact area and bonding sites between the particles, and aggregated and shaped the mixed powder easy. Moreover, MCC showed a synergistic effect, and the combined application with SuperTab 40 ll could effectively improve the fluidity and compressibility of the musk sustained-release powder. When the ratio of SuperTab 40 LL and MCC was 2∶1, musk sustained-release mini-tablets had a high drug loading capacity and good compactibility in line with the design objectives.
Sujets)
Préparations à action retardée , Préparation de médicament , Excipients , Acides gras monoinsaturés , Modèles théoriques , Poudres , ComprimésRésumé
Hot melt pressure-sensitive adhesive(HMPSA) has broad application potential in the field of traditional Chinese medicine(TCM) plasters due to its high drug loading, weak skin irritation, satisfactory adhesion, etc. compared with rubber plasters.However, the structure of HMPSA is prone to suffer from the damage caused by volatile oils in TCM plasters. In view of this, a kind of HMPSA with a stable structure was prepared by physical blending of DINCH, polypropylene wax and liquid rubber(LIR) in the present study, which is denoted as DPL. The dosage of cinnamon volatile oil(CVO), the model drug, was selected with viscosity, softening point and cohesion as evaluation indexes. The interaction between DPL and HMPSA was investigated by Fourier transform infrared spectroscopy(FT-IR) and differential scanning calorimetry(DSC). The compatibility of HMPSA with CVO and its transdermal ability were studied by in vitro transdermal test, adhesion, scanning electron microscopy( SEM) and rheological evaluation. The results showed that 5% CVO began to damage the structure of HMPSA. The initial adhesion and holding adhesion of DPL-modified HMPSA(DPL-HMPSA) were not significantly changed compared with those of HMPSA, whereas the 180° peel strength was decreased. FI-IR unraveled that DPL formed the n-π conjugated system with styrene-isoprene-styrene block copolymer(SIS), and there was no significant difference in the glass transition temperature according to DSC results, which indicated the good compatibility of DPL with HMPSA. With 5% CVO loaded, the drug content of DPL-HMPSA was 1. 14 times higher than that of HMPSA, and the decrease rate of drug content in DPL-HMPSA was 16% lower than that in HMPSA after 3 months. SEM demonstrated that CVO did not cause obvious structural damage to DPL-HMPSA. Rheological evaluation revealed that the storage modulus and loss factor of DPL-HMPSA were higher than those of HMPSA, and the cohesion was also stronger. The percutaneous penetration rate of cinnamaldehyde in DPL-HMPSA was 2. 25 times that of HMPSA. In conclusion, DPL-HMPSA had more stable structure, better compatibility with CVO, and higher in vitro transdermal efficiency of cinnamaldehyde than before the modification. This study can provide reference for the mitigation of the matrix structure damage caused by volatile oil components in TCM plasters and the enhancement of the content and in vitro transdermal rate of drug.
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Adhésifs , Administration par voie cutanée , Cinnamomum zeylanicum , Huile essentielle , Spectroscopie infrarouge à transformée de FourierRésumé
Nanocarriers for delivering active ingredients from Chinese materia medica play an important role in improving their solubility, membrane permeability and in vivo biological behavior, enhancing the therapeutic efficiency and reducing side effects. They are promising for extensive research and application. As novel nanocarriers, organic-inorganic hybrid nanocarriers composed of organic materials or carriers and inorganic parts possess the dual advantages of organic carriers and inorganic carriers. They may exert desirable action in drug delivery. In addition, they have been designed to improve the stability and biocompatibility, further increase the therapeutic efficiency and reduce side effects. They have also been investigated to achieve multi-functionality. In this paper, the research and application of organic-inorganic hybrid nanocarriers delivering active ingredients from Chinese materia medica were summarized and analyzed. The development and application prospect of organic-inorganic hybrid nanocarriers are prospected. The aim of this review is to provide a reference for the investigation of new drug delivery system for delivering active ingredients from Chinese materia medica efficiently and safely.
Résumé
The epithelial-to-mesenchymal transition (EMT), a process during which cells undergo transition from a polarized epithelial phenotype to a non-polarized mesenchymal phenotype, executed by transcription factors of Twist, Snail and Zeb families. EMT plays an important role in multiple stages of cancer progression such as initiation, tumor growth, and metastasis. Some active ingredients from Chinese materia medica can inhibit EMT by regulating transcription factors and signaling pathways by multiple targets. However, their therapeutic effect was hindered due to various limitation such as solubility, stability, tissue specificity and safety. Therefore, in order to improve the druggability of active ingredients from Chinese materia medica, enhance the therapeutic effect in inhibiting tumor metastasis mediated by EMT and reduce the toxic and side effects, a variety of nano-drug delivery systems have been developed in recent years. Here, we made a review about these drug delivery systems modulating EMT and their research progress in inhibiting tumor metastasis.
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In the current study, schisandrin B(SchB)-loaded F127 modified lipid-polymer hybrid nanoparticles(SchB-F-LPNs) were developed to improve the inhibition of breast cancer lung metastasis. Modified nanoprecipitation method was used to prepare SchB-F-LPNs. The nanoparticles were spherical in shape with shell-core structure by TEM observation. SchB-F-LPNs showed a mean particle size of(234.60±6.11) nm with zeta potential of(-5.88±0.49) mV. XRD results indicated that SchB existed in the nanoparticles in an amorphous state. The apparent permeability coefficient through porcine mucus of F-LPNs was 1.43-fold of that of LPNs as shown in the in vitro mucus penetration study. The pharmacokinetics study showed that the C_(max) of SchB was(369.06±146.94) μg·L~(-1),(1 121.34±91.65) μg·L~(-1) and(2 951.91±360.53) μg·L~(-1) respectively in SchB suspensions group, SchB-LPNs group and SchB-F-LPNs group after oral administration in rats. With SchB suspensions as the reference formulation, the relative bioavailability of SchB-F-LPNs was 568.60%. SchB-F-LPNs inhibited the morphological change during transforming growth factor-β1(TGF-β1)-induced epithelial-mesenchymal transition. In addition, SchB-F-LPNs significantly decreased the number of metastatic pulmonary nodules in 4 T1 tumor-bearing mice, suggesting that SchB-F-LPNs may inhibit the metastasis of breast cancer. These results reveal the promising potential of SchB-F-LPNs in treatment of breast cancer lung metastasis.
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Animaux , Souris , Rats , Cyclooctanes , Lignanes , Lipides , Tumeurs du poumon/traitement médicamenteux , Nanoparticules , Composés polycycliques , Polyéthylènes , Polymères , Polypropylènes , SuidaeRésumé
Based on the Chinese medicines with topical administration in umbilical region approved by China Food and Drug Administration (CFDA), this paper would comb and analyze their dosage forms, varieties and clinical applications. On the other hand, through consulting literature materials, the research progress was reviewed and the main challenges faced by the medicines were discussed in detail as well. This paper elaborates that the preparations with topical administration in umbilical region, as an important branch in Chinese medicine external therapy, have unique advantages. However, there are still some problems such as rough workmanship, lacking internationally accepted quality control standards, scarcity of pharmacological and clinical evidences and biopharmaceutical researches. Meanwhile, proper measures and suggestions are put forward.
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<p><b>OBJECTIVE</b>To improve the stability and dissolution of realgar nano-particles by solid dispersion.</p><p><b>METHOD</b>Using polyethylene glycol 6000 and poloxamer-188 as carriers, the solid dispersions were prepare by melting method. XRD, microscopic inspection were used to determine the status of realgar nano-particles in solid dispersions. The content and stability test of As(2)0(3) were determined by DDC-Ag method. Hydride generation atomic absorption spectrometry was used to determine the content of Arsenic and investigated the in vitro dissolution behavior of solid dispersions.</p><p><b>RESULT</b>The results of XRD and microscopic inspection showed that realgar nano-particles in solid dispersions were amorphous. The dissolution amount and rate of Arsenic from realgar nano-particles of all solid dispersions were increased significantly, the reunion of realgar nano-particles and content of As(2)0(3) were reduced for the formation of solid dispersions.</p><p><b>CONCLUSION</b>The solid dispersion of realgar nano-particles with poloxamer-188 as carriers could obviously improve stability, dissolution and solubility.</p>
Sujets)
Chimie pharmaceutique , Méthodes , Vecteurs de médicaments , Chimie , Stabilité de médicament , Médicaments issus de plantes chinoises , Chimie , Nanoparticules , Chimie , Poloxamère , Chimie , Polyéthylène glycols , Chimie , SolubilitéRésumé
Objective To observe the distribution of bone marrow mesenchymal stem cells(MSCs) and the effects on expression of apoptosis relative proteins Caspase 3 and Bcl-2 after intravenous transplanted into ischemic rat brains.Methods MSCs from SD rats were cultivated and proliferated in vitro and marked with CFSE.MSCs were then intravenously transplanted into middle cerebral artery occlusion(MCAO)models of SD rats.The rats were killed at different time points to observe the distribution of MSCs under fluorescence microscoDe as well as the effects on expression of apoptosis relative proteins Caspase 3 and Bcl-2 using immunohistochemical method.Results Density of Caspase 3 in immunohistochemically positive area in transplantion group were(2.81±0.35)%,(3.98±0.67)%,(5.58±0.92)%,(3.51±0.63)%,(1.64±0.29)%in 6,12,24,72 hours and in 7 days,respectively,and decreased significantly compared with those of control group[(3.92±0.44)%,(5.23±0.30)%,(6.89±0.57)%,(4.39±0.57)%,(2.29±0.21)%],the difference being significant(t=4.37,3.34,2.60,2.32,3.90,P<0.05 or<0.01).The density of Bcl-2 in immunohistochemically positive area in transplantation group were(4.70±0.16)%,(5.61±0.26)%,(3.00±0.28)%respectively in 6,12 hours and in 7 days,which had improved significantly compared with those of control group[(3.28±0.27)%,(4.54±0.59)%,(2.15±0.62)%],the difference being significant(t=8.32,3.25,2.54,P<0.05 or<0.01).Conclusions Bone marrow MSCs can exert protective effects on brain ischemia and reperfusion injury possibly by down-regulating Caspase 3 and up-regulating Bcl-2.
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<p><b>OBJECTIVE</b>To investigate the release characteristics and mechanism of oridnonin self-microemulsifying drug delivery system (SMEDDS) in vitro.</p><p><b>METHOD</b>The concentration of oridonin was determined by HPLC. In vitro release studies were conducted by reverse dialysis technique. The effects of release medium, agitation rate and preparations on the oridonin release were studied. The similarity factor (f2) was applied to the release profile comparisons. Model fitting was used to determine the kinetics and mechanism.</p><p><b>RESULT</b>The release media and agitation rate from 50-100 r x min(-1) had no distinctive effect on the oridonin release kinetics, which the similarity factors were greater than 50. The oridonin release profiles for oridonin SMEDDS and oridonin ethanol solution were similar. 65% of oridonin were released in 30 min for oridonin SMEDDS in pH 7.8 PBS. Oridonin SMEDDS fit the Hixson-Crowell model best.</p><p><b>CONCLUSION</b>The release data from oridonin SMEDDS showed it release fast. The deduced release mechanism is that the surface and particle sizes of self-microemulsion in water solution are changing during the process of release and the drug penetration through membrane is a passive diffusion process.</p>
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Chromatographie en phase liquide à haute performance , Diterpènes de type kaurane , Chimie , Systèmes de délivrance de médicaments , Méthodes , Émulsions , Chimie , CinétiqueRésumé
<p><b>OBJECTIVE</b>To develop an HPLC method to determine vitexin-rhamnoside in plasma of Beagle dogs and study the pharmacokinetics and bioavailability of Yixintong sustained release tablets in Beagle dogs.</p><p><b>METHOD</b>A newly-developed HPLC method using C18 column and methanol-acetonitrile-tetrahydrogenfuran-0.5% acetic acid (1:1:19.4:78.6) as mobile phase was validated, and then was employed to determine vitexin-rhamnoside in plasma of Beagle dogs after oral administration of Yixintong sustained release tablets and general tablets. The main pharmacokinetic parameters were estimated by pharmacokinetic program 3p87. The non-compartmental pharmacokinetic parameters were also calculated on basis of the statistic moment theory.</p><p><b>RESULT</b>The pharmacokinetic profiles of Yixintong sustained release tablets and the general tablets were fitted to a one-and two-compartment open model, respectively. The T1/2, Tmax, AUC0-infinity and MRT for Yixintong sustained release tablets were 5.22 h, 4.0 h, 6,792.75 ng x h x mL(-1) and 8.4 h, respectively, compared with 8.94 h, 1.0 h, 5,880.4 ng x h x mL(-1) and 6.1 h for the general tablets. The relative bioavailability of the Yixintong sustained release tablets was 115.5% in Beagle dogs.</p><p><b>CONCLUSION</b>The sustained-release characteristic of Yixintong sustained release tablets were confirmed by pharmacokinetic study.</p>
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Animaux , Chiens , Femelle , Mâle , Administration par voie orale , Apigénine , Chimie , Biodisponibilité , Médicaments issus de plantes chinoises , Pharmacocinétique , Plasma sanguin , Chimie , Comprimés , PharmacocinétiqueRésumé
<p><b>UNLABELLED</b>To investigate the effects of Shizhang Cataplasm (SC) and Xuzhang Cataplasm (XC) in treating liver cirrhosis caused ascites of excessive syndrome (ES) type and deficient syndrome (DS) type respectively.</p><p><b>METHODS</b>All the 77 patients (37 of ES type and 40 of DS type) enrolled were treated by conventional treatment but with restrictive use of diuretics. SC and XC were given respectively to 26 patients of ES type and 26 of DS type additionally by umbilical sticking, they were regarded as the treated group, and those (11 of ES type and 14 of DS type) not received the cataplasm treatment were regarded as the control group. The changes of symptoms, body weight, abdominal perimeter and amount of urine before and after treatment were observed, and amount of ascites was examined with B-ultrasound to evaluate the efficacy according to comprehensive grading criteria. Also, the toxicity was observed.</p><p><b>RESULTS</b>Sixty-two cases completed the full course, 15 were withdrawn. As compared with the corresponding control group, body weight, abdominal perimeter and amount of ascites decreased, while amount of urine and flatus discharging increased remarkably in the treated group (P < 0.05). The comprehensive efficacy in patients of ES type was better than that in DS type (P < 0.05). The effective rate of grade I/II was 7.1% and 9.1% for patients in the control group of DS type and ES type respectively, while it was 57.2% and 69.2% in the treated group of DS and ES type respectively. Better therapeutic effect was shown in patients of ES type treated with SC.</p><p><b>CONCLUSION</b>SC and XC showed good assistant effects in treating patients with liver cirrhosis caused ascites of ES and DS type respectively.</p>