Pharmacodynamic Experiment of Dachengqi Decoction and Separated Decoction on Incomplete Intestinal Obstruction in Rats

[Objectives]To investigate the effect and mechanism of Dachengqi Decoction and separated decoction on incomplete intestinal obstruction in rats.[Methods]80 healthy SD rats were selected to establish incomplete intestinal obstruction model by silk ligation.The dosage was 20 mL/kg for 3 d,and the damage index of ileocecal mucosa was analyzed;the morphology of ileocecal mucosa was observed by HE staining;the serum levels of IL-1α,IL-1β,IL-6,IL-18,Ach,NO,ET,IL-1,TNF-αand ultra-micro Na+-K+-ATPase were detected by ELISA.[Results]Compared with the model group,the mucosal damage index of Dachengqi Decoction and each separated decoction group decreased significantly(P<0.05);compared with the normal group and sham operation group,the serum level of IL-1,IL-6,TNF-αand other factors in the model group increased significantly(P<0.05);compared with the model group,the serum IL-1,IL-6 and TNF-αsecretion levels of rats in Dachengqi Decoction group and separated decoction group decreased(P<0.01).[Conclusions]Dachengqi Decoction and each separated decoction can effectively improve intestinal tissue pathological damage in the incomplete intestinal obstruction model rats,and reduce the inflammatory reaction in the rat body.

Effect of Dachengqi Decoction on NF-κB p65 Expression in Lung of Rats with Partial Intestinal Obstruction and the Underlying Mechanism

To investigate the effect of Dachengqi decoction on NF-κB p65 expression in lung of rats with partial intestinal obstruction and the underlying mechanism, 30 SD rats were randomly divided into three groups： sham-operation group, model group and Dachengqi decoction treatment group （Dachengqi group）, with 10 animals in each group. The models were made by partially ligating their large intestines outside the body. The pathological changes were analyzed by HE staining. The expression of NF-κB p65 in rats lung were measured by using real-time polymerase chain reaction and immunohistochemistry respectively. Moreover, the expression of caveolin-1 in rats lung was also measured to. Increased edema, interstitial thickening, hemorrhage, and infiltration of inflammatory cells were found in the model group. In contrast, this change was significantly reduced in Dachengqi group as compared with model group. In addition, the up-regulated caveolin-1 and NF-κB p65 were also suppressed by Dachengqi decoction in lung of rats with partial intestinal obstruction. We are led to concluded that the caveolin-l-NF-κB pathway plays an important role in the development of lung injury of rats with partial intestinal obstruction and Dachengqi decoction could down-regulate the expression of caveolin-1 and NF-κB p65 in lung of rats with partial intestinal obstruction.

Optimal dosing time of Dachengqi decoction for protection of extrapancreatic organs in rats with experimental acute pancreatitis

BACKGROUND Acute pancreatitis(AP)is a pancreatic inflammatory disorder that is commonly complicated by extrapancreatic organ dysfunction.Dachengqi decoction(DCQD)has a potential role in protecting the extrapancreatic organs,but the optimal oral administration time remains unclear.AIM To screen the appropriate oral administration time of DCQD for the protection of extrapancreatic organs based on the pharmacokinetics and pharmacodynamics of AP rats.METHODS This study consisted of two parts.In the first part,24 rats were divided into a sham-operated group and three model groups.The four groups were intragastrically administered with DCQD(10 g/kg)at 4 h,4 h,12 h,and 24 h postoperatively,respectively.Tail vein blood was taken at nine time points after administration,and then the rats were euthanized and the extrapancreatic organ tissues were immediately collected.Finally,the concentrations of the major DCQD components in all samples were detected.In the second part,84 rats were divided into a sham-operated group,as well as 4 h,12 h,and 24 h treatment groups and corresponding control groups(4 h,12 h,and 24 h control groups).Rats in the treatment groups were intragastrically administered with DCQD(10 g/kg)at 4 h,12 h,and 24 h postoperatively,respectively,and rats in the control groups were administered with normal saline at the same time points.Then,six rats from each group were euthanized at 4 h and 24 h after administration.Serum amylase and inflammatory mediators,and pathological scores of extrapancreatic organ tissues were evaluated.RESULTS For part one,the pharmacokinetic parameters(C max,T max,T 1/2,and AUC 0→t)of the major DCQD components and the tissue distribution of most DCQD components were better when administering DCQD at the later(12 h and 24 h)time points.For part two,delayed administration of DCQD resulted in lower IL-6 and amylase levels and relatively higher IL-10 levels,and pathological injury of extrapancreatic organ tissues was slightly less at 4 h after administration,while the results were similar between the treatment and corresponding control groups at 24 h after administration.CONCLUSION Delayed administration of DCQD might reduce pancreatic exocrine secretions and ameliorate pathological injury in the extrapancreatic organs of AP rats,demonstrating that the late time is the optimal dosing time.

Effects of Dachengqi Decoctions Made from Raw Rhubarb and Vinegar-processed Rhubarb on Levels of Endotoxin,NO and TNF-αin Serum

[Objectives]The effects of Dachengqi decoctions made from raw rhubarb and vinegar-processed rhubarb on serum endotoxin,NO and TNF-αlevels were investigated.[Methods]Total 105 mice were randomly divided into Dachengqi decoction made from raw rhubarb groups(6,10 g/kg),Dachengqi decoction made from vinegar-processed rhubarb groups(6,10 g/kg),positive control group,blank control group and model group.After administration at a dose of 20 mL/kg,the levels of endotoxin,NO and TNF-αin serum were determined.The effects of Dachengqi decoctions made from raw rhubarb and vinegar-processed rhubarb on serum endotoxin,NO and TNF-αlevels in mice were compared.[Results]Dachengqi decoctions made from raw rhubarb and vinegar-processed rhubarb both increased the NO level and reduced the endotoxin and TNF-αlevels in serum of ABP mice.[Conclusions]Dachengqi decoctions made from raw rhubarb and vinegar-processed rhubarb have different effects on endotoxin,NO and TNF-αcontents.These changes correspond to the effects of Dachengqi Decoctions made from raw rhubarb and vinegar-processed rhubarb.The change in the content of rhubarb anthraquinones has a certain effect on the efficacy of Dachengqi decoction.

Effects of Dachengqi Decoctions Made from Different Processed Products of Rhubarb on ABP Mice

[Objectives]This study aims to investigate the effects of Dachengqi decoctions made from different processed products of rhubarb on water intake,defecation amount,urination amount,urination volume,dryness of stool,mental state and activity of ABP mice.[Methods]Total 165 mice were randomly divided into Dachengqi decoction groups(made from different processed products of rhubarb,6 and 10 g/kg),positive control group,blank control group and model group.The administration dosage was 20 mL/kg.With the metabolic cage integral method,the effects of Dachengqi decoctions made from different processed products of rhubarb on the water intake,defecation amount,urination volume,dryness of stool,mental state and activity of ABP mice were compared.[Results]Dachengqi decoctions all could soften stool and promote rapid defecation of the mice with fecal peritonitis of excess heat stagnation type except that made from carbonized rhubarb.The water intakes of all the Dachengqi decoction groups were higher than those of the positive control group and the model group,except the carbonized rhubarb-made Dachengqi decoction groups.[Conclusions]Dachengqi decoctions all have obvious purgative effect except those made from carbonized rhubarb.

Morphological Changes in Network of Enteric Nerve-Interstitial Cells of Cajal-Smooth Muscle Cells in Rats with Multiple Organ Dysfunction Syndrome and Therapeutic Effects of Dachengqi Decoction (大承气汤)

Objective： To observe the effects of Dachengqi Decoction （大承气汤, DCQD） on morphological changes in the network of enteric nerve-interstitial cells of Cajal （ICCs）-smooth muscle cells （SMC） of enteric deep muscular plexuses （DMP） in the rats with multiple organ dysfunction syndrome （MODS）. Methods： One hundred Wistar rats of both sexes weighing 200 to 250 g were randomly divided into the control group, MODS group, and DCQD group. The morphologic changes of enteric nerve-ICC-SMC network in the DMP of intestine was observed using c-Kit and vesicular acetylcholine transporter/neuronal nitric oxide synthase immunohistochemical double-staining with whole-mount preparation technique, confocal laser scanning microscopy, and electron microscopy. Results： Compared with the control group, the distribution and densities of cholinergic/nitrergic nerves and ICC in the DMP （ICC-DMP） of intestine in the MODS group were significantly decreased （P0.01）, and the network of cholinergic nerve-ICC-SMC was disrupted; and the ultrastructural features of ICC-DMP, enteric nerve, and SMC were severely damaged. After treatment with DCQD, the damage in the network of enteric nerve-ICC-SMC was significantly recovered. Compared with the MODS group, the distribution and densities of cholinergic/nitrergic nerves and ICC-DMP in the DCQD group were significantly increased （P0.01）; and the ultrastructural features of ICC-DMP, enteric nerve, smooth muscle cells were significantly recovered. Conclusions： DCQD can improve the gastrointestinal motility in MODS. The mechanism may be related to the effect of repairing the damages in the network of enteric nerve-ICC-SMC.

Effect of Formula Compatibility on the Pharmacokinetics of Components from Dachengqi Decoction (大承气汤) in Rats

Objective： To investigate the effect of prescription compatibility on the pharmacokinetics of components from Dachengqi Decoction （DCQD, 大承气汤） in rats. Methods： Twenty-four male rats were randomly and equally divided into the DCQD group, Dahuang （Radix et Rhizoma Rhei, Polygonaceae） group, Houpo （Magnolia officinalis Rehd., Magnoliaceae） group, and Zhishi （Fructus Aurantii Immaturus, Rutaceae） group. The blood samples were collected before dosing and subsequently at 10, 15, 20, 30, 45 min, 1, 2, 4, 8, and 12 h following gavage. The levels of aloe-emodin, rhein, emodin, chrysophanol, honokiol, magnolol, hesperidin, and naringin in rat serum were quantified using a liquid chromatography tandem mass spectrometry （LC-MS/MS） method for pharmacokinetic study. Results： The area under the curve （AUC）, mean retention time （MRT）, the peak concentration （Cmax） of aloe-emodin, rhein, emodin, and chrysophanol in the DCQD group were significantly different compared with the Dahuang group （P〈0.05, respectively）. The mean plasma concentration, Cmax, and the absorption of Dahuang＇s component in the DCQD group were obviously lower at each time point than those in the Dahuang group, while the elimination process of Dahuang＇s component was obviously delayed （P〈0.05）. Half-lives of aloe-emodin, chrysophanol, and rhein were also extended in the DCQD group （P〈0.05, respectively）. In the DCQD group, the mean plasma concentration, AUC, Cmax and absorption of honokiol, and magnolol were significantly lower （P〈0.01, respectively） at each time point than those in the Houpo group, while the drug distribution half-life time （T1/2α）, the drug eliminated half-life time （T1/2β）, MRT, and time of peak concentration （Tmax） were significantly delayed （P〈0.05, respectively）. Pharmacokinetic parameters of hesperidin and naringin in the Zhishi group were not significantly different as compared with the DCQD group （P〉0.05, respectively）, while the MRT of naringin was significantly longer. Conclusions： The compatibility in Chinese medicine could affect the drug＇s pharmacokinetics in DCQD, which proves that the prescription compatibility principle of Chinese medicine formulations has its own pharmacokinetic basis.

Twenty Cases of Diabetic Gastric Retention Treated by Dachengqi Decoction

Objective: To study the effect of Dachengqi Decoction in Treating diabetic gastric retention.Methods: Twenty Patients of diabetic gastric retention were treated with Dachengqi Decoction with their electrogastrogram, urinary glucose and clinical symptoms observed. Results: After treatment, the parameters of electrogastrogram and urinary glucose lowered significantly, and the symptoms relieved. The effect of the treated group was significantly better than that of the control group who were treated with metoclopramide. Conclusion: Dachengqi Decoction is an effective recipe in treating diabetic gastric retention.

Clinical and Experimental Study of Effect on Acute Phase Protein of Multiple Organ Dysfunction Syndrome Treated with Dachengqi Decoction

Objective: To investigate the level of acute phase proteins (APP)-synthesized in hepatocytes in pathogenic process of multiple organ dysfunction syndrome (MODS) and the effect of Dachengqi Decoction (DCQD) on it. Methods: The levels of C-reactive protein (CRP),α1-acid glycoprotein (AAG), α1-antitrypsin total (α1AT), α2-macroglobulin (α2-MG), ceruloplasmine (CP), hepatoglobin (HP) and transferrin (TF) synthesis were determined in 32 cases of MODS patients and rat models of MODS induced by acute infective peritonitis and mesenterial artery ischemia-reperfusion.Results: The serum APP level in MODS patients was increased and higher than that in the control group (P < 0. 01 ). After 3 days of DCQD treatment it reduced significantly (P <0. 05). Serum APP level in MODS model was also increased significantly, and after 3 days of DCQD treatment, it reduced significantly (P < 0. 05). The APP secreting level of rat hepatocytes cultured in vitro raised after stimulated and activated by lipopolysacchride, which was reduced after cultured with rabbits serum containing different concentration of effective ingredients of DCQD. The APP inhibiting effect of DCQD was dose dependent. Conclusion: Purgation therapy with DCQD could reduce the stimulation of pathogenic factors on hepatocytes, protect tissues and organs from damage caused by excessive inflammatory reaction.Original article on CJIM(Chin) 1998; 18(8): 453

Clinical Study on Therapy of Clearing Hallow Viscera in Treating Critical Patients with Gastro-enteric Function Disorder

Objective： To explore the clinical effect of therapy of clearing hallow viscera in treating critical patients with gastro-enteric function disorder （GEFD）. Methods： Retrospective analysis was carried out on 96 critical patients. They were 48 patients in the treated group treated with Dachengqi Decoction （ 大承气汤） and 48 patients in the control group treated with Western medicine for promoting gastric dynamic force. The recovery rate, recovery time of gastro-enteric function, incidence rate and fatality rate of multiple organ dysfunction syndrome （MODS）, as well as the level of plasma endotoxin （ET） before and after treatment between the two groups were compared. Results： Comparison between the two groups in gastro-enteric function recovery rate （81.3% vs 45.8 %）, functional disorder sustaining time in patients who got recovered （1.2± 0.3 daysvs4.0±1.1 days）, incidence rate （29. 17% vs 52.08%） and fatality rate （28.57% vs 56.00%） of MODS all showed significant difference （ P〈0.05 or P〈0.01 ）. The plasma level of ET after treatment in the treated group was significantly lower than that in the control group （P〈0.05）. Conclusion： Therapy of clearing hallow viscera has a good effect in treating critical patients with gastro-enteric function disorder, and could reduce the incidence and fatality of MODS.

EffectsofDachengqiDecoction（大承气汤）andRhubarbonCellularElectricalActivityintheSmoothMuscleofGuinea－PigTaeniaColi

The effects of Dachengqi decoction (DCQ) and rhubarb (Rb) on the spontaneous cellularelectrical activities of guinea-pig taenia coli have been studied by intracellular microelectrode technique.DCQ and Rb both improve the depolarization of cell membrane , speed up the burst ot slow wave and spikepotentials (when the drug concentration was 1 % ,P>0. 05 , 10 % or 20 % ,P<O. 05) , which were dose de-pendent. At the same concentration the effects of Rb were more significant than those of DCQ. These re-sults suggest DCQ and Rb directly enhance the cellular electrical excitability so as to strengthen the con-traction of the colon , is one of the mechanisms of the purgative actiort of these drugs at the cellular level.The ionic basis of the effects might be that DCQ and Rb reduce the K+ conductance of the cell membranesin a resting state.

Effects of Dachengqi (大承气)Decoction on the CytoplasmicFree Calcium in Peritoneal Macrophages of Miceof Bacteria Peritonitis

Effects of Dachengqi Decoction (DCQD) on the cytoplasmic free calcium ([Ca2+ ]i ) in theperitoneal macrophages (PM) of mice were measured with Ca2+ fluorescent indicator Fura-2/Am. Resultsshowed that the level of Ca2+ in PM of the mice with bacterial peritonitis induced by injecting Proteus vul-garis and Escherichia coli in resting was obviously increased compared with that of normal saline (NS) group.In the groups of DCQD, the mice after treated with DCQD for 2 days suffered from bacterial peritonitis, andthen they were continuously treated with DCQD for 3 days. Under this condition, the levels of PM[Ca2+ ] i,in resting or when the same doses of CaCI2 were added, were obviously decreased compared with that of theperitonitis model group (P < 0. 01 ) . Futhermore, the decrease of Ca2+ levels of DCQD groups was dose de-pendent. This result shows that DCQD has excellent protective effects on the bacterial peritonitis induced byProteus vulgaris or Escherichia coli .

Clinical Observation on the Effect of Dexamethasone and Chinese Herbal Decoction for Purgation in Severe Acute Pancreatitis Patients

Objective：To investigate the effect of dexamethasone（Dx） combined with modified Dachengqi Decoction（大承气汤,DCQD）,a Chinese herbal decoction for purgation,on patients with severe acute pancreatitis（SAP） accompanied with systematic inflammatory response syndrome（SIRS）.Methods：A total of 81 patients diagnosed as SAP were randomly assigned to a control group or treatment group according to a random number table generated from an SPSS software.The patients in the control group（38 cases） received standard treatment and Chinese herbal decoction for purgation;those in the treatment group（43 cases） received additional 1 mg/（kg·d） dexamethasone（Dx） treatment for three days based on the above treatment.The mortality rate,acute respiratory distress syndrome（ARDS）,renal failure,hemorrhage,sepsis,pancreatic pseudocyst, pancreatic abscess,operability,and days of hospitalization were compared between the two groups.Results： Three patients in the control group and eight patients in the treatment group dropped out from the study with a drop-out rate of 7.8%and 18.6%,respectively,and no statistics difference was shown between the two groups （P0.05）.Dx treatment significantly reduced ARDS rate and shortened the length of hospitalization compared to those in the control group（7/35,20.0%versus 15/35,42.9%,P=0.0394;32.5±13.2 days versus 40.2±17.5 days,P=0.0344）.Other parameters including the mortality rate were not significant different between the two groups.Conclusion：Dx combined with DCQD could decrease the risk of developing ARDS in SAP patients with SIRS and shorten their length of hospitalization.

Effects of traditional Chinese medicine on intestinal mucosal permeability in early phase of severe acute pancreatitis

Background Traditional Chinese medicine has been used widely for many years in China to treat acute pancreatitis. We have investigated the effects of Dachengqi decoction on intestinal mucosal permeability and outcome in patients with severe acute pancreatitis （SAP）. Methods Forty patients with sustained SAP that required admission to the surgical intensive care unit were enrolled prospectively in the study. All of these patients were divided randomly into the Dachengqi decoction group （n=-20） and control group （n=-20） on admission. Intestinal permeability was assessed by measuring absorption of two metabolically inert markers, lactulose （L） and mannitol （M）, which were administered orally. Serum concentrations of endotoxin （lipopolysaccharide, LPS） and the ratio of lactulose to mannitol in urine （L/M） were detected in all patients. Results Compared with those in the control group, urinary L/M ratio decreased significantly in the Dachengqi decoction group on the 7th day after admission （P=0.001）. Also, serum concentrations of LPS were reduced on the 5th and 7th day after admission （P=-0.006, P=0.008, respectively）. Incidence of multiple organ dysfunction syndrome （MODS） and pancreatic infection was significantly lower in the Dachengqi decoction group compared with those in the control group （P=-0.038, P=-0.025, respectively）. Conclusion Dachengqi decoction may promote the recovery of intestinal mucosal permeability and decrease the incidence of MODS and pancreatic infection in patients with SAP.