Objective To explore the effects of ulinastatin (UTI) on renal apoptosis and expression of bcl-2 in rats with severe acute pancreatitis (SAP). Methods Sixty rats weighing 250-300 g were randomized divided into 3 groups: pseudo-operation group (SO group, n=20), SAP group (n=20) and UTI treated group (UTI group, n=20). The model of SAP was established by retrograde injection of 5% sodium taurocholate solution into the biliopancreatic duct in the rats. Serum Cr and BUN were determined. The left kidneys were resected for light and electronic microscopic study. Renal cell apoptosis was determined by TUNEL. Expression of bcl-2 was detected by immunohistochemical staining of SABC. Results Serum Cr, BUN, renal cell apoptotic index and bcl-2 expression were markedly increased in SAP group compared with SO group （P＜0.05， P＜0.01）, Renal tissue injuries were aggravated in SAP group under light and electronic microscopic study as well. In UTI group, serum Cr, BUN and renal cell apoptotic index were decreased significantly while the expression of bcl-2 increased remarkably and renal tissue injuries relieved compared with SAP group （P＜0.05）. Positive correlations were found between the renal cell apoptotic index and BUN as well as Cr (r=0.807, P＜0.05; r=0.812, P＜0.05). Conclusion The protective effect of UTI on SAP renal injury is probably through increasing bcl-2 expression and decreasing apoptosis.
Objective To evaluate the effectiveness and safety of Octreotide combined with Ulinastatin for treating acute pancreatitis in China. Methods The databases such as CBM, VIP, CNKI and WanFang Data were searched to collect randomized controlled trials (RCTs) from the date of their establishment to February 2011, and the relevant references of the included studies were also retrieved. Studie were screened, data were extracted, and the methodological quality was assessed by two reviewers independently. Meta-analyses were conducted by using RevMan 5.1 software. Results A total of 12 studies involving 1 023 participants were included. The results showed that compared with the group of routine therapies and the group of single administration of either Octreotide or Ulinastatin, the experimental group of Octreotide combined with Ulinastatin was superior in the following aspects with singnificant differences: the total effective rate (RR= 0.34, 95%CI 0.23 to 0.52), the remission time of abdominal pain and distention (SMD= –0.89, 95%CI –1.09 to –0.70), the remission time of signs of abdominal tenderness (SMD= –0.95, 95%CI –1.48 to –0.42), the average length of hospital stay (SMD= –1.10, 95%CI –1.58 to –0.63), the time for blood amylase returning to normal (SMD= –1.14, 95%CI –2.10 to –0.17) and the positive cases at the end of treatment (RR= 0.20, 95%CI 0.08 to 0.51), the time for urine amylase returning to normal (SMD= –0.86, 95%CI –1.04 to –0.68) and the positive cases at the end of treatment (RR= 0.27, 95%CI 0.12 to 0.63), the IL-6 level at the end of treatment (SMD= –2.25, 95%CI –4.39 to –0.11), the incidence rate of complications (RR= 0.39, 95%CI 0.28 to 0.55), the required rate of operation (RR= 0.41, 95%CI 0.24 to 0.69), and the mortality (RR= 0.43, 95%CI 0.29 to 0.64). But the experimental group showed a little longer time for blood calcium returning to normal without statistic difference (MD =0.15, 95%CI 0.05 to 0.26).Conclusion According to the domestic evidence, Octreotide combined with Ulinastatin for treating acute pancreatitis is superior to both the routine therapies and the singe administration of either Octreotide or Ulinastatin. It provides a new and prospective therapeutic method for AP. However, this conclusion has to be further verified by high quality, large scale and double blinded RCTs.
Objective To investigate the effects of high dose ulinastatin with lung protective ventilatory strategies on respiratory function and prognosis in critical disease patients combined with acute lung injury/acute respiratory distress syndrome. Methods Using retrospective analysis, we involved the critical disease patients combined with ALI/ARDS in ICU of The Second Affiliated Hospital of Anhui Medical University. According to whether they were treated with high dose ulinastatin with lung protective ventilatory strategies or not, the patients were divided into the treatment group and the control group. Then pulmonary vascular permeability index (PVPI), extravascular lung water index (EVLWI), oxygenation index, length of SIRS, length of stay in ICU and APACHE Ⅱ score were observed. Statistic analysis was conducted using SPSS 19.0 software. Results A total of 24 patients were included, 13 cases in the treatment group and 11 cases in the control group. After 72 h, PVPI (P=0.016), EVLWI (P=0.045), length of SIRS (P=0.002), length of stay in ICU (P=0.024) and APACHE Ⅱ score (P=0.002) decreased significantly, while oxygenation index (P=0.004) increased significantly in the treatment group compared with the control group. Conclusion High dose ulinastatin with lung protective ventilatory strategies decreased lung capillary permeability, reduced lung blood capillary leakage and extravascular lung water, resulted in the improvement of lung oxygenation function, decreased of length of stay in ICU and the improvement of prognosis in critical disease patients combined with acute lung injury/acute respiratory distress syndrome.
Objective To investigate the protective mechanism of ulinastatin（UTI） in pulmonary microvascular endothelial cells （PMVECs） attacked by serum from the patients with severe sepsis. Methods PMVECs were cultured in vitro and randomly divided into 4 groups，ie. a normal group （culture medium with 10% fetal bovine serum，group N），a health group （culture medium with 10% healthy human serum，group H），a patient group （culture medium with 10% human septic shock serum，group S），and a ulinastatin group （culture medium with 1000 U/mL UTI and 10% human septic shock serum，group U）. The proliferation activity of PMVECs was measured by MTT expressed by optical density （OD）. The concentration of TNF-α in supernatant of culture medium was examined by ELISA at 0，1，2，4，6 hours. The expression of NF-κB was examined by immunohistochemistry at 1 hour. Results Compared with group N，the cell proliferation activity of group S decreased significantly，and the cell proliferation activity of group U decreased slightly at each time poi nt. Compared with group N，the cell proliferation activity of group S and group U at 1，4，6 hours were significant different （Plt;0.05 ）. Compared with group S，the cell proliferation activity of group U at 1，2，6 hours increased significantly （Plt;0.05）. Obviously positive expression of NF-κB in PMVECs could be seen in group S，a little positive expression in group S，and no expression in group N and group H. Compared with group N，the TNF-α levels of group S and group U increased significantly at each time point with significant differences （Plt;0.01）. Compared with group S，the TNF-α levels were significantly reduced at each time point in group U （Plt;0.01）. Conclusions UTI can reduce the release of TNF-α by inhibiting NF-κB activation，thus reduce PMVECs injury attacked by serum from severe sepsis patients.
Objective To investigate the protective effects of ulinastatin on acute lung injury ( ALI)induced by seawater drowning in rats. Methods Thirty male SD rats were randomly divided into three groups, ie. a control group, a model group, and an ulinastatin treatment group. The rats in the model group and the ulinastatin treatment group received intratracheal artificial seawater ( 4 mL/kg) instillation. Then the ulinastatin treatment group received ulinastatin ( 100 000 U/kg) injection after infusion of seawater while the model group received an injection of same amount of saline. The rats were sacrificed at 4 hours after instillation. The pathological changes of lung were evaluated by hematoxylin-eosin stain under light microscope. Lung wet/dry weight ratios were measured to assess the level of pulmonary edema.Concentrations of tumor necrosis factor ( TNF) -α, interleukin ( IL) -1β, IL-6, and IL-10 in bronchoalveolar lavage fluid ( BALF) were detected by enzyme-linked immunosorbent assay ( ELISA) . The myeloperoxidase activity in lung tissue homogenates were measured by colorimetric method. Results Ulinastatin treatmentsignificantly relieved the decline of PaO2 and lung pathological changes, inhibited myeloperoxidase activity,and reduced lung wet/dry weight ratios. Ulinastatin also inhibited the release of TNF-α, IL-1β, and IL-6,whereas increased the expression of IL-10 simultaneously. Conclusion Ulinastatin attenuates seawater induced ALI, which may be related to its inhibitory effects on inflammation reaction through regulating cytokine secretion.
【Abstract】Objective To investigate therapeutic effect and mechanism of hyperbaric oxygen and ulinastatin respectively or combinatively used to treat acute necrotizing pancreatitis (ANP). Methods One hundred and twenty SD rats were divided into 6 groups randomly: group of normal control, group receiving sham operation, group of untreated acute necrotizing pancreatitis (ANP group), group of acute necrotizing pancreatitis treated with hyperbaric oxygen (HBO group), group of acute necrotizing pancreatitis treated with ulinastatin (ULT group), and group of acute necrotizing pancreatitis treated with combined hyperbaric oxygen and ulinastatin (HBO+ULT group). The rat model of acute necrotizing pancreatitis was established according to Aho HJ et al. Concentrations of amylase, TNFα, TXB2 and 6ketoPGF1α in blood were measured through ELISA or radioimmunoassay. Changes of pancreatic histopathology were investigated. SPSS 10.0 was used in statistical analysis. Results The concentrations of amylase, TNFα, TXB2 in the ANPtreated groups were significantly lower than those of ANP group (P＜0.01) except for 6ketoPGF1α and the levels of amylase and TNFα of HBO group were strikingly higher than those in HBO+ULT group. Only the level of AMS was significantly different between ULT group and HBO+ULT group (P＜0.01). Pancreas histopathological scores(HS) and CD8 counts of ANP group were significantly higher than those the other three group, but CD4 counts and CD4/CD8 ratio were on the contrary (P＜0.05). HS of HBO and ULT were strikingly higher than those of HBO+ULT (P＜0.05).Conclusion ①Hyperbaric oxygen or ulinastatin can effectively decrease the blood levels of enzymes and cytokines and improve the pancreatic immunity. ②Hyperbaric oxygen in combination with ulinastatin are more effective than either of them in the treatment of ANP.
Objective To assess the effectiveness and safety of ulinastatin in the treatment of patients with acute pancreatitis. Methods A systematic review of randomized controlled trials (RCT) of ulinastatin for acute pancreatitis was performed. Trials were identified by searching The Cochrane Library (issue 3, 2004), MEDLINE, EMBASE (1984-2004) and Chinese Biological Medicine Database (1978-2004), handsearching, and personal contact with pharmaceutical companies. All RCTs comparing ulinastatin with other interventions were included. Two reviewers assessed the quality of each studiy, and extracted data independently. Statisticsal analysis was performed by using RevMan 4.2. Results Seventeen trials involving 1 199 patients were included. Most included trials were of poor quality. Only two trials reported death at the end of follow-up. Meta-analysis of 6 RCTs showed that the clinical effective rate of Ulinastatin plus basic treatment group was 93.12% (176/189), and was 73.33% in basic treatment group. A statistic significant difference was found between the two groups (Peto OR 4.29, 95%CI 2.49 to 7.37, P＜0.000 01). Compared with basic treatment group, Ulinastatin plus basic treatment group significantly reduced the mean hospitalization (WMD -4.93, 95%CI -7.76 to -2.09, P＜0.000 7). Meta-analysis of 2 RCTs showed that the clinical effective rate of Ulinastatin plus basic treatment group was 86.75% (131/151), and was 80.49% (99/123) in other drugs plus basic treatment group. No statistic significant difference was found between the two groups (Peto OR 1.46, 95%CI 1.76 to 2.80, P＜0.26). One trial found that comparing with control group (23.5±7.5 days), Ulinastatin group (34.0±6.4 days) significantly reduced the mean hospitalization (P＜0.05).The reported severe adverse events of ulinastatin appeared to be rare (7/488, 1.43%). Conclusion Ulinastatin appears to be a modality of safe and effective treatment with a favorable trend, but there is no enough evidence to support this conclusion at present as the published trials with poor quality. More trials with enough sample size and scientifically sound methodology are required.
Objective To investigate the effects of ulinastatin on Treg/Th17 and immune status in patients with severe sepsis.Methods A total of 80 patients with severe sepsis, who were hospitalized in ICU during October 2011 to July 2012, were randomly divided into a routine group and a ulinastatin group. The patients in the ulinastatin group were intravenously administered 30mg ulinastatin three times per day for 5 days in addition to routine bundle treatment. The expression of Treg, Th17 and HLA-DR were detected on the first day in ICU and 5 days after treatment. 20 healthy individuals served as controls. Results Compared with the control group, the severe sepsis group had overexpression of Treg and Th17 ( P lt;0. 01) , higher ratio of Treg/Th17( P lt;0. 01) , and decreased HLA-DR expression of CD14 monocyte ( P lt; 0. 01) . In the severe sepsis patients, ulinastatin injection reduced the abnormal expression of Treg and Th17 ( P lt; 0. 01) , decreased the ratio of Treg/Th17( P lt; 0. 01) , and improved the expression of HLA-DR ( P lt; 0. 01) more effectively compared with the routine treatment. Ulinastatin also lowered 28-day mortality of the patients with sepsis, but the difference between the ulinastatin group and the routine group was not significant. Conclusions In severe sepsis patients, there were abnormal overexpression of Treg and Th17, imbalance of Treg/Th17, and underexpression of HLA-DR which imply an immune suppression. Ulinastatin can decrease the expression of Treg and Th17, inverses the ratio of Treg/Th17, and improve the expression of HLA-DR, so as to improve the prognosis of severe sepsis patients.
ObjectiveTo observe the clinical efficacy of ulinastatin combined with low-dose arginine vasopressin in treating severe pulmonary contusion. MethodSixty patients with severe pulmonary contusion were enrolled in our hospital between April 2012 to June 2014 year. All the patients were randomly divided into three groups. They were respectively defined as a routine treatment group (group A, n=20), an ulinastatin treatment group (group B, n=20), and a combined treatment group (group C, n=20). The respiratory frequency (RR), oxygenation index, partial pressure of carbon dioxide (PaCO2), the change of chest X-ray and the change of serum interleukin-6 (IL-6), IL-8 levels were compared among three groups before and after therapy. ResultThe respiration frequency(RR) and the concentration of serum IL-6, IL-8 levels were decreased in the group C before and after treatment with statistical differences (P=0.000, 0.000, 0.000). PaO2/FiO2 and PaCO2 were significantly increased in the group C before and after treatment (P=0.000, 0.000). After treatment for 7 d, the respiration frequency (RR) and the concentration of serum IL-6, IL-8 of patients in the group B decreased significantly compared with those in the group A (P=0.000, 0.043, 0.000). While PaO2/FiO2, PaCO 2 and the score of chest X-ray increased significantly in the group B (P=0.010, 0.000, 0.000). Compared with those in the group B, RR and the concentration of serum IL-6, IL-8 of patients in the group C decreased significantly (P=0.000, 0.045, 0.000), while PaO2/FiO2, PaCO2 and the score of chest X-ray increased significantly (P=0.043, 0.010, 0.001). ConclusionUlinastatin combined with low-dose arginine vasopressin shows obvious effects in the patients with severe pulmonary contusion. And its therapeutical effects are better than that of the other two treatment options.
Objective To study the protective effects of ulinastatin( UTI) on lung function after cardiopulmonary bypass( CPB) . Methods 42 Patients, ASA score Ⅱ ～Ⅲ, scheduled for elective cardiac valve replacement, were randomly allocated into three groups, ie. a control group, a low dose UTI group( UTI 8000U/kg) , and a high dose UTI group( UTI 12 000 U/kg) . Inspiratory pressure( PIP) , Plateau pressure ( Pplat) , alveolar-arterial oxygen pressure difference ( AaDO2 ) , static lung compliance ( Cs) and dynamic lung compliance ( Cd) were recorded before operation ( T1 ) and at 1 hour ( T2 ) , 4 hours ( T3 ) , 24 hours ( T4 ) after CPB termination. Results Compared with pre-CPB, postoperative PIP, Pplat and AaDO2 increased, and Cs and Cd decreased significantly in the control group( all P lt; 0. 05) . Compared with the control group at T2 ～T3 , postoperative PIP, Pplat, AaDO2 were significantly lower( P lt;0. 05) , and Cs and Cd were significantly higher in the two UTI groups( P lt;0. 05) . Compared with the low dose UTI group at T2 ～T3 , the PIP, Pplat and AaDO2 were significantly reduced( P lt;0. 05) , and the Cs and Cd were significantly increased in the high dose UTI group( P lt; 0. 05) . Conclusion UTI can alleviate lung injury and improve lung function during valve replacement surgery with CPB in a dose dependent manner.