A comparative analysis of sivelestat sodium hydrate and ulinastatin combination therapy in the treatment of sepsis with acute respiratory distress syndrome.

OBJECTIVE: This comparative analysis aimed to investigate the efficacy of Sivelestat Sodium Hydrate (SSH) combined with Ulinastatin (UTI) in the treatment of sepsis with acute respiratory distress syndrome (ARDS). METHODS: A control group and an observation group were formed with eighty-four cases of patients with sepsis with ARDS, with 42 cases in each group. The control group was intravenously injected with UTI based on conventional treatment, and the observation group was injected with SSH based on the control group. Both groups were treated continuously for 7 days, and the treatment outcomes and efficacy of both groups were observed. The Murray Lung Injury Score (MLIS), Sequential Organ Failure Assessment (SOFA), and Acute Physiology and Chronic Health Evaluation II (APACHE II) were compared. Changes in respiratory function, inflammatory factors, and oxidative stress indicators were assessed. The occurrence of adverse drug reactions was recorded. RESULTS: The total effective rate in the observation group (95.24%) was higher than that in the control group (80.95%) (P < 0.05). The mechanical ventilation time, intensive care unit (ICU) hospitalization time, and duration of antimicrobial medication in the observation group were shorter and multiple organ dysfunction syndrome incidence was lower than those in the control group (P < 0.05). The mortality rate of patients in the observation group (35.71%) was lower than that in the control group (52.38%), but there was no statistically significant difference between the two groups (P > 0.05). MLIS, SOFA, and APACHE II scores in the observation group were lower than the control group (P < 0.05). After treatment, respiratory function, inflammation, and oxidative stress were improved in the observation group (P < 0.05). Adverse reactions were not significantly different between the two groups (P > 0.05). CONCLUSION: The combination of SSH plus UTI improves lung injury and pulmonary ventilation function, and reduces inflammation and oxidative stress in patients with sepsis and ARDS.

Serum interα-trypsin inhibitor heavy chain H4 may be an anti-inflammatory marker reflecting disease risk, activity and treatment outcome of ankylosing spondylitis.

Interα-trypsin inhibitor heavy chain H4 (ITIH4) modulates inflammation and immunity, which take part in the pathogenesis of ankylosing spondylitis (AS). The current research intended to discover the clinical value of serum ITIH4 quantification for AS management. Serum ITIH4 among 80 AS patients before current treatment initiation (baseline) at weeks (W) 4, 8 and 12 after treatment was detected by ELISA. Serum ITIH4 from 20 disease controls (DCs) and 20 healthy controls (HCs) was detected. ITIH4 expression was lower in AS patients than in DCs (p = 0.002) and HCs (p < 0.001). Among AS patients, ITIH4 was negatively associated with C-reactive protein (CRP) (r = -0.311, p = 0.005), bath AS disease activity index (BASDAI) (r = -0.223, p = 0.047), total pack pain (r = -0.273, p = 0.014) and AS disease activity score (ASDAS) (CRP) (r = -0.265, p = 0.018). Meanwhile, ITIH4 was negatively related to tumor necrosis factor (TNF)-α (r = -0.364, p = 0.001), interleukin (IL)-1ß (r = -0.251, p = 0.025), IL-6 (r = -0.292, p = 0.009) and IL-17A (r = -0.254, p = 0.023). After treatment, the assessment of the spondylitis arthritis international society 40 response rate was 28.7% at W4, 46.3% at W8 and 55.0% at W12; ITIH4 showed an increasing trend from baseline to W12 (p < 0.001). Furthermore, ITIH4 at W8 (p = 0.020) and W12 (p = 0.035), but not at baseline or W4 (both p > 0.05), was enhanced in response patients vs. nonresponse patients. Additionally, ITIH4 at W12 was increased in AS patients receiving TNF inhibitors vs. those receiving nonsteroidal anti-inflammatory drugs (NSAIDs) (p = 0.024). Serum ITIH4 increases after treatment, and its augmentation is correlated with lower disease activity, decreased inflammation and enhanced treatment response in AS patients.

Targeting protein-protein interaction for immunomodulation: A sunflower trypsin inhibitor analog peptidomimetic suppresses RA progression in CIA model.

Protein-protein interactions (PPI) of co-stimulatory molecules CD2-CD58 are important in the early stage of an immune response, and increased expression of these co-stimulatory molecules is observed in the synovial region of joints in rheumatoid arthritis (RA) patients. A CD2 epitope region that binds to CD58 was grafted on to sunflower trypsin inhibitor (SFTI) template structure to inhibit CD2-CD58 PPI. The peptide was incorporated with an organic moiety dibenzofuran (DBF) in its structure. The designed peptidomimetic was studied for its ability to inhibit CD2-CD58 interactions in vitro, and its thermal and enzymatic stability was evaluated. Stability studies indicated that the grafted peptidomimetic was stable against trypsin cleavage. In vivo studies using the collagen-induced arthritis (CIA) model in mice indicated that the peptidomimetic was able to slow down the progress of arthritis, an autoimmune disease in the mice model. These studies suggest that with the grafting of organic functional groups in the stable peptide template SFTI stabilizes the peptide structure, and these peptides can be used as a template to design stable peptides for therapeutic purposes.

Nafamostat Mesylate is Not Effective in Preventing Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is associated with complications such as post-ERCP pancreatitis (PEP). Protease inhibitors, including nafamostat mesylate (NM), have been evaluated for prophylaxis against PEP. AIM: We describe the first multicenter randomized controlled trial assessing the prophylactic efficacy of NM against PEP. METHODS: In this multicenter prospective study, we aimed to enroll 800 patients aged ≥ 20 years with a planned ERCP between December 2012 and March 2019. The primary outcome was the incidence and severity of PEP in patients who did not receive NM (non-NM) versus those who did (NM; 20 mg). Secondary outcomes included the incidence of PEP by NM initiation (pre- and post-ERCP), risk factors for PEP, and NM-related adverse events. RESULTS: Only 441 of the planned 800 patients were enrolled (non-NM: n = 149; NM: n = 292 [pre-ERCP NM: n = 144; post-ERCP NM: n = 148]). Patient characteristics were balanced at baseline with no significant differences between groups. PEP occurred in 40/441 (9%) patients (non-NM: n = 15 [10%]; NM: n = 25 [9%]), including 17 (12%) and eight (8%) in the pre-ERCP and post-ERCP NM groups, respectively. In the NM group, the incidence of PEP was lower in the low-risk group than in the high-risk group. Pancreatic injection and double-guidewire technique were independent risk factors for PEP. NM-related adverse events of hyperkalemia occurred in two (0.7%) patients. CONCLUSIONS: We found no evidence for the prophylactic effect of NM against PEP, regardless of the timing of administration; however, further studies are needed.

Effect of ulinastatin on interleukins and pulmonary function in bypass patients: a meta-analysis of randomized controlled trials.

BACKGROUND: Our aim was to evaluate the effect of urinary trypsin inhibitors (UTI) on interleukin, tumor necrosis factor-α (TNF-α), and polymorphonuclear neutrophil elastase (PMNE) levels as well as on pulmonary function in patients undergoing cardiopulmonary bypass. MATERIALS AND METHODS: We searched the following databases for relevant studies: PubMed, Medline (Ovid SP), Cochrane Library, Wanfang Data, China Biology Medicine Database, Chinese Periodical Database, China Knowledge Resource Integrated Database, and Chinese Clinical Trial Registry. Two investigators independently collected the data and assessed the quality of each study. RevMan 5.3 was used for the meta-analysis. RESULTS: In total, 15 randomized controlled trials (646 patients) met the inclusion criteria. There was a significant decrease in TNF-α, interleukin-6 (IL-6), IL-8, and PMNE levels at 6 h and 24 h after UTI treatment and an increase in IL-10 levels; additionally, there was a decrease in respiratory index and an improvement in the oxygenation index. Nevertheless, UTI treatment did not affect the length of intensive care unit stay, alveolar-arterial oxygen partial pressure difference, adverse lung events, or hospital mortality. Because of the high heterogeneity of the included trials, the results should be assessed carefully. CONCLUSION: UTI treatment can suppress proinflammatory cytokine elevation and upregulate the release of anti-inflammatory mediators, thereby reducing pulmonary injury and improving pulmonary function after cardiopulmonary bypass.

Alpha-1 Antitrypsin Deficiency and Pregnancy.

Alpha-1 Antitrypsin Deficiency (A1AD) is a hereditary condition characterized by low levels of circulating alpha-antitrypsin (AAT) in plasma. It is the best understood genetic risk factor for the development of chronic obstructive pulmonary disease (COPD). The diagnosis of A1AD is under-recognized. While there is a significant heterogeneity in disease presentation in relation to the severity of symptoms and prognosis, it is not uncommon for young individuals, including pregnant women to already have moderate to advanced lung disease at the time of diagnosis. Reductions in AAT levels may have unique implications for a gravid patient beyond that of lung disease. Care of the pregnant A1AD patient with chronic lung disease follows the principles of care for the management of airways disease in general with control of symptoms and reduction in exacerbation risk the main tenets of treatment. The effect of A1AD and augmentation in pregnancy has not been studied and thus care is reliant on expert opinion and clinical experience. Providers caring for pregnant patients with A1AD should consider referral to health care systems and providers with specific expertise in A1AD. Ultimately the decision is left to the individual patient and their physician to weigh the risk benefit of cessation or continuation of therapies. In this review, we present the perinatal course of a woman with A1AD and review the available literature pertaining to AAT and pregnancy and discuss the clinical implications.

Ulinastatin attenuates vascular endothelial cell damage in pregnant women with severe pre-eclampsia.

The use of ulinastatin for pancreatitis and sepsis have been described. This study was designed to evaluate the effect of ulinastatin on vascular endothelial cell damage and coagulation in pregnant women with severe pre-eclampsia (PE).From October 2015 to November 2017 at Tianjin Central Hospital of gynecology and obstetrics in China. Eighty pregnant women with severe PE, who elected to deliver by cesarean section, were randomly assigned to a control group or an ulinastatin group. The plasma concentration of von Willebrand factor (vWF) and platelet granule membrane protein (GMP-140), platelet count, fibrinogen levels, prothrombin time (PT), and partial prothrombin activation time (APTT) were recorded before combined spinal-epidural anesthesia and 40 min after administration in both groups.Ulinastatin attenuates vascular endothelial cell damage in pregnant women with PE as indicated by decreased plasma concentrations of vWF and prolonged APTT.

Xuebijing combined with ulinastation benefits patients with sepsis: A meta-analysis.

BACKGROUND: The potential benefits and possible risks associated with Xuebijing when combined with ulinastatin for sepsis treatment are not fully understood. METHODS: Databases, such as PubMed, Web of Science, CNKI, WanFang and VIP, were searched to collect randomized, controlled trials. Studies were screened, data were extracted, and the methodological quality was assessed by two reviewers independently. A meta-analysis was carried out with Stata 11.0 software. RESULTS: A total of 16 studies involving 1192 participants were enrolled for meta-analysis based on the inclusion and exclusion criteria. The results showed that compared with the group using routine therapies and the group using a single administration of either ulinastatin or Xuebijing, the trial group using Xuebijing combined with ulinastatin was significantly superior in the following aspects: mortality (RR = 0. 54,95% CI (0. 41, 0. 70, P = .000), 7 d APACHE II (SMD = -1.21, 95%CI (-1.62, -0.80), P = .000), duration of mechanical ventilation (SMD = -1.21, 95%CI (-1.62, -0.80), P = .000), average length of time in the intensive care unit (SMD = -1.21, 95%CI (-1.62, -0.80), P = .000), incidence of multiple organ dysfunction syndromes (RR = 0. 54, 95% CI (0.41, 0. 70, P = .000), interleukin-6 (SMD = -1.36,95%CI (-2.46, -0.27), P = .000), lipopolysaccharide (SMD = -9.92, 95%CI (-11.7, -7.90), P = .006), and procalcitonin (SMD = -0.30, 95%CI (-0.34, -0.26), P = .012). CONCLUSIONS: Our results found that Xuebijing when combined with ulinastatin was superior to both routine therapies and the single administration of either ulinastatin or Xuebijing. This finding provides a new therapeutic option for the treatment of sepsis.

Rhubarb combined with trypsin inhibitor for severe acute pancreatitis: A systematic review and meta-analysis.

The objective of this study is to evaluate the efficacy and safety of rhubarb combined with trypsin inhibitor for severe acute pancreatitis (SAP). This meta-analysis was performed in accordance with the Transparent Reporting of Systematic Reviews and Meta-analysis protocol (PRISMA-P) and Cochrane Handbook. Relevant studies from inception to 2016 were searched through 7 related databases. The Cochrane Library was searched to assess the bias of the included trials. Data were analysed with Review Manager 5.3 software. A total of 16 randomized controlled trials (RCTs) involving 912 participants with SAP were included in this meta-analysis. The result showed that when compared with trypsin inhibitor used alone, rhubarb combined with trypsin inhibitor showed intensive effects on decreasing mortality, increasing overall efficacy, shorting length of hospitalization, reducing abdominal pain relief time, and decreasing the level of serum amylase. There was no serious adverse event reported in these RCTs. It should be noted that potential publication bias was observed. This meta-analysis demonstrated that rhubarb combined with trypsin inhibitor could be an effective and safe treatment for patients with SAP. However, the small sample size and poor quality of these RCTs should be noted. And more rigorously designed, multicentre, large-scale worldwide trials with more practitioners and higher quality are required.

Quantitative disease progression model of α-1 proteinase inhibitor therapy on computed tomography lung density in patients with α-1 antitrypsin deficiency.

AIMS: Early-onset emphysema attributed to α-1 antitrypsin deficiency (AATD) is frequently overlooked and undertreated. RAPID-RCT/RAPID-OLE, the largest clinical trials of purified human α-1 proteinase inhibitor (A1 -PI; 60 mg kg-1  week-1 ) therapy completed to date, demonstrated for the first time that A1 -PI is clinically effective in slowing lung tissue loss in AATD. A posthoc pharmacometric analysis was undertaken to further explore dose, exposure and response. METHODS: A disease progression model was constructed, utilizing observed A1 -PI exposure and lung density decline rates (measured by computed tomography) from RAPID-RCT/RAPID-OLE, to predict effects of population variability and higher doses on A1 -PI exposure and clinical response. Dose-exposure and exposure-response relationships were characterized using nonlinear and linear mixed effects models, respectively. The dose-exposure model predicts summary exposures and not individual concentration kinetics; covariates included baseline serum A1 -PI, forced expiratory volume in 1 s and body weight. The exposure-response model relates A1 -PI exposure to lung density decline rate at varying exposure levels. RESULTS: A dose of 60 mg kg-1  week-1 achieved trough serum levels >11 µmol l-1 (putative 'protective threshold') in ≥98% patients. Dose-exposure-response simulations revealed increasing separation between A1 -PI and placebo in the proportions of patients achieving higher reductions in lung density decline rate; improvements in decline rates ≥0.5 g l-1  year-1 occurred more often in patients receiving A1 -PI: 63 vs. 12%. CONCLUSION: Weight-based A1 -PI dosing reliably raises serum levels above the 11 µmol l-1 threshold. However, our exposure-response simulations question whether this is the maximal, clinically effective threshold for A1 -PI therapy in AATD. The model suggested higher doses of A1 -PI would yield greater clinical effects.

Autodigestion by migrated trypsin is a major factor in small intestinal ischemia-reperfusion injury.

BACKGROUND: The pathophysiological role of pancreatic digestive hydrolases in intestinal ischemia-reperfusion (I/R) injury is still not clear. Here, we studied whether ischemia-induced injury to the small intestine can be explained by the autodigestion hypothesis. MATERIALS AND METHODS: Mesenteric I/R was induced in rats by superior mesenteric artery occlusion (90 min) and reopening (120 min). Thirty minutes before superior mesenteric artery occlusion, aprotinin (14.7 mg/kg), orlistat (5 mg/kg), and their combination or α1-proteinase inhibitor (60 mg/kg) were injected into the lumen of the small intestine. Systemic and vital parameters, intestinal microcirculation, and mucosal barrier function were monitored during the observation phase; markers of small intestinal injury, as well as trypsin-, chymotrypsin-, elastase-, and lipase-like activities in intestinal effluates were assessed at the end. RESULTS: The pattern of small intestinal injury correlated inversely with the local alterations in microvascular tissue perfusion and corresponded with the intestinal distribution of trypsin-like activity. Aprotinin almost completely inhibited trypsin-like activity (P < 0.05) and significantly reduced intestinal tissue injury. Combined with orlistat, it also increased the postischemic blood pressure (P < 0.05) but not the intestinal barrier function. Macroscopic as well as the histologic alterations were decreased by α1-proteinase inhibitor, which significantly improved postischemic blood pressure (P < 0.05). CONCLUSIONS: The I/R-induced pattern of small intestinal injury is likely to result from both local differences in tissue ischemia and the digestive activity of migrated pancreatic trypsin. Therefore, administration of aprotinin and orlistat into ischemic small intestines may be a therapeutic option in patients with a poor diagnosis.

Intraintestinal administration of ulinastatin protects against sepsis by relieving intestinal damage.

BACKGROUND: Intravenous administration of ulinastatin (UTI), a broad spectral protease inhibitor, has been used on an experimental basis with severe sepsis patients in Asia. However, the effects of intraintestinal administration of UTI on intestinal and multiple organ damage in sepsis have not been reported. MATERIALS AND METHODS: In this study, we established a sepsis model in rats using cecal ligation and puncture and compared the effects of intraintestinal administration of UTI through an artificial fistula of duodenum and intraperitoneal administration of UTI on the pathophysiological changes of sepsis. RESULTS: It was found that intraintestinal administration of UTI (1) significantly improved the survival of septic rats, (2) significantly reduced the serum levels of tumor necrosis factor-α, interleukin-1ß, interleukin-6 as well as intestinal injury biomarkers diamine oxidase, D-lactic acid, and fluorescein isothiocyanate-dextran 4, and (3) significantly reduced intestinal microscopic and ultrastructural damage of septic rats. In addition, the protective effects of intraintestinal administration of UTI were significantly better than those of intraperitoneal administration of UTI. CONCLUSIONS: Overall, the present study for the first time revealed that intraintestinal administration of protease inhibitor UTI could reduce systemic inflammatory responses and multiple organ dysfunction in rats with sepsis by inhibiting autodigestion of intestinal wall due to proteases and provided new research ideas and experimental evidences for treatment of sepsis by intraintestinal administration of UTI.

Biochemical comparison of four commercially available human α1-proteinase inhibitors for treatment of α1-antitrypsin deficiency.

Intravenous therapy with purified plasma-derived alpha1-proteinase inhibitor (α1-PI) concentrates is the only specific treatment for α1-PI deficiency. For the therapy to be safe and efficacious, α1-PI concentrates should be highly pure and contain high amounts of functional protein. This study compared the four plasma-derived α1-PI products commercially available in Europe (Respreeza, Prolastin, Alfalastin, Trypsone) by biochemical methods with respect to function, purity, structure, and chemical modifications. Respreeza had the highest level of functional protein (48.8 mg/mL) and the highest specific activity (0.862 mg active α1-PI per mg total protein). By size exclusion chromatography, Respreeza was 97.4% pure, followed by Alfalastin 88.1%, Prolastin 76.9%, and Trypsone 70.8%. By reversed phase chromatography, Respreeza had an α1-PI purity of 97.7%, followed by Trypsone 88.0%, Prolastin 78.0%, and Alfalastin 69.5%. The main protein band by sodium dodecyl sulphate-polyacrylamide gel electrophoresis was found for all products at approximately 50 kDa. Additional protein bands were found for Prolastin, Alfalastin, and Trypsone. The α1-PI products differed in cysteine oxidation state and C-terminal lysine status. α1-PI products tested differ in purity, concentration, and chemical variation. Respreeza has the highest level of purity. The impact of the non-therapeutic proteins identified has not been evaluated.

Understanding alpha-1 antitrypsin deficiency: A review with an allergist's outlook.

Alpha-1 antitrypsin (AAT) is the prototypical protease inhibitor from the serine protease inhibitor (serpin) superfamily that protects lung tissue from proteolytic damage by inhibiting neutrophil elastase. Approximately 1 in 2750 to 1 in 4500 individuals have an autosomal codominant condition that leads to a deficiency of circulating AAT. In individuals with AAT deficiency (AATD), AAT is retained in liver cells, which predisposes them to liver disease, and does not reach lung tissues through circulation, where it normally acts as the primary natural regulator of proteolytic activity in the pulmonary tissues, which thus leads to lung disease. Despite being commonly labeled as a rare disease, AATD is one of the most common autosomal genetic disorders and is considered highly underrecognized, with ≤10% of individuals suspected with AATD identified. Screening guidelines have been established, and the diagnosis is easy to confirm when the condition is suspected. Early recognition is key to prevent morbidity and mortality associated with the disease. For this reason, all patients with chronic obstructive pulmonary disease and patients with asthma and fixed obstruction should be tested to exclude the diagnosis of AATD. Augmentation therapy of the deficient protein is available for those with significant lung disease and protein deficiency, and analysis of recent data supported preservation of lung tissue with this treatment. In this review, oriented toward specialists in allergy and immunology, we focused our discussion on the presentation, diagnosis, and treatment of pulmonary symptoms of AATD.

Alpha-1-Antitrypsin Deficiency: Disease Management and Learning from Studies.

Alpha-1-antitrypsin deficiency (AATD) is one of the most frequent genetic causes of liver and lung diseases. Despite its known association with chronic obstructive pulmonary disease (COPD), AATD is largely unrecognised and underdiagnosed. Cases of AATD exist within every COPD or spirometry population but must be actively investigated. AATD is a laboratory diagnosis that must be confirmed by a blood test. A number of clinical 'clues' can raise suspicion of AATD, potentially facilitating earlier diagnosis and initiation of appropriate treatment. Alpha-1-antitrypsin augmentation therapy has a clear role in patients with severe AATD and a FEV1 ≤65% predicted. Emerging evidence suggests that attenuating the decline in lung density may prolong the time to respiratory failure.

[Clinical value of the early use of ulinastatin in patients with moderately severe or severe acute pancreatitis].

Objective: To observe the clinical efficacy and the effects on serum inflammatory factors of early use of ulinastatin in patients with moderately severe or severe acute pancreatitis (MSAP/SAP). Methods: This prospective, randomized, controlled trial was conducted in the First Affiliated Hospital of Soochow University from September 2013 to May 2016. A total of 42 cases were enrolled and assigned into either observation group or conventional treatment group (n=21 each). The conventional treatment group received somatostatin, while the observation group received somatostatin combined with ulinastatin. After treatment, clinical characteristics, serum indicators, clinical complications and serum level of inflammatory factors were analyzed. Results: Intra-abdominal pressure and relief time of abdominal pain were significantly decreased in observation group [ (10.4±2.1) cmH(2)O; (2.5±1.2) d ] compared with the conventional treatment group [ (11.7±2.2) cmH(2)O; (3.33± 1.2) d ], P<0.05. White blood cells (WBC) were lower in observation group than those in conventional treatment group [ (11.2±1.8) ×10(9)/L vs (12.5±2.3) ×10(9)/L; P<0.05 ]. After treatment serum levels of interleukin-6 (IL-6), IL-8 and tumor necrosis factor-α(TNF-α) in observation group [ (30.5±3.3), (34.7± 6.5), (22.6±4.0) µg/L] were significantly lower than those in conventional treatment group [ (39.6±4.0), (40.9±3.4), (33.1±6.6) µg/L], P<0.05. There were no differences between the two groups in modified CT severity index (MCTSI), recovery time of defecation, ICU length of stay, serum amylase, C-reactive protein (CRP) and incidence rates of clinical complications. Conclusions: The early use of ulinastatin in the patients with MSAP/SAP can down-regulated the levels of TNF-α, IL-6 and IL-8, reduce the inflammatory response, decrease intra-abdominal pressure and shorten abdominal pain time. It was beneficial and worthy of wider popularization.

Trypsin inhibitors for the treatment of pancreatitis.

Proline-based trypsin inhibitors occupying the S1-S2-S1' region were identified by an HTS screening campaign. It was discovered that truncation of the P1' moiety and appropriate extension into the S4 region led to highly potent trypsin inhibitors with excellent selectivity against related serine proteases and a favorable hERG profile.

[Preventive effects of ulinastatin on acute respiratory distress syndrome].

OBJECTIVE: To explore the effect of ulinastatin on prevention of acute respiratory distress syndrome (ARDS). METHODS: A prospective multicentral cohort study was conducted. The patients from three intensive care units (ICUs) of grade A tertiary hospitals in Beijing and a ICU of grade A tertiary hospitals in Cangzhou from January 2012 to December 2014, included 77 ARDS at-risk patients with ulinastatin treatment and 108 ARDS at-risk patients without ulinastatin treatment (control) were eligible. Both groups received normal treatment; additionally, the intervention group received 600 000 units of ulinastatin via intravenous infusion for 5 days. The control group received the same amount of saline via intravenous infusion for 5 days. Venous blood human neutrophil elastase (HNE) and peptidase inhibitor 3 (PI3) levels were measured on days 1, 3, and 7, respectively. Other outcomes included acute physiology and chronic health evaluation scoring II (APACHE II), body temperature, respiratory rate, heart rate, mean arterial pressure, white blood cell counts, PaO2/FiO2, ARDS incident, mechanical ventilation time, ICU treatment and hospitalization duration, 28 days mortality. RESULTS: The PI3 levels showed no statistical difference on day 1, but significant differences on day 3 and day 7 between the two groups (P<0.01). HNE/PI3 ratio showed no statistical difference on day 1, but significant differences on day 3 and day 7 (P<0.05). PaO2/FiO2 was significantly higher in ulinastatin group on day 3 and day 7 (P<0.05). The incident rate for ulinastatin group was 15.58%, lower than that for the control group (33.33%), and the difference was statistically significant (P<0.05). The mechanical ventilation time and ICU treatment time in ulinastatin group was shorter than that in the control group, and the difference was statistically significant (P<0.05). There were no significant effects in other factors. CONCLUSION: Increased dose of ulinastatin can recover the balance of HNE and its antagonist, lower the HNE's damage to lungs, and further reduce the ARDS incident rate.

Oral Cancer Chernoprevention: Current Status and Future Direction.

The aim of this study is to review the current status of cancer chemoprevention and its effectiveness in treatment of oral premalignant lesions and prevention of their progression to oral cancer. The challenges encountered in the different oral cancer chemoprevention clinical trials, including lack of surrogate endpoints, reversal of histologic premalignant changes as study endpoints, tobacco use, human papillomavirus, delivery system, adverse effects and risk of bias in clinical studies, are presented.

In vivo efficacy of anuran trypsin inhibitory peptides against staphylococcal skin infection and the impact of peptide cyclization.

Staphylococcus aureus is a virulent pathogen that is responsible for a wide range of superficial and invasive infections. Its resistance to existing antimicrobial drugs is a global problem, and the development of novel antimicrobial agents is crucial. Antimicrobial peptides from natural resources offer potential as new treatments against staphylococcal infections. In the current study, we have examined the antimicrobial properties of peptides isolated from anuran skin secretions and cyclized synthetic analogues of these peptides. The structures of the peptides were elucidated by nuclear magnetic resonance (NMR) spectroscopy, revealing high structural and sequence similarity with each other and with sunflower trypsin inhibitor 1 (SFTI-1). SFTI-1 is an ultrastable cyclic peptide isolated from sunflower seeds that has subnanomolar trypsin inhibitory activity, and this scaffold offers pharmaceutically relevant characteristics. The five anuran peptides were nonhemolytic and noncytotoxic and had trypsin inhibitory activities similar to that of SFTI-1. They demonstrated weak in vitro inhibitory activities against S. aureus, but several had strong antibacterial activities against S. aureus in an in vivo murine wound infection model. pYR, an immunomodulatory peptide from Rana sevosa, was the most potent, with complete bacterial clearance at 3 mg · kg(-1). Cyclization of the peptides improved their stability but was associated with a concomitant decrease in antimicrobial activity. In summary, these anuran peptides are promising as novel therapeutic agents for treating infections from a clinically resistant pathogen.