Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: HUMANGGP:023979 (neutrophil elastase)
 3,151 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study examined whether the specific inhibition of neutrophil elastase by sivelestat sodium hydrate (sivelestat) reduced deaths associated with severe acute lung injury after hydrochloric acid (HCl) aspiration in hamsters. Animals that received a single intratracheal instillation of HCl (0.2 N, 200 microL) time-dependently died by occlusion of their trachea with inflammatory exudate. In a time course study, these animals developed severe lung injury, peaking 12 to 24 h after HCl instillation, as indicated by hemorrhage and a massive increase in the protein concentration of bronchoalveolar lavage fluid. These changes were closely correlated with neutrophil elastase activity in bronchoalveolar lavage fluid. Sivelestat (0.01, 0.1 and 1 mg/kg/h), when intravenously infused during the first 48 h post-HCl instillation, dose-dependently reduced death in HCl-instilled hamsters. In a separate experiment, analysis of bronchoalveolar lavage fluid parameters and partial pressure of arterial oxygen (PaO(2)) 8 h post-HCl instillation showed that sivelestat at 1 mg/kg/h, i.v. significantly improved both bronchoalveolar lavage fluid parameters and PaO(2) levels with evidence of the inhibition of neutrophil elastase activity in bronchoalveolar lavage fluid. These results suggest that neutrophil elastase plays a significant role in this type of severe acute lung injury that leads to death by respiratory failure.
 ...
PMID:Elastase inhibition reduced death associated with acid aspiration-induced lung injury in hamsters. 1504 49

ONO-5046 (sivelestat) is a competitive inhibitor of human neutrophil elastase from Ono Pharmaceutical, which is awaiting FDA approval for the treatment of pulmonary fibrosis and idiopathic interstitial pneumonia [349488]. An NDA was filed in Japan in September 1998 [299667]. It is in phase II trials for the treatment of acute circulatory failure [171678]. It is also being investigated as a potential treatment of arthritis [230100]. In animal models of asthma, sivelestat decreased the level of hemorrhage and protein extravasation into the bronchoalveolar lavage fluid after the administration of a 40 mg/kg injection of phorbol myristate acetate [188186]. The compound also inhibited the growth of human lung cancer cell lines in SCID mice [269736]. Sivelestat inhibits gastric lesion formation in rats subjected to water immersion restraint stress. Low oral bioavailability in vivo is due to extensive hepatic first-pass metabolism. Endotoxin-induced lung injury in rabbits was attenuated by pretreatment with sivelestat [276401]. In 1996, analysts at Yamaichi estimated sivelestat would be launched in Japan between 1998/9 and peak annual sales would be less than 5 billion yen [216018].
 ...
PMID:ONO-5046 (Ono Pharmaceutical). 1610 41

Many studies have suggested that neutrophil elastase (NE) may contribute to multiple organ failure (MOF) and acute injury of lung endothelial cells. It is therefore conceivable that NE inhibitors may improve the outcome of MOF patients. A synthetic NE inhibitor, sivelestat, which was developed and released in Japan, inhibited inflammatory reactions in various animal models. We examined the medical records of patients requiring more than two days of respiratory care in four intensive care units to investigate whether sivelestat contributed to improvement of their conditions. A total of 110 patients were divided into two groups (sivelestat treated group of 57 patients and untreated group of 53 patients). The conditions and age of the patients were similar in both groups. Sivelestat (0.2 mg/kg/hr) was administered continuously for 14 days beginning on the day of the intensive care unit (ICU) admission or for less than 14 days until discharge from the ICU. Hospital mortality differed significantly between the two groups (treated: 19% and untreated: 40%, p < 0.05). The severity of acute lung injury is defined by the ratio of arterial oxygen partial pressure (PaO2)/fraction concentration of oxygen in the inspired air (FiO2). When the PaO2/FiO(2) ratio is more than 200 mmHg, the morbidity is lower. In patients with PaO2/FiO2 ratio more than 200 mmHg, the hospital mortality was 33.3% (7/21) in the untreated group and 6.0% (1/18) in the treated group (p = 0.0236). We conclude that administration of sivelestat reduces mortality of critically ill patients.
 ...
PMID:Sivelestat, a neutrophil elastase inhibitor, reduces mortality rate of critically ill patients. 1614 83

The underlying mechanism involved in the interaction between neutrophil elastase inhibitors and tachykinins has not been elucidated. In this study we have examined the effects of sivelestat, a neutrophil elastase inhibitor, on the in vitro responses of airways from lipopolysaccharide (LPS)-untreated or -treated guinea-pigs to substance P. Substance P (0.01-30 micromol/l) produced concentration-dependent contractions of both tracheal and bronchial ring preparations of LPS-untreated or -treated guinea-pigs. Responsiveness to substance P in these isolated airway preparations was augmented by either epithelium removal or LPS treatment. In epithelium-intact tracheal ring preparations isolated from LPS-untreated guinea-pigs, sivelestat (100 micromol/l) significantly inhibited substance P-induced contractions. The inhibitory action was markedly attenuated by pretreatment with L-NAME (100 micromol/l) or indomethacin (2 micromol/l), and was almost undetected following removal of the epithelium. On the other hand, in bronchial ring preparations isolated from LPS-untreated guinea-pigs, sivelestat had only a very slight effect on substance P-induced contraction of the epithelium-intact preparation, whereas sivelestat greatly inhibited contraction in epithelium-removed bronchial ring preparations. In LPS-treated guinea-pigs, whether the epithelium was intact or not, sivelestat significantly inhibited the substance P-induced contraction of bronchial ring preparations. Pretreatment with L-NAME (100 micromol/l) or indomethacin (2 micromol/l) did not affect the inhibitory effect of sivelestat in bronchial ring preparations. In conclusion, epithelium removal or LPS treatment induced hyperreactivity to substance P in the guinea-pig airway. Sivelestat caused epithelium-, nitric oxide- and prostaglandin-dependent inhibition of the substance P-induced contraction of isolated guinea-pig tracheal ring preparations. In contrast, the inhibitory effect of sivelestat on substance P-induced contraction of guinea-pig bronchial ring preparations is mediated by epithelium-, nitric oxide- and prostaglandin-independent mechanisms. Sivelestat may be effective in reducing the airway hyperresponsiveness to tachykinins induced by epithelial injury as occurs in LPS-mediated inflammatory lung diseases.
 ...
PMID:Epithelium-dependent and -independent inhibitory effects of sivelestat, a neutrophil elastase inhibitor, on substance P-induced contraction of airway smooth muscle in lipopolysaccharide-treated guinea-pigs. 1642 65

Neutrophil elastase is a neutral serine proteinase produced by polymorphonuclear leukocytes and monocytes/macrophages, especially under surgical stress. In the present study, we investigated whether NE promotes cell growth by activation of EGFR to elucidate whether surgical stress induces tumor proliferation and progression. Furthermore, we examined the antitumor effect of a specific NE inhibitor, sivelestat. Cell growth assays were carried out in vitro and in vivo using TMK-1 gastric cancer cells. TMK-1 cell growth was stimulated to 118% of that of the control cells after 48 h stimulation with 1 microg/mL NE according to an MTT assay. Sivelestat inhibited cell growth to 23.4 and 58.0% of control values at concentrations of 100 and 1,000 microg/mL, respectively. NE rapidly phosphorylated EGFR in only 5 min and triggered the ERK1/2-mitogenic signaling pathway in TMK-1. It was further demonstrated that NE-induced EGFR phosphorylation was transactivated through TGF-alpha, using ELISA. NE increased the cleavage of TGF-alpha from the cell surface 30-fold compared with the cells without treatment. Interestingly, sivelestat significantly reduced NE-induced EGFR phosphorylation and ERK1/2 activation and completely blocked the release of TGF-alpha from the TMK-1 cell surface. In a xenograft study, the addition of ventrotomy as a surgical stress promoted tumor growth. Sivelestat significantly suppressed the tumor growth induced by surgical stress. These results indicate that sivelestat suppresses the growth of gastric cancer cells by inhibiting the release of TGF-alpha stimulated by NE, which often occurs after surgical stresses.
 ...
PMID:Sivelestat, a specific neutrophil elastase inhibitor, suppresses the growth of gastric carcinoma cells by preventing the release of transforming growth factor-alpha. 1691 98

Treatment with all-trans retinoic acid (ATRA) improves the prognosis of patients with acute promyelocytic leukemia (APL), but ATRA syndrome may occur as a possible fatal side effect, especially in cases refractory to medication or involving pulmonary hemorrhage. We describe two patients with APL who suffered from intracranial hemorrhage. The first patient was a 16-yr-old girl who was treated with ATRA and then developed respiratory distress refractory to treatment with dexamethasone combined with anthracycline-cytarabine cytoreduction therapy. Treatment with Sivelestat, a small molecule inhibitor of neutrophil elastase, achieved rapid improvement in oxygenation and chest radiograph findings, and the patient has been in complete remission for 24 months. The second patient was a 10-yr-old boy in whom pulmonary hemorrhage developed following administration of ATRA, dexamethasone and cytoreduction therapy. Aspiration and administration of Sivelestat improved oxygenation and he remained stable. Hematological improvement was also achieved, but the patient died of brain dysfunction because of cerebral edema accompanied by intracranial bleeding. The two cases suggest that Sivelestat may be effective as an additional agent in the treatment of refractory ATRA syndrome, and, therefore, prospective randomized studies of treatment protocols are warranted.
 ...
PMID:Sivelestat relieves respiratory distress refractory to dexamethasone in all-trans retinoic acid syndrome: a report of two cases. 1693 Jan 40

An excessive amount of neutrophil elastase (NE) released from neutrophils accumulated in the lung can cause tissue damage, despite its importance to host defense against microbial pathogens in severe pneumonia. Therefore, NE inhibitors may reduce tissue damage in lungs with severe pneumonia. In this study, the efficacy of a specific NE inhibitor, sivelestat sodium hydrate (sivelestat), was examined using a murine model of severe pneumonia with Streptococcus pneumoniae. Male mice (CBA/JNCrj, aged 5 weeks) were inoculated intranasally with penicillin-susceptible S. pneumonia (1.0 x 10(5) CFU/mouse). Sivelestat (3 mg/kg) or physiological saline was administered every 12 hours beginning at 12 hours after inoculation. Survival was primarily evaluated. Bronchoalveolar lavage fluid (BALF) and blood were collected at 30 hours after inoculation. Thus, cell counts in BALF and numbers of viable bacteria in blood were determined. Histopathological analysis was also performed. Sivelestat significantly prolonged survival when compared with the control group (P < .05), although all animals died within 4 days. Cell count and histopathological analysis indicated that sivelestat prevented the progression of lung inflammation, such as alveolar neutrophil infiltration and hemorrhage. Furthermore, the number of viable bacteria in blood was significantly lower in the sivelestat group than in the control group (5.69 +/- 0.27 and 6.75 +/- 0.32 log CFU/mL, respectively; mean +/- SEM, P < .01). Sivelestat prolonged survival in this model. A possible explanation for the improved survival is that sivelestat prevents tissue damage by inhibiting NE activity in the lung. Therefore, NE inhibitors may be useful for treating with patients with severe pneumonia.
 ...
PMID:Effects of specific neutrophil elastase inhibitor, sivelestat sodium hydrate, in murine model of severe pneumococcal pneumonia. 1745 3

Mechanical ventilation can paradoxically cause acute lung injury, which is termed ventilator-induced lung injury. Neutrophil recruitment and neutrophil elastase release play a central role in the pathogenesis of ventilator-induced lung injury including cell damage, extracellular matrix degradation and alveolar-capillary hyperpermeability. We therefore speculated that neutrophil elastase inhibition ameliorates ventilator-induced lung injury. Anesthetized C57/BL6 mice received mechanical ventilation with a high tidal volume (V(T); 20 ml/kg) for 4 h. The neutrophil elastase inhibitor (sivelestat, 100 mg/kg) or saline was given intraperitoneally (i.p.) 30 min before ventilation. Sivelestat completely inhibited both neutrophil elastase and myeloperoxidase activities that were increased by ventilation, and attenuated the histopathological degree of lung damage, neutrophil accumulation and lung water content, as well as the concentration of macrophage inflammatory protein (MIP)-2, interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha in bronchoalveolar lavage fluid and serum. Moreover, mechanical ventilation increased the phosphorylation of c-Jun NH2-terminal kinase (JNK) and the expression of early growth response gene-1 (Egr-1) mRNA, and these increases were also recovered by sivelestat. The terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) staining revealed apoptotic cells mainly in alveolar epithelial cells and their numbers corresponded to histological damage. These data suggested that sivelestat could protect against ventilator-induced lung injury by suppressing apoptotic responses through mechanical stress-induced cell signaling in addition to inhibiting neutrophil chemotaxis.
 ...
PMID:Neutrophil elastase inhibitor (sivelestat) attenuates subsequent ventilator-induced lung injury in mice. 1759 28

Idiopathic interstitial fibrosis (IPF) is a chronic, usually fatal lung disease of unknown etiology. There are few specific therapies for acute exacerbation of IPF and factors predicting the onset or severity of this syndrome are not clearly understood. A neutrophil elastase inhibitor, sivelestat (ONO-5046) has been commercially available in Japan since 2002. This inhibitor has a potent effect in the treatment of ALI/ARDS. To evaluate the outcome of patients with acute exacerbation of IPF treated with sivelestat and estimate prognostic factors, we investigated 10 patients with acute exacerbation of IPF who were intubated and mechanically ventilated. We analyzed the outcome of patients with acute exacerbation of IPF until day 180 and measured the P/F ratio, PEEP levels, the values of peripheral white blood cell number, and C-reactive protein (CRP) on day 0, 3, 7 after admission. Serum KL-6 and surfactant protein D (SP-D) concentration on day 0 were also analyzed. All patients were treated with sivelestat and methylprednisolone (mPSL) pulse therapy for 3 days from day 0 and maintenance therapy with prednisone (0.5 mg/kg/day) were continued. Of the 10 patients. 4 patients had survived (40%) and 6 patients had died (60%) at day 180 from the onset of acute exacerbation of IPF. In survivors, P/F ratio, PEEP levels, and CRP values significantly improved on day 7 (p<0.05). Serum KL-6 and SP-D were lower in survivors on day 0 (p<0.05). Taken together, serum KL-6 and SP-D may prove valuable as biochemical markers of prognosis in acute exacerbation of IPF. Sivelestat may have potential in the treatment of acute exacerbation of IPF.
 ...
PMID:[Outcome of patients with acute exacerbation of idiopathic interstitial fibrosis (IPF) treated with sivelestat and the prognostic value of serum KL-6 and surfactant protein D]. 1764 40

Sivelestat sodium hydrate is a selective inhibitor of neutrophil elastase (NE), and is effective in acute lung injury associated with systemic inflammatory response syndrome (SIRS). The effect of Sivelestat for postoperative clinical courses after transthoracic esophagectomy was investigated. Consecutive patients with carcinoma of the thoracic esophagus who underwent transthoracic esophagectomy between 2003 and 2004 were assigned to the Sivelestat-treated group (n = 18), and those between 1998 and 2003 were assigned to the control group (n = 25). The morbidity rate, duration of postoperative SIRS, mechanical ventilation, and intensive care unit (ICU) stay, and the sum of the sequential organ failure assessment scores at all time points after the operation were compared. Serum NE activities and serum concentrations of TNF-alpha, IL-1beta, IL-6, and high mobility group box chromosomal protein 1 (HMGB1) were measured. Postoperative complications developed in three patients in the control group, and one in the Sivelestat-treated group. The durations of SIRS, mechanical ventilation, and ICU stay were significantly shorter in the Sivelestat-treated group. Even in patients without complications, the durations of mechanical ventilation, and ICU stay were also significantly shorter, and the arterial oxygen pressure/fraction of inspired oxygen ratio at postoperative day 1 was significantly higher in the Sivelestat-treated group. Serum NE activities and serum concentrations of IL-1beta, IL-6, and HMGB1 were significantly suppressed in the Sivelestat-treated group. Postoperative Sivelestat treatment after transthoracic esophagectomy improves the condition of SIRS and postoperative clinical courses, even in patients without complications.
 ...
PMID:Neutrophil elastase inhibitor improves postoperative clinical courses after thoracic esophagectomy. 1795 22


1 2 3 4 Next >>