Disease relevance of EI 546

• To define the role of neutrophil elastase (NE) in the progression of acute lung injury (ALI), we examined the effects of post-treatment with a specific NE inhibitor, sivelestat sodium hydrate (sivelestat), on ALI induced by endotoxin (ET) inhalation in hamsters [1].
• Histopathological analysis also indicated that sivelestat prevented the progression of lung inflammation such as alveolar neutrophil infiltration and hemorrhage [1].
• Additional clinical and preclinical studies with sivelestat and various other NE inhibitors should not only clarify the clinical potential of this intervention strategy, but also better define the activities of NE in inflammatory disorders such as ALI and multiple organ failure [2].
• Sivelestat, a neutrophil elastase inhibitor, attenuates neutrophil priming after hepatoenteric ischemia in rabbits [3].
• Histopathological study indicated that sivelestat (30 mg/kg/h) markedly attenuated lung histopathological changes, alveolar hemorrhage and white blood cells migration with evidence of inhibition of NE activity in BALF [4].

High impact information on EI 546

• We conclude that delayed inhibition of NE activity with sivelestat prevents subsequent progression of ALI in hamsters after ET inhalation [1].
• OBJECTIVE: The purpose of this study was to evaluate the effect of a neutrophil elastase inhibitor, sivelestat, on lipopolysaccharide-induced acute lung injury through analysis of hemodynamic changes in the pulmonary microcirculation [5].
• The number of adherent leukocytes did not increase in the sivelestat group [5].
• Protective effects of a selective neutrophil elastase inhibitor (sivelestat) on lipopolysaccharide-induced acute dysfunction of the pulmonary microcirculation [5].
• CONCLUSIONS: Intravenous sivelestat had no effect on 28-day all-cause mortality or ventilator-free days in a heterogeneous acute lung injury patient population managed with low tidal volume mechanical ventilation [6].

Chemical compound and disease context of EI 546

• 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 [7].

Biological context of EI 546

• Inhibition of the elevated plasma neutrophil elastase activity (36.5%, 66.9% and 104.3%) by continuous i.v. infusion with sivelestat (0.1, 0.3 and 1 mg/kg/h), dose-dependently attenuated the increase in lung vascular permeability 30 min after CVF injection [8].
• A specific NE inhibitor, sivelestat, significantly inhibited the NE-induced cell proliferation, cell invasion and subsequently inhibited the signal transduction pathway [9].
• Sivelestat inhibited cell growth to 23.4 and 58.0% of control values at concentrations of 100 and 1000 microg/mL, respectively [10].

Anatomical context of EI 546

• In the current study, we assessed the effects of sivelestat on the production of chemokines from cultured A549 cells, a human AEC-II-like cell line [11].
• Pulsed methylprednisolone, gamma-globulin, granulocyte colony-stimulating factor and sivelestat sodium hydrate were administrated, and thereafter the patient recovered from cytopenia and organ failure [12].
• 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 [13].

Associations of EI 546 with other chemical compounds

• Sivelestat (ONO-5046, Elaspol) is a small molecular weight inhibitor of neutrophil elastase [6].
• 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 [13].

Gene context of EI 546

• A neutrophil elastase inhibitor, sivelestat, ameliorates lung injury after hemorrhagic shock in rats [14].
• RESULTS: Sivelestat reduced both neutrophil elastase levels (p = 0.0006) and interleukin-8 production (p < 0.0001) at 120 minutes of recirculation [15].
• 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 [10].

Analytical, diagnostic and therapeutic context of EI 546

• The primary objectives of this study were to determine whether sivelestat would reduce 28-day all-cause mortality or increase the number of ventilator-free days (days alive and free from mechanical ventilation from day 1 to day 28) compared with placebo in mechanically ventilated patients with acute lung injury [6].
• In a trial of ALI patients with systemic inflammatory response syndrome, conducted in Japan by Ono Pharmaceutical scientists, sivelestat treatment improved the investigator assessment of global improvement and the percentages of patients who were removed from ventilators and transferred out of the intensive care unit [2].
• In addition, a synthetic NE inhibitor, sivelestat (ONO-5046 and LY544349), is effective in reducing measures of inflammation and injury in multiple animal models of ALI [2].
• Levels of interleukin-6 were lower in the sivelestat group than in the controls at 24, 48, and 72 h after treatment [16].
• Furthermore, sivelestat at 1 mg/kg/h almost totally prevented the increase in protein concentration in the bronchoalveolar lavage fluid without affecting lung neutrophil accumulation [8].

References