Uses
Treatment of acute lung injury; acute respiratory distress syndrome (elastase inhibitor).
Definition
ChEBI: Sivelestat is a N-acylglycine and a pivalate ester. It is functionally related to a N-benzoylglycine.
General Description
A cell-permeable, potent, substrate-competitive, and highly specific inhibitor of neutrophil elastase (IC50 = 19-49 nM using rat, rabbit, hamster, human, and mouse leukocyte elastase). Displays about 100-fold greater selectivity over pancreatic elastase (IC50 = 5.6 μM) and is inactive against trypsin, thrombin, plasmin, kallikrein, chymotrypsin, and cathepsin G even at concentrations as high as 100 μM. Effectively suppresses human neutrophil elastase-induced lung hemorrhage and skin capillary permeability in vivo. Also reported to inhibit mast cell Stat6-protease.
Biological Activity
sivelestat (ono-5046) is a neutrophil elastase inhibitor.human neutrophil elastase is a protease that hydrolyzes most connective tissue components, and it has been reported to participate in the tissue injury of rheumatoid arthritis, emphysema, adult respiratory distress syndrome as well as septic shock.
Biochem/physiol Actions
Sivelestat is a competitive human neutrophil elastase (HNE) inhibitor (IC50 = 44 nM, Ki = 0.2 μM). It also inhibits leukocyte elastase obtained from rabbit, rat, hamster and mouse (IC50 = 19 to 49 nM). However, it does not inhibit trypsin, thrombin, plasmin, plasma kallikrein, pancreas kallikrein, chymotrypsin and cathepsin G even at 100 μM. In in-vivo studies, it suppressed lung hemorrhage in hamster (ID50 = 82 μg/kg) by intratracheal administration and increase of skin capillary permeability in guinea pig (ID50 = 9.6 mg/kg) by intravenous administration, both of which were induced by human neutrophil elastase.
in vitro
sivelestat was found to be able to competitively inhibit the human neutrophil elastase, and it could inhibit leukocyte elastase from rat, rabbit, mouse and hamster. whereas, sivelestat even at 100 microm could not inhibit thrombin, plasmin, trypsin, pancreas kallikrein, plasma kallikrein, chymotrypsin and cathepsin g [1].
in vivo
in animal study, 50 or 100 mg/kg sivelestat were immediately administered by i.p. injection after the surgical procedure to male sprague-dawley rats with bacterial infection caused by cecal ligation and puncture. results showed that in the untreated rats, the mean arterial pressure(map) and glomerular filtration rate(gfr) decreased, while serum blood urea nitrogen(bun) and neutrophil gelatinase-associated lipocalin(ngal) levels increased. sivelestat was found to promot the survival of the rats with sepsis, restored the impairment of map and gfr, and inhibited the increased bun and ngal levels. in addition, sivelestat could suppress the clp-induced macrophage infiltration in the rats [2].
storage
4°C, protect from light
References
[1] kawabata k,suzuki m,sugitani m,imaki k,toda m,miyamoto t. ono-5046, a novel inhibitor of human neutrophil elastase. biochem biophys res commun.1991 jun 14;177(2):814-20.
[2] li g,jia j,ji k,gong x,wang r,zhang x,wang h,zang b. the neutrophil elastase inhibitor, sivelestat, attenuates sepsis-related kidney injury in rats. int j mol med.2016 sep;38(3):767-75.
[3] aikawa n,kawasaki y. clinical utility of the neutrophil elastase inhibitor sivelestat for the treatment of acute respiratory distress syndrome. ther clin risk manag.2014 aug 5;10:621-9.
