Clinical utility of the neutrophil elastase inhibitor sivelestat for the treatment of acute respiratory distress syndrome

Figures & data

Figure 1 Possible role of neutrophil elastase in pathogenesis of acute lung injury/acute respiratory distress syndrome.

Table 1 Nonclinical studies of sivelestat in lung injury models

Reference	Experimental disease models	Animal species	Main outcome measures	Findings
Kawabata et al^Citation26	Endotoxin inhalation-induced lung injury	Hamster	Protein concentration, leukocyte count, and NE activity in BALF	Sivelestat inhibited NE activity, and decreased protein concentration and leukocyte count in BALF.
Hagio et al^Citation27	Complement-mediated lung injury	Hamster	Lung vascular permeability and NE activity in plasma	Sivelestat inhibited plasma NE activity and prevented the increase in lung vascular permeability.
Sakamaki et al^Citation28	Endotoxin-induced lung injury	Guinea pig	Lung tissue wet to dry weight ratio and lung vascular permeability Neutrophil count and NE activity in BALF	Sivelestat inhibited NE activity in BALF, and prevented the increase in neutrophil count in BALF, the lung tissue wet to dry weight ratio and lung vascular permeability.
Kubo et al^Citation29	Endotoxin-induced lung injury	Sheep	Pulmonary artery pressure, pulmonary vascular resistance, and lung lymph flow Neutrophil count in lung	Sivelestat prevented the increase in pulmonary artery pressure, pulmonary vascular resistance, lung lymph flow, and neutrophil count in lung.
Kishima et al^Citation30	Ischemia and reperfusion lung injury	Rabbit	Filtration coefficient, shunt fraction, and histology	Sivelestat improved filtration coefficient, shunt fraction, and histology.
Miyazaki et al^Citation31	TNFα-induced lung injury	Rabbit	Pulmonary artery pressure and lung vascular permeability	Sivelestat attenuated the increase in pulmonary artery pressure and lung vascular permeability.
Hagio et al^Citation32	Acid aspiration-induced lung injury	Hamster	Survival rate Protein concentration, leukocyte count, and NE activity in BALF PaO2	Sivelestat reduced death by respiratory failure, and improved the increase in BALF parameters and the decrease in PaO2.
Hagio et al^Citation33	Streptococcus pneumoniae-induced pneumonia	Hamster	Lung vascular permeability Bacterial count, leukocyte count, and NE activity in BALF	Sivelestat inhibited NE activity and reduced the increase in lung vascular permeability without affecting leukocyte count. Sivelestat inhibited digestion of surfactant protein D and facilitated bacterial clearance.

Abbreviations: BALF, bronchoalveolar lavage fluid; NE, neutrophil elastase; TNF, tumor necrosis factor; PaO₂, partial pressure of arterial oxygen.

Table 2 Summary of clinical studies of sivelestat in the treatment of ALI/ARDS

Reference	Study design/location	Patients	Number of patients (sivelestat/control)	Main outcome measures	Findings
Tamakuma et al^Citation37	Phase III, double-blind, Japan	Mechanically ventilated patients with ALI with SIRS	230 (116/114)	PFI rating, mechanical ventilation weaning, discharge from ICU, and survival	Sivelestat improved PFI, ventilator-weaning rate, and ICU discharge rate. No effect on survival was observed
Zeiher et al^Citation38	Double-blind, placebo-controlled, multicenter, internationala	Mechanically ventilated patients with ALI	492 (241/246)b	Ventilator-free days and 28-day all-cause mortality	Sivelestat had no effect on ventilator-free days or 28-day mortality. The study was discontinued following a negative trend in long-term (180-day) mortality
Aikawa et al^Citation39	Phase IV, open-label, nonrandomized, Japan	Patients with ALI associated with SIRS	581 (404/177)	Ventilator free days, ventilator-weaning rate, ICU discharge rate, and 180-day survival rate	Ventilator weaning, ICU discharge, and 180-day survival rates were significantly higher in the sivelestat group than in the control group
Suda et al^Citation41	Historically controlled study, Japan	Patients who received surgery for esophageal cancer	43 (18/25)	Morbidity, duration of SIRS, mechanical ventilation, ICU stay, and organ failure assessment scores	Duration of SIRS, mechanical ventilation, and ICU stay were significantly shorter in the sivelestat group, including in patients without complications
Hayashida et al^Citation42	Prospective cohort, Japan	ALI patients with evidence of gastric aspiration	44 (23/21)	Lung injury score and P/F ratio	Sivelestat improved lung injury scores and P/F ratio compared with the control group
Tsuboko et al^Citation43	Retrospective analysis, Japan	Patients with ALI/ARDS following abdominal sepsis surgery	49 (34/15)	Ventilator-free days, ICU stay, ICU mortality, in-hospital mortality, and multiple organ dysfunction score	Duration of mechanical ventilation and ICU stay were shorter, and improvements in oxygenation, thrombocytopenia, and multiple organ dysfunction score were significantly better in the sivelestat group than in the control group
Hayakawa et al^Citation44	Retrospective analysis, Japan	Patients with sepsis complicated by ARDS and DIC	167 (34/133)	Lung injury score, P/F ratio, and length of ICU stay	The length of ICU stay in sepsis patients with DIC and ARDS was significantly shorter in the sivelestat group than in the control group. Treatment with sivelestat was an independent predictor of survival
Miyoshi et al^Citation45	Retrospective analysis, Japan	Sepsis patients with ALI associated with SIRS	110 (70/40)	Survival rate, ventilator-free days, and change in P/F ratio	Ventilator-free days and change in P/F ratio were significantly greater in the sivelestat group than in the control group. There was no significant difference in survival. Sivelestat was more effective in ALI patients with a P/F ratio ≥140 mmHg or sepsis

Notes:

a United States, Canada, Belgium, Spain, Australia, and New Zealand

b at the time the study was discontinued, 487 patients had received sivelestat or placebo.

Abbreviations: ALI, acute lung injury; ARDS, acute respiratory distress syndrome; DIC, disseminated intravascular coagulation; F₁O₂, fraction of inspired oxygen; ICU, intensive care unit; P/F, PaO₂/F_IO₂; PaO₂, partial pressure of arterial oxygen; PFI, pulmonary function improvement; SIRS, systemic inflammatory response syndrome.

Figure 2 Lung injury scores of patients included three different clinical studies for sivelestat.

Notes: The white bars represent a postmarketing study in Japan³⁹ (n=542), the black bars represent a Phase III study in Japan³⁷ (n=221), and the hatched bars represent the STRIVE (Sivelestat Trial in ALI Patients Requiring Mechanical Ventilation) study³⁸ (n=454). Data from a post hoc analysis of patient data by Ono Pharmaceutical Co Ltd (Osaka, Japan; data on file, 2008).

Table 3 Summary of adverse events of sivelestat⁴⁶

Disorders	Incidence
	1%–10%	<1%
Hypersensitivity	–	Rash
Hepatobiliary disorders	Blood bilirubin increased Alanine aminotransferase increased Aspartate aminotransferase increased Gamma-glutamyltransferase increased Blood alkaline phosphatase increased	Urobilinogen urine increased Blood lactate dehydrogenase increased
Blood and lymphatic system disorders	–	Eosinophilia Thrombocytopenia Thrombocytosis Anemia Hemorrhage
Renal and urinary disorders	–	Blood urea nitrogen increased, Blood creatinine increased Polyuria Protein urine
Others	–	Hyperkalemia Protein total decreased Injection site phlebitis

KawabataKHagioTMatsumotoSDelayed neutrophil elastase inhibition prevents subsequent progression of acute lung injury induced by endotoxin inhalation in hamstersAm J Respir Crit Care Med200016162013201810852782

 PubMed Web of Science ®Google Scholar

HagioTNakaoSMatsuokaHInhibition of neutrophil elastase activity attenuates complement-mediated lung injury in the hamsterEur J Pharmacol20014261–213113811525781

 PubMed Web of Science ®Google Scholar

SakamakiFIshizakaAUranoTEffect of a specific neutrophil elastase inhibitor, ONO-5046, on endotoxin-induced acute lung injuryAm J Respir Crit Care Med199615313913978542148

 PubMed Web of Science ®Google Scholar

KuboKKobayashiTHayanoTEffects of ONO-5046, a specific neutrophil elastase inhibitor, on endotoxin-induced lung injury in sheepJ Appl Physiol1994773133313407836137

 PubMed Web of Science ®Google Scholar

KishimaHTakedaSMiyoshiSMicrovascular permeability of the non-heart-beating rabbit lung after warm ischemia and reperfusion: role of neutrophil elastaseAnn Thorac Surg19986549139189564900

 PubMed Web of Science ®Google Scholar

MiyazakiYInoueTKyiMEffects of a neutrophil elastase inhibitor (ONO-5046) on acute pulmonary injury induced by tumor necrosis factor alpha (TNF alpha) and activated neutrophils in isolated perfused rabbit lungsAm J Respir Crit Care Med1998157189949445283

 PubMed Web of Science ®Google Scholar

HagioTMatsumotoSNakaoSElastase inhibition reduced death associated with acid aspiration-induced lung injury in hamstersEur J Pharmacol20044881–317318015044049

 PubMed Web of Science ®Google Scholar

HagioTKishikawaKKawabataKInhibition of neutrophil elastase reduces lung injury and bacterial count in hamstersPulm Pharmacol Ther200821688489118992355

 PubMed Web of Science ®Google Scholar

TamakumaSOgawaMAikawaNRelationship between neutrophil elastase and acute lung injury in humansPulm Pharmacol Ther200417527127915477122

 PubMed Web of Science ®Google Scholar

ZeiherBGArtigasAVincentJLNeutrophil elastase inhibition in acute lung injury: results of the STRIVE studyCrit Care Med20043281695170215286546

 PubMed Web of Science ®Google Scholar

AikawaNIshizakaAHirasawaHReevaluation of the efficacy and safety of the neutrophil elastase inhibitor, sivelestat, for the treatment of acute lung injury associated with systemic inflammatory response syndrome; a phase IV studyPulm Pharmacol Ther201124554955421540122

 PubMed Web of Science ®Google Scholar

SudaKKitagawaYOzawaSNeutrophil elastase inhibitor improves postoperative clinical courses after thoracic esophagectomyDis Esophagus200720647848617958722

 PubMed Web of Science ®Google Scholar

HayashidaKFujishimaSSasaoKEarly administration of sivelestat, the neutrophil elastase inhibitor, in adults for acute lung injury following gastric aspirationShock201136322322721617577

 PubMed Web of Science ®Google Scholar

TsubokoYTakedaSMiiSClinical evaluation of sivelestat for acute lung injury/acute respiratory distress syndrome following surgery for abdominal sepsisDrug Des Devel Ther20126273278

 PubMed Web of Science ®Google Scholar

HayakawaMKatabamiKWadaTSivelestat (selective neutrophil elastase inhibitor) improves the mortality rate of sepsis associated with both acute respiratory distress syndrome and disseminated intravascular coagulation patientsShock2010331141819487982

 PubMed Web of Science ®Google Scholar

MiyoshiSHamadaHItoRUsefulness of a selective neutrophil elastase inhibitor, sivelestat, in acute lung injury patients with sepsisDrug Des Devel Ther20137305316

 PubMed Web of Science ®Google Scholar

Elaspol^® (sivelestat sodium hydrate) [package insert]Osaka, JapanOno Pharmaceutical Co., Ltd2002 Available from http://www.info.pmda.go.jp/downfiles/ph/PDF/180188_3999422D1020_1_09.pdfAccessed July 10, 2014 Japanese

 Google Scholar