Sivelestat Sodium Research Articles

Acute Lung Injury with Alveolar Hemorrhage Due to a Novel Swine-Origin Influenza A (H1N1) Virus

A 40-year-old woman with no major medical illness except for morbid obesity (BMI 40.7) was admitted to our hospital because of bilateral pneumonia due to a novel swine-origin influenza A (H1N1) virus (S-OIV). Non-invasive ventilation was introduced because of the hypoxemia. The description of bronchoalveolar lavage fluid findings showed an alveolar hemorrhage and neutrophilic inflammation. No evidence of bacterial infection was found. She was treated with oseltamivir and sivelestat sodium, neutrophil elastase inhibitor and thereafter was successfully discharged from the hospital. This case is the first report of a patient with acute lung injury with an alveolar hemorrhage caused by the S-OIV.

Effect of Neutrophil Elastase Inhibitor (Sivelestat Sodium) in the Treatment of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS): A Systematic Review and Meta-Analysis

Sivelestat is neutrophil elastase inhibitor, which is widely used in Japan for the treatment of acute lung injury. However, the clinical efficacy of the medication has not been convincingly demonstrated. We conducted a systematic review and meta-analysis of randomized controlled trials on sivelestat for the treatment of acute lung injury and acute respiratory distress syndrome. Studies were identified using MEDLINE, EMBASE, Cochrane library, conference proceedings, and references of included studies. Authors were contacted if necessary. ICHUSHI, the Japanese database for medical literature and conference proceedings was also used for the search, since many studies on sivelestat were published in Japanese language and not registered in major databases such as MEDLINE. The primary outcome was mortality within 28-30 days after randomization. Relative risks were pooled with the random effect model. 8 trials were included in the analysis. There was no difference in mortality within 28-30 days after randomization (relative risk 0.95, 95% confidence interval 0.72 to 1.26). Subgroup analysis conducted only on studies conducted in Japan showed the same result (0.59, 0.28 to 1.28). There was no difference in mechanical ventilation days (standardized mean difference -0.43, -1.12 to 0.27), but sivelestat was associated with a better short term PaO(2)/FiO(2) ratio (0.30, 0.05 to 0.56). Heterogeneity was not significant for the main analysis and funnel plot did not suggest publication bias. Sivelestat was not associated with decreased mortality, even when including studies published in Japanese language.

Prospective randomized controlled study on the effects of perioperative administration of a neutrophil elastase inhibitor to patients undergoing video-assisted thoracoscopic surgery for thoracic esophageal cancer

Sivelestat sodium hydrate (Ono Pharmaceutical Co., Osaka, Japan) is a selective inhibitor of neutrophil elastase (NE) and is effective in reducing acute lung injury associated with systemic inflammatory response syndrome (SIRS). We conducted a prospective randomized controlled study to investigate the efficacy of perioperative administration of sivelestat sodium hydrate to prevent postoperative acute lung injury in patients undergoing thoracoscopic esophagectomy and radical lymphadenectomy. Twenty-two patients with thoracic esophageal cancer underwent video-assisted thoracoscopic esophagectomy with extended lymph node dissection in our institution between April 2007 and November 2008. Using a double-blinded method, these patients were randomly assigned to one of two groups preoperatively. The active treatment group received sivelestat sodium hydrate intravenously for 72 hours starting at the beginning of surgery (sivelestat-treated group; n= 11), while the other group received saline (control group; n= 11). All patients were given methylprednisolone immediately before surgery. Postoperative clinical course was compared between the two groups. Two patients (one in each group) were discontinued from the study during the postoperative period because of surgery-related complications. Of the remaining 20 patients, 2 patients who developed pneumonia within a week after surgery were excluded from some laboratory analyses, so data from 18 patients (9 patients in each group) were analyzed based on the arterial oxygen pressure/fraction of inspired oxygen ratio, white blood cell count, serum C-reactive protein level, plasma cytokine levels, plasma NE level, and markers of alveolar type II epithelial cells. In the current study, the incidence of postoperative morbidity did not differ between the two groups. The median duration of SIRS in the sivelestat-treated group was significantly shorter than that in the control group: 17 (range 9-36) hours versus 49 (15-60) hours, respectively (P= 0.009). Concerning the parameters used for the diagnosis of SIRS, the median heart rates on postoperative day (POD) 2 were significantly lower in the sivelestat-treated group than in the control group (P= 0.007). The median arterial oxygen pressure/fraction of inspired oxygen ratio of the sivelestat-treated group were significantly higher than those of the control group on POD 1 and POD 7 (POD 1: 372.0 [range 284.0-475.0] vs 322.5 [243.5-380.0], respectively, P= 0.040; POD 7: 377.2 [339.5-430.0] vs 357.6 [240.0-392.8], P= 0.031). Postoperative white blood cell counts, serum C-reactive protein levels, plasma interleukin-1beta, tumor necrosis factor-alpha levels, and plasma NE levels did not differ significantly between the two groups at any point during the postoperative course, nor did serum Krebs von den Lungen 6, surfactant protein-A, or surfactant protein-D levels, which were used as markers of alveolar type II epithelial cells to evaluate the severity of lung injury. Plasma interleukin-8 levels were significantly lower in the sivelestat-treated group than in the control group on POD 3 (P= 0.040). In conclusion, perioperative administration of sivelestat sodium hydrate (starting at the beginning of surgery) mitigated postoperative hypoxia, partially suppressed postoperative hypercytokinemia, shortened the duration of SIRS, and stabilized postoperative circulatory status after thoracoscopic esophagectomy.

A pilot randomized study of the neutrophil elastase inhibitor, Sivelestat, in patients undergoing cardiac surgery

The primary objective of this study was to determine the feasibility and safety of treatment with Sivelestat in humans to attenuate post-cardiopulmonary bypass lung injury. Twenty patients scheduled to undergo on-pump coronary artery bypass surgery were randomized to receive either 0.3 mg/kg/h intravenous Sivelestat sodium (Sivelestat group; n=10) or isotonic sodium chloride solution (placebo group, n=10), peri-operatively. Postoperative adverse events were recorded until hospital discharge. The alveolar-arterial oxygen gradient (A-aDO(2)), intrapulmonary shunt (Qs/Qt) and dynamic lung compliance were determined four times peri-operatively as secondary exploratory outcomes. All patients completed study protocol without discontinuation of intervention. The number of total adverse clinical outcomes, including atrial fibrillation and superficial wound infection, was nine in seven patients in the placebo group and four in four patients in the Sivelestat group (P=0.37). The mean duration of the postoperative hospital stay was shorter in the Sivelestat group (19.0+/-3.4 vs. 25.6+/-9.1, P=0.04). The exploratory analysis of relative changes in lung functions showed trends toward attenuation of lung injury in the Sivelestat group in all three pulmonary parameters, though the inter-group difference could be due to chance (P>0.05). It is feasible to administer Sivelestat as a preventive measure against lung dysfunction after cardiopulmonary bypass.

Protective effect of sivelestat sodium hydrate (ONO-5046) on ischemic spinal cord injury

Prevention of paraplegia remains an important issue in repair of descending thoracic and thoracoabdominal aneurysms. Therefore, we investigated the protective effect of sivelestat sodium hydrate (ONO-5046) on ischemia-induced spinal cord damage in a rabbit model. Twenty New Zealand white rabbits were divided into two equal groups; ONO-5046 (1.6 mg/kg)+isotonic NaCl (30 ml) was administered selectively to the spinal cord via the lumbar arteries for the first 3 min during 30 min of infra-renal aorta clamping in the experimental group (group E), whereas NaCl was given alone in the control group (group C). Motor function of the lower limbs was assessed two days later by Tarlov criteria. The number of intact motor neurons in the anterior segment of the cord (L5 level) was counted after hematoxylin-eosin staining and the number of apoptotic motor neurons after TUNEL staining. Motor function of the lower limbs in group E was significantly better (P=0.003) than that in group C. The number of intact motor neurons was greater and of apoptotic motor neurons was less in group E than C. Selective infusion of sivelestat sodium hydrate directly into the spinal cord via the lumbar arteries significantly attenuated functional and morphological ischemia-induced spinal cord injury.

Neutrophil elastase inhibitor (sivelestat) reduces the Levels of inflammatory mediators by inhibiting NF-kB

Sivelestat sodium hydrate (sivelestat) is a specific synthetic inhibitor of neutrophil elastase (NE). Various studies suggest that sivelestat treatment reduces inflammation. In this study, we tested the hypothesis that sivelestat acts as an inhibitor of inflammatory mediators and prevents nuclear factor-kB (NF-kB) activation. In the presence and absence of sivelestat, the mouse macrophage cell line RAW 264.7 was stimulated with lipopolysaccharide (LPS) and the levels of inflammatory mediators (TNF-alpha, IL-6 and high mobility group box 1 (HMGB1)) and nitrite in the cell supernatant were measured, along with inducible nitric oxide synthase (iNOS) expression. While LPS administration increased the secretion of inflammatory mediators and nitric oxide (NO), sivelestat decreased the secretion of these mediators. Cell signaling studies demonstrated that sivelestat decreased NF-kB activation by inhibiting IkB phosphorylation. Sivelestat may inhibit the various inflammatory mediators through NF-kB inhibition.

An Overwhelming Postsplenectomy Infection Syndrome Associated with Diabetes Mellitus

A 72-year-old male diabetic patient was admitted due to autoimmune hemolytic anemia (AIHA). We started 1mg/kg weight of prednisolone daily and multiple daily insulin infusion for hyperglycemia. Gall bladder cancer and early stage gastric cancer were then diagnosed. We removed the gall bladder and the spleen for treatment of AIHA without prednisolone for better control of diabetes mellitus. Five weeks later, endoscopic gastromucosal resection (EMR) was performed for gastric cancer. The patient suffered from fever and respiratory failure after 4 days. Chest computed tomography showed consolidation, bronchial wall thickening and a ground glass appearance in bilateral lungs. Although the sputum and blood culture were negative, β-D-glucan and mannan antigen increased. Neutrophilia (87%) was shown. The WBC count had not increased (7300/μl) compared with the CRP elevation (21.8mg/dl). Therefore, we diagnosed overwhelming postsplenectomy infection syndrome followed by atypical pathogen infection. We used ciprofloxacin and fosfluconazol, respirator at low tidal volume ventilation, sivelestat sodium hydrate and methylprednisolone for respiratory failure and regular insulin aiming for a blood glucose range of from 80 to 140mg/dl. The patient subsequently recovered.

Effects of Sivelestat Sodium on Perioperative Organ Function in Acute Aortic Syndrome

Effects of Sivelestat Sodium on Perioperative Organ Function in Acute Aortic Syndrome

肺切除後の術後経過に及ぼす，シベレスタットナトリウムの効果

要旨 【目的】 急性肺障害発症後の治療薬である好中球エラスターゼの選択的阻害薬であるシベレスタットナトリウムの予防的投与の有効性についての研究は未だ十分ではない．そこで今回，肺癌切除手術例に対して，術中よりシベレスタットナトリウムを使用し，その効果について検討した．【対象と方法】 肺癌症例 10 例を対象とした．性は男性，5 例，女性 5 例，年齢は 60～80 歳 (平均 70 歳)．術式は 9 例が肺葉切除で，1 例が肺摘除であ った．この 10 例を無作為に抽出し対照群とシベレスタット使用群 (以下 Siv. 群) に 5 例ずつ振り分けた．Siv. 群については，麻酔開始後より 24 時間 0.2 mg/kg/h を投与した．【結果】 E-XDP, HMGB1, BNP, IL-1b に両群間の差は無かった．酸素化能では，統計学的有意差は無かったが，Siv. 群の方が対照群に比べ P/F 比が保たれていた． 【まとめ】 肺癌の術中術後にシベレスタットナトリウムを使用することが，術後の肺機能障害を軽度にとどめる可能性があると考えられた．

Multiple Organ Failure Followed by Intrauterine Klebsiella Pneumoniae Infection Associated with Diabetes Mellitus

A 49-year-old semi-conscious woman was admitted due to fever and dehydration. Disseminated intravascular coagulation (DIC), renal dysfunction and diabetic ketoacidosis were detected. Whole body computed tomography showed multiple nodular lesions in bilateral lungs and kidneys indicating septic emboli, and intrauterine lesions. We diagnosed multiple organ failure followed by intrauterine infection due to untreated diabetes mellitus. Vaginal discharge and blood culture revealed Klebsiella pneumoniae. We used multi-antibiotics for sepsis, respirator at low tidal volume ventilation, 200mg of sivelestat sodium hydrate and 300mg of hydrocortisone for respiratory failure, gabexate mesilate and anti-thrombin III for DIC, transfusion for bleeding from uterus and regular insulin aiming for a blood glucose range of from 80 to 140mg/dl. When we extracted the myoma uteri, the patient's fever subsided and the C-reactive protein became negative. Treating diabetes mellitus is important for the prevention of severe infection.

Sivelestat attenuates postoperative pulmonary dysfunction after total arch replacement under deep hypothermia

Total arch replacement necessitating deep hypothermia with circulatory arrest has a greater effect on pulmonary function than other cardiac surgery using cardiopulmonary bypass (CPB). Since April 2004, 100mg of sivelestat sodium hydrate was administrated by bolus injection into pulp circuit at the initiation of CPB in every case performed total arch replacement. We investigated the hypothesis that prophylactic use of the drug attenuates post-pump pulmonary dysfunction. A retrospective analysis of 120 consecutive patients who underwent total arch replacement from August 2001 to December 2006 was conducted. Patients were divided into two groups according to the date of surgery, April 2004, when we started sivelestat administration. Group A (n=60), operated after April 2004, was administrated sivelestat at the initiation of CPB. Group B (n=60), before April 2004, was not administrated. Time courses of hemodynamic variables were evaluated until 24h after surgery and those of respiratory variables and inflammatory markers until 48 h after surgery. There were no significant differences in patient age, sex, prevalence of chronic obstructive lung disease, preoperative lung function, time of operation and CPB, minimum temperature, and aprotinin usage. Hospital mortality occurred in two patients in the group B (3.3%) and no patient in group A (0%). Postoperative hemodynamic variables were not different between the two groups. Respiratory index, oxygenation index were significantly better in patients pretreated with sivelestat (respiratory index; p<0.001, oxygenation index; p<0.001, respectively). CRP was significantly lower in patients pretreated with sivelestat (p=0.022). Except for patients who required tracheostomy or re-exploration for bleeding, patients pretreated with sivelestat were extubated significantly shorter (group A: 12.6+/-10.8h, group B: 25.5+/-12.9h, p=0.033). No patient with postoperative respiratory failure requiring tracheostomy was noted in sivelestat group. Prophylactic administration of sivelestat at the initiation of CPB results in better postoperative pulmonary function, leading to earlier extubation time. Our study suggests that sivelestat was effective in facilitating postoperative respiratory management in total arch replacement.

The effect of sivelestat sodium on post-cardiopulmonary bypass acute lung injury in a neonatal piglet model

Cardiopulmonary bypass may cause acute lung injury and can seriously affect postoperative outcome, especially in younger patients. A synthesized neutrophil elastase inhibitor, sivelestat sodium, may be most effective when used during cardiopulmonary bypass. After anesthesia induction, sivelestat (2 mg/kg/h) was given to the SS group (n=7), and 0.9% saline solution to the placebo group (n=7). Piglets were placed on hypothermic cardiopulmonary bypass and subjected to myocardial ischemia (2 h) induced by cold crystalloid cardioplegia. At 24 h after surgery, PaO(2)/FiO(2) ratio and alveolar-arterial oxygen difference were significantly better in the SS group (379.1+/-93.9 mmHg and 250.5+/-89.3 mmHg) than the placebo group (232.4+/-105.3 mmHg, and 378.3+/-90.8 mmHg, P<0.05). Interleukin-8 level in the epithelial lining fluid was above the lowest standard in 6 out of 7 (4.5, 12.9, 24.6, 27.7, 37.7, and 159.8; mean=44.5+/-57.6 g/l) in the placebo group, and in 2 out of 7 (36.1 and 67.8 g/l) in the SS group (P<0.05). The median histological score of acute lung injury in the harvested lung was 3 (2-5) in the placebo group and 1 (1-5) in the SS group (P<0.05). Intraoperative administration of sivelestat effectively reduced neutrophil induction and activation in the lung and improved oxygenation after cardiopulmonary bypass in a piglet model.

A Neutrophil Elastase Inhibitor, Sivelestat, Reduces Lung Injury Following Endotoxin-Induced Shock in Rats by Inhibiting HMGB1

Neutrophil elastase (NE) plays an important role in the progression of acute lung injury (ALI). Sivelestat sodium hydrate (Sivelestat) is a highly specific synthetic inhibitor of NE. High mobility group box 1 (HMGB1) is one of the key mediators in the development of sepsis. The aim of this study was to evaluate the effect of sivelestat and to determine whether it can reduce lipopolysaccharide (LPS)-induced acute lung injury in rats. Rats were randomly divided into a negative control group, an LPS-induced sepsis group, and a group treated with sivelestat prior to LPS administration. Animals in the sivelestat group received a bolus of 10 mg/kg of sivelestat injected into the intraperitoneal cavity before the LPS treatment. Furthermore, rats were administered sivelestat at 0, 1, 3, and 6 h following LPS treatment. We measured cytokine and HMGB1 levels in the serum after the induction of sepsis. In addition, we observed histopathology, wet/dry weight ratio, inducible nitric oxide synthase and HMGB1 expression in the lung tissue. Lung histopathology was significantly improved in the sivelestat group compared to the LPS group. Serum and pulmonary HMGB1 levels were lower over time among sivelestat-treated animals. Furthermore, inhibition of NF-kappaB activity was observed with the administration of sivelestat. These results suggest that sivelestat reduces LPS-induced lung injury at least partially by inhibiting inflammation and NF-kappaB activity.

Sivelestat Relaxes Porcine Coronary Artery via Inhibition of Ca2+ Sensitization Induced by a Receptor Agonist

Sivelestat sodium hydrate (sivelestat) is a novel synthetic drug and specific inhibitor of neutrophil elastase that has been approved in Japan as a treatment for acute lung injury associated with systemic inflammatory response syndrome. There are no reports on the effects of sivelestat on the contractile regulation of vascular smooth muscle. The purpose of the present study was to assess the effects of sivelestat on porcine coronary artery. Sivelestat induced concentration-dependent (3 x 10 to 3 x 10 M) vasorelaxation in U46619 (100 nM)-precontracted porcine coronary artery with or without endothelium. Simultaneous measurements of tension and the cytosolic Ca concentration ([Ca]i) revealed that sivelestat shifted the [Ca]i-tension curve to the right and downward during stimulation with 118 mM K and 100 nM U46619. In beta-escin-permeabilized arterial strips, sivelestat abolished GTP plus U46619-induced contractions at constant [Ca]i, whereas it had no effect on Ca-induced contractions. Thus, sivelestat relaxes porcine coronary artery smooth muscle via the selective inhibition of Ca sensitization induced by a receptor agonist, without affecting Ca-induced contraction.

Efficient Synthesis of Sivelestat Sodium Hydrate

An efficient and scaleable synthesis of sivelestat sodium hydrate has been developed.

CONTINUOUS INFUSION OF SIVELESTAT SODIUM HYDRATE PREVENTS LIPOPOLYSACCHARIDE‐INDUCED INTESTINAL PARALYSIS AND HYPOTENSION IN CONSCIOUS GUINEA‐PIGS

1. Sivelestat sodium hydrate (sivelestat), a neutrophil elastase inhibitor, is used to treat acute lung injury associated with systemic inflammatory response syndrome, but its effects have not been described for endotoxaemia. In the present study, we examined the effects of a continuous infusion of sivelestat on intestinal mechanical activity and blood pressure using an endotoxaemic model in conscious, unrestrained guinea-pigs. 2. Guinea-pigs underwent laparotomy while anaesthetized and were implanted with a force transducer sutured onto the taenia caecum. With this transducer, changes in tension in the intestinal longitudinal muscle were measured continuously via telemetry. Catheters were inserted into the carotid artery and jugular vein, were tunnelled subcutaneously and were accessed from the back of the neck. These catheters were connected to a cannula swivel and were used to monitor arterial pressure as well as to administer drugs i.v. in conscious, unrestrained guinea-pigs. Twenty hours after surgery, guinea-pigs received a single dose of lipopolysaccharide (LPS; 0.3 mg/kg, i.p.) 10 min after the start of a continuous 2 h i.v. infusion of sivelestat (30 mg/kg per h) or vehicle (saline). Elastase activity before and after sivelestat or vehicle administration was measured spectrometrically using a specific synthetic substrate. 3. We confirmed that intestinal longitudinal muscle tension decreased 2-3 h after LPS administration in the control group, with a concurrent decline in blood pressure. In guinea-pigs treated with sivelestat, the LPS-induced decreases in muscle tension and blood pressure were significantly reduced. In LPS-treated control guinea-pigs, serum elastase activity was elevated and this increase was significantly attenuated by administration of sivelestat. 4. The findings from the present study suggest that sivelstat can effectively reduce intestinal dysfunction and attenuate LPS-induced decreases in blood pressure in endotoxaemia.

A Patient with Fulminant Influenza-Related Bacterial Pneumonia Due to Streptococcus pneumoniae Followed by Mycobacterium tuberculosis Infection

A 74-year-old man with poorly controlled diabetes mellitus was admitted to our hospital because of severe respiratory disturbance, fever, and sputum. We found massive consolidation of the right lung and nodular shadows on the left lung on chest X-ray, and detected influenza virus and Streptococcus pneumoniae antigen from a nasopharyngeal swab and urine sample, respectively. Co-infection with influenza virus and bacteria was suspected, and oseltamivir and biapenem were prescribed. Laboratory data improved after the addition of sivelestat sodium hydrate, an inhibitor of neutrophil-derived elastase; however, chest X-ray findings became worse on Day 8, and we administered 1 g methylprednisolone intravenously for two days. On Day 12, we detected Mycobacterium tuberculosis in the sputum, even though we did not previously detect any acid-fast bacilli, and started anti-tuberculosis drugs, such as isoniazid, rifampicin, ethambutol hydrochloride, and pyrazinamide; however, the patient died 12 days later. Severe influenza-related bacterial pneumonia with Streptococcus pneumoniae and subsequently secondary tuberculosis infection were finally suspected in this case. This was a very rare case in which additional tuberculosis infection was found in a patient with fulminant pneumonia due to co-infection of influenza virus and bacteria. It is necessary to observe patients with influenza carefully, especially when steroids are used, even if antibiotics are also administered.

Neutrophil elastase inhibitor, sivelestat sodium hydrate prevents ischemia–reperfusion injury in the rat bladder

In the present study, we evaluated the effect of neutrophil elastase inhibitor, sivelestat sodium hydrate on ischemia-reperfusion injury in the rat bladder. Rat abdominal aorta was clamping with a small clip to induce ischemia-reperfusion injury in the bladder. Eight-week-old male Sprague Dawley rats were divided into four groups; sham-operated control rats, 30 min ischemia-60 min reperfusion (IR) rats, and IR rats treated with 15 or 60 mg/kg of sivelestat sodium hydrate. Sixty minutes prior to induction of ischemia, sivelestat sodium hydrate was administrated intraperitoneally. Real-time monitoring of blood flow and nitric oxide (NO) release were measured simultaneously with a laser Doppler flowmeter and an NO-selective electrode, respectively. The NO2-NO3 and malonaldehyde (MDA) concentrations were measured in the experimental urinary bladders. Clamping of the abdominal aorta, blood flow was rapidly decreased and NO release was gradually increased. After removing the clip, blood flow was rapidly increased and NO release was gradually returned to the basal level. These movements of blood flow and NO release were inhibited by treatment with sivelestat sodium hydrate in a dose-dependent manner. Both NO2-NO3 and MDA concentrations in the bladder were increased by induction of IR, and NO2-NO3 and MDA concentrations were decreased by treatment with high dose of sivelestat sodium hydrate significantly. Our data indicated that sivelestat sodium hydrate could inhibit increasing NO2-NO3 and MDA concentrations by IR, and it has potentiality protective effects on IR injury in the rat urinary bladder.

Effects of sivelestat sodium hydrate on the reduction of radiation pneumonitis

In this study, we irradiated the murine lung and analyzed the inhibitory effects of sivelestat sodium hydrate, a neutrophil elastase (NE) inhibitor, on lung injury in mice. Sivelestat sodium hydrate (3 mg/kg) was administered by intraperitoneal injection immediately, 3, 6, and 12 h after irradiation in groups RE-0, RE-3, RE-6, and RE-12, respectively. A control group and a group receiving radiation without sivelestat (group R) were also used. NE activity was measured 24 and 48 h after irradiation. The lungs were simultaneously extirpated and stained with hematoxylin and eosin and a naphthol AS-D chloroacetate esterase stain (N-ASDCLA). NE activity increased in the groups in which the murine lungs were irradiated. There was no increase in NE activity in the control group. Among the sivelestat-administered groups, NE activity was slightly elevated in group RE-0 and was suppressed, compared to group R, in groups RE-3, RE-6, and RE-12 at 24 h after irradiation. In the irradiated groups, intra-alveolar neutrophil infiltration, perivascular edema, and alveolar wall thickness were observed, but these changes were mild in the sivelestat-administered groups. The number of N-ASDCLA-positive cells increased in the sivelestat-administered groups, while group R had low values. This indicated that sivelestat sodium hydrate blocked the release of NE from the neutrophils in the irradiated lungs. NE plays an important role in the development of radiation-induced lung injury. Sivelestat is thus expected to decrease radiation-induced lung toxicity by suppressing NE release from neutrophils.

Effects of Neutrophil Elastase Inhibitor on Progression of Acute Lung Injury Following Esophagectomy

The purpose of this study was to evaluate the effect of sivelestat sodium hydrate, a selective inhibitor of neutrophil elastase in the systemic inflammatory response, pulmonary function, and the postoperative clinical course following esophagectomy. Patients with hypoxia associated with surgical stress in the intensive care unit (ICU) immediately after an esophagectomy were eligible for this study. The degree of hypoxia was calculated according to the ratio of arterial oxygen tension (PaO(2)) to the fractional concentration of inspired oxygen (FiO(2))-PaO(2)/FiO(2). Patients with PaO(2)/FiO(2) < 300 mmHg were enrolled in this study. Seven patients were treated with sivelestat, and 10 were not so treated. The degree of hypoxia, the criteria for systemic inflammatory response syndrome (SIRS), and the postoperative clinical course were compared between the two groups. The postoperative decreases in the PaO(2)/FiO(2) ratio were significantly suppressed in the sivelestat group (p < 0.05, by analysis of variance, or ANOVA). Furthermore, 9 of the 10 control group patients developed SIRS on postoperative day 2, whereas only 2 of 7 of the sivelestat group patients developed SIRS (p < 0.05). The postoperative increases in the heart rate were significantly suppressed in the sivelestat group (p < 0.05, ANOVA). The postoperative decreases in the platelet counts were significantly suppressed in the sivelestat group (p < 0.05, ANOVA). The duration of mechanical ventilation and the length of ICU stay for the sivelestat group were shorter than that for the control group. We demonstrated that the postoperative decreases in the PaO(2)/FiO(2) ratio following esophagectomy were significantly suppressed in the sivelestat-treated group. This clinical study showed that a neutrophil elastase inhibitor may thus be a potentially useful drug for treating acute lung injury following esophagectomy.