Regional cerebral oxygen saturation monitoring for predicting interventional outcomes in patients following out-of-hospital cardiac arrest of presumed cardiac cause: A prospective, observational, multicentre study.

AIM: This study investigated the value of regional cerebral oxygen saturation (rSO2) monitoring upon arrival at the hospital for predicting post-cardiac arrest intervention outcomes. METHODS: We enrolled 1195 patients with out-of-hospital cardiac arrest of presumed cardiac cause from the Japan-Prediction of Neurological Outcomes in Patients Post-cardiac Arrest Registry. The primary endpoint was a good neurologic outcome (cerebral performance categories 1 or 2 [CPC1/2]) 90 days post-event. RESULTS: A total of 68 patients (6%) had good neurologic outcomes. We found a mean rSO2 of 21%±13%. A receiver operating characteristic curve analysis indicated an optimal rSO2 cut-off of ≥40% for good neurologic outcomes (area under the curve 0.92, sensitivity 0.81, specificity 0.96). Good neurologic outcomes were observed in 53% (55/103) and 1% (13/1092) of patients with high (≥40%) and low (<40%) rSO2, respectively. Even without return of spontaneous circulation (ROSC) upon arrival at the hospital, 30% (9/30) of patients with high rSO2 had good neurologic outcomes. Furthermore, 16 patients demonstrating ROSC upon arrival at the hospital and low rSO2 had poor neurologic outcomes. Multivariate analyses indicated that high rSO2 was independently associated with good neurologic outcomes (odds ratio=14.07, P<0.001). Patients with high rSO2 showed favourable neurologic prognoses if they had undergone therapeutic hypothermia or coronary angiography (CPC1/2, 69% [54/78]). However, 24% (25/103) of those with high rSO2 did not undergo these procedures and exhibited unfavourable neurologic prognoses (CPC1/2, 4% [1/25]). CONCLUSION: rSO2 is a good indicator of 90-day neurologic outcomes for post-cardiac arrest intervention patients.

Characteristics of regional cerebral oxygen saturation levels in patients with out-of-hospital cardiac arrest with or without return of spontaneous circulation: A prospective observational multicentre study.

AIM: Our study aimed at filling the fundamental knowledge gap on the characteristics of regional brain oxygen saturation (rSO2) levels in out-of-hospital cardiac arrest (OHCA) patients with or without return of spontaneous circulation (ROSC) upon arrival at the hospital for estimating the quality of cardiopulmonary resuscitation and neurological prognostication in these patients. METHODS: We enrolled 1921 OHCA patients from the Japan - Prediction of Neurological Outcomes in Patients Post-cardiac Arrest Registry and measured their rSO2 immediately upon arrival at the hospital by near-infrared spectroscopy using two independent forehead probes (right and left). We also assessed the percentage of patients with a good neurological outcome (defined as cerebral performance categories 1 or 2) 90 days post cardiac arrest. RESULTS: After 90 days, 79 (4%) patients had good neurological outcomes and a median lower rSO2 level of 15% (15-20%). Compared to patients without ROSC upon arrival at the hospital, those with ROSC had significantly higher rSO2 levels (56% [39-65%] vs. 15% [15-17%], respectively; P<0.01), and significantly correlated right- and left-sided regional brain oxygen saturation levels (R=0.94 vs. 0.66, respectively). In both groups, the percentage of patients with a good 90-day neurological outcome increased significantly in proportion to their rSO2 levels upon arrival at the hospital (P<0.01). CONCLUSION: Our data indicate that measuring rSO2 levels might be effective for both monitoring the quality of resuscitation and neurological prognostication in patients with OHCA.

Intravenous immunoglobulin improves sepsis-induced coagulopathy: A retrospective, single-center observational study.

INTRODUCTION: Inflammation and coagulation are closely interrelated processes in the pathogenesis of sepsis. This study aimed to determine whether intravenous immunoglobulin (IVIg) could improve the hyperinflammatory state and coagulation/fibrinolysis abnormalities in patients with sepsis. METHODS: Forty-one patients with sepsis were included. Nineteen patients were treated with IVIg (IVIg group; 5.0 g daily for 3 days within 2 days after hospitalization), and 22 patients were not (non-IVIg group). Inflammatory and coagulation/fibrinolysis molecular markers, Japanese Association for Acute Medicine disseminated intravascular coagulation score, and the Sequential Organ Failure Assessment score were evaluated in each group. RESULTS: On admission, patients in the IVIg group had a significantly more severe condition. In the IVIg group, after treatment, C-reactive protein, procalcitonin, and interleukin-6 levels significantly decreased relative to values on admission. Also, compared with admission, the various coagulation/fibrinolysis molecular markers decreased after treatment. Moreover, the Japanese Association for Acute Medicine disseminated intravascular coagulation score and the Sequential Organ Failure Assessment score also significantly decreased after treatment. In contrast, in the non-IVIg group, only interleukin-6 level and thrombin-antithrombin complex levels significantly decreased. The 28-day mortality rate of the IVIg group was approximately one third of the value of the non-IVIg group (IVIg: 5.3% vs non-IVIg: 18.2%). CONCLUSIONS: Intravenous immunoglobulin treatment significantly improved hemostatic abnormalities along with the hyperinflammatory state in patients with sepsis. Accordingly, IVIg treatment should be classified as an adjunctive therapy for patients complicated with sepsis-induced coagulopathy.

Potential use of procalcitonin as biomarker for bacterial sepsis in patients with or without acute kidney injury.

INTRODUCTION: There are few investigations regarding the relationships between procalcitonin (PCT) and the acute kidney injury (AKI) in the diagnosis of sepsis. The purpose of this study was to clarify the diagnostic accuracy of the use of PCT levels in patients with or without AKI. METHODS: This study was conducted as a single-center retrospective study. We enrolled 393 patients in whom PCT were measured on admission. We grouped the patients into non-AKI and AKI, and those with AKI were classified according to the RIFLE criteria (Risk, Injury, Failure). The patients in each group were further classified into the sepsis and the non-sepsis group. We subsequently investigated the diagnostic accuracy of the PCT for detecting sepsis in these groups. RESULTS: The levels of PCT were significantly higher in the sepsis group than in the non-sepsis group among the non-AKI and each AKI patients (p < 0.0001). The diagnostic accuracy of the PCT for detecting sepsis was determined according to a ROC analysis; AUC value was 0.958 in the non-AKI group, in the Risk, Injury and Failure groups were 0.888 and 0.917, 0.857, respectively. AUC value for non-AKI group was significantly different from that of Failure group (p < 0.05). CONCLUSIONS: In Failure AKI patients, the diagnostic accuracy of the PCT level is significantly lower than non-AKI patients. It is therefore suggested that we should be careful in using PCT value to diagnose sepsis in patients with Failure under RIFLE criteria.

Usefulness of presepsin in the diagnosis of sepsis in patients with or without acute kidney injury.

BACKGROUND: Presepsin is useful for differentiating sepsis from non-infection related systemic inflammatory response syndrome. However, there are no studies investigating the usefulness of presepsin in diagnosing sepsis involving patients with acute kidney injury (AKI). The purpose of this study is to determine levels of blood presepsin in patients with or without sepsis and among non-AKI patients or patients with different degrees of AKI severity. METHODS: This is a single center retrospective study. 247 patients admitted to the ICU between June 2010 and October 2012 were analyzed for their presepsin levels. We classified the patients into non-AKI and AKI according to the RIFLE (Risk, Injury, Failure, and Loss of kidney function and End-stage kidney disease or simply Loss and ESKD) criteria. We then sub-classified the patients in each group into either non-sepsis or sepsis sub-group and analyzed the accuracy of diagnosing sepsis based on their levels of presepsin. RESULTS: The number of patients for each group was: non-AKI, 112; under AKI: Risk, 50; Injury, 36; Failure, 42; Loss and ESKD, 7. The levels of presepsin in sepsis groups were significantly higher than that in the non-sepsis group among the non-AKI, Risk and Injury patients (p < 0.0001, p < 0.01, p < 0.01, respectively). However, no significant difference in the level of presepsin between non-sepsis and sepsis groups among patients with Failure. In the receiver operating characteristic (ROC) analysis, the area under the curve (AUC) was 0.784 in the non-AKI group and 0.698 in the AKI comprising Risk, Injury and Failure groups. AUC value for non-AKI was not significantly different from that of AKI (p = 0.200). When 670 pg/mL was used as the cutoff value for presepsin, sensitivity and specificity were 70.3% and 81.3%, respectively. When 864 pg/mL was used as the cutoff value for presepsin, sensitivity and specificity were 71.4% and 63.8%, respectively. CONCLUSIONS: Presepsin level can be a reliable indicator of sepsis not only among non-AKI patients but also patients with less severe forms of AKI. However, it may not be a reliable indicator of sepsis in patients with a more advanced form of AKI.

Noninvasive regional cerebral oxygen saturation for neurological prognostication of patients with out-of-hospital cardiac arrest: a prospective multicenter observational study.

AIM: To investigate the association between regional brain oxygen saturation (rSO2) at hospital arrival and neurological outcomes at 90 days in patients with out-of-hospital cardiac arrest (OHCA). METHODS: The Japan-Prediction of neurological Outcomes in patients post cardiac arrest (J-POP) registry is a prospective, multicenter, cohort study to test whether rSO2 predicts neurological outcomes after OHCA. We measured rSO2 in OHCA patients immediately after hospital arrival using a near-infrared spectrometer placed on the forehead with non-blinded fashion. The primary endpoint was "neurological outcomes" at 90 days after OHCA. RESULTS: EMS providers are not permitted to terminate CPR in the field in Japan, and so most patients with OHCA who are treated by EMS personnel are transported to emergency hospitals. Among 1017 OHCA patients, 672 patients including 52 comatose patients with pulses detectable (8%) and 620 cardiac arrest patients (92%) at hospital arrival were enrolled prospectively and consecutively. Twenty-nine patients with good neurological outcome had a significantly higher value of rSO2 at hospital arrival than 643 patients with poor neurological outcome (mean [±SD] 55.6±20.8% vs. 19.7±11.0%, p<0.001). Receiver operating curve analysis indicated an optimal rSO2 cutoff point of >42% for predicting good neurological outcome, with sensitivity 0.79 (95% confidence interval [CI], 0.60-0.92), specificity 0.95 (95% CI, 0.93-0.96), positive predictive value, 0.41 (95% CI, 0.28-0.55), negative predictive value, 0.99 (95% CI, 0.98-1.00), and area under the curve 0.90 (95% CI, 0.88-0.92). CONCLUSION: The rSO2 at hospital arrival can predict good neurological outcome at 90 days after OHCA.

Presepsin as a powerful monitoring tool for the prognosis and treatment of sepsis: a multicenter prospective study.

Presepsin is a protein whose levels increase specifically in the blood of patients with sepsis. It is proposed as a diagnostic and prognostic marker for assessing the degree of sepsis severity. The present multicenter prospective study compared the clinical utility of presepsin with other conventional sepsis biomarkers including procalcitonin, interleukin-6, and C-reactive protein for evaluating the severity of sepsis during follow-up. Patients with sepsis (n = 103) admitted to the emergency room or intensive care unit were enrolled in this study and classified into 3 diagnostic groups: sepsis, severe sepsis, and septic shock. Blood samples were obtained from each patient on admission and after 1, 3, 5, and 7 days. The patients were further divided into the favorable and unfavorable prognosis groups on the basis of several indicators of sepsis severity (i.e., Sequential Organ Failure Assessment score, and Acute Physiology and Chronic Health Evaluation II score). The patients in the favorable prognosis group exhibited significant decreases in all biomarker levels on days 3 and 7 after admission. In the unfavorable prognosis group, only presepsin levels did not decrease significantly during follow-up. The period of antibiotics treatment in the unfavorable prognosis group was significantly longer than those in the favorable prognosis group (P < 0.05). The unfavorable prognosis group had significantly higher 28-day mortality than the favorable prognosis group (P < 0.05). Therefore, the results suggest that presepsin levels correlated with the severity of sepsis during follow-up in comparison with other conventional sepsis biomarkers.

New diagnostic strategy for sepsis-induced disseminated intravascular coagulation: a prospective single-center observational study.

INTRODUCTION: Inflammation and coagulation are closely interrelated pathophysiologic processes in the pathogenesis of sepsis. However, the diagnostic criteria of sepsis and disseminated intravascular coagulation (DIC) are different. This study aimed to define a biomarker panel to predict sepsis-induced DIC in emergency department patients. METHODS: Eighty-two patients who were admitted to the emergency department of a tertiary university hospital were included in this study. The inclusion criteria were as follows: (1) age >18 years; (2) ≥1 systemic inflammatory response syndrome (SIRS) criteria. Patients were excluded if they lacked biomarker data or apparent clinical manifestations. Eleven biomarkers were assayed from blood drawn on ED admission. Receiver operating curve (ROC) analysis including the area under the ROC and multivariable logistic regression were used to identify an optimal combination of biomarkers to create a diagnostic panel. The derived formula for weighting biomarker values was used to determine the severity of sepsis-induced DIC, which was divided into three categories: mild, moderate, and severe. We also investigated the ability of this classification to predict secondary outcome measures of rates of sepsis and DIC, DIC score, acute physiology and chronic health evaluation (APACHE) II score, sequential organ failure score (SOFA) score, and 28-day all-cause mortality. RESULTS: Among the 11 biomarkers tested, the optimal 2-marker panel comprised presepsin and protein C. The area under the curve for the accuracies of predicting sepsis and DIC from these two biomarkers were 0.913 and 0.880, respectively. When patients were divided according to the severity of sepsis-induced DIC, all secondary outcomes except for mortality were significantly higher depending on the severity (P < .0001). The overall mortality rates of mild, moderate, and severe sepsis-induced DIC were 7.14%, 15.4%, and 28.6%, respectively (P = .0994). CONCLUSIONS: A biomarker panel of presepsin and protein C is predictive of the severity of sepsis-induced DIC in suspected ED patients. These criteria for sepsis-induced DIC are very simple, easy to implement, and can be used in intensive care units as a point-of-care test.

Bladder pain relief by HMGB1 neutralization and soluble thrombomodulin in mice with cyclophosphamide-induced cystitis.

High mobility group box 1 (HMGB1), one of damage-associated molecular patterns (DAMPs), plays roles in not only inflammation but also processing of somatic pain. Given that no evidence for roles of HMGB1 in visceral pain signaling is available, we asked if HMGB1 participates in bladder pain accompanying cystitis caused by cyclophosphamide in mice, using the anti-HMGB1 neutralizing antibody and recombinant human soluble thrombomodulin (rhsTM) that sequesters HMGB1 and promotes its degradation by thrombin. Cyclophosphamide, administered i.p., caused bladder pain-like nociceptive behavior and referred hyperalgesia accompanying cystitis symptoms including increased bladder weight, an indicator of edema, in mice. The cyclophosphamide-induced bladder pain and referred hyperalgesia, but not increased bladder weight, were prevented by i.p. preadministration of the anti-HMGB1 neutralizing antibody or rhsTM. HMGB1, given i.p., facilitated the bladder pain and referred hyperalgesia caused by a subeffective dose of cyclophosphamide, an effect blocked by rhsTM. In the cyclophosphamide-treated mice, HMGB1 levels greatly decreased in the bladder tissue, particularly in the urothelial cells, but did not change in the plasma. Low molecular weight heparin, known to inhibit the receptor for advanced glycation end products (RAGE), but not lipopolysaccharide from Rhodobacter sphaeroides, an inhibitor of toll-like receptor 4 (TLR4), blocked the cyclophosphamide-induced bladder pain and referred hyperalgesia. Thus, our data indicate involvement of HMGB1 in the cyclophosphamide-induced bladder pain signaling, but not cystitis itself, and suggest that targeting HMGB1 with rhsTM or blocking RAGE might serve as a novel therapeutic strategy for the management of bladder pain.

Effect of a selective neutrophil elastase inhibitor on mortality and ventilator-free days in patients with increased extravascular lung water: a post hoc analysis of the PiCCO Pulmonary Edema Study.

BACKGROUND: Neutrophil elastase plays an important role in the development and progression of acute respiratory distress syndrome (ARDS). Although the selective elastase inhibitor, sivelestat, is widely used in Japan for treating ARDS patients, its effectiveness remains controversial. The aim of the current study was to investigate the effects of sivelestat in ARDS patients with evidence of increased extravascular lung water by re-analyzing a large multicenter study database. METHODS: A post hoc analysis of the PiCCO Pulmonary Edema Study was conducted. This multicenter prospective cohort study included 23 institutions in Japan. Adult mechanically ventilated ARDS patients with an extravascular lung water index of >10 mL/kg were included and propensity score analyses were performed. The endpoints were 28-day mortality and ventilator-free days (VFDs). RESULTS: Patients were categorized into sivelestat (n = 87) and control (n = 77) groups, from which 329 inverse probability-weighted group patients (162 vs. 167) were generated. The overall 28-day mortality was 31.1% (51/164). There was no significant difference in 28-day mortality between the study groups (sivelestat vs. control; unmatched: 29.9% vs. 32.5%; difference, -2.6%, 95% confidence interval (CI), -16.8 to 14.2; inverse probability-weighted: 24.7% vs. 29.5%, difference, -4.8%, 95% CI, -14.4 to 9.6). Although administration of sivelestat did not alter the number of ventilator-free days (VFDs) in the unmatched (9.6 vs. 9.7 days; difference, 0.1, 95% CI, -3.0 to 3.1), the inverse probability-weighted analysis identified significantly more VFDs in the sivelestat group than in the control group (10.7 vs. 8.4 days, difference, -2.3, 95% CI, -4.4 to -0.2). CONCLUSIONS: Although sivelestat did not significantly affect 28-day mortality, this treatment may have the potential to increase VFDs in ARDS patients with increased extravascular lung water. Prospective randomized controlled studies are required to confirm the results of the current study.

Early-phase changes of extravascular lung water index as a prognostic indicator in acute respiratory distress syndrome patients.

BACKGROUND: The features of early-phase acute respiratory distress syndrome (ARDS) are leakage of fluid into the extravascular space and impairment of its reabsorption, resulting in extravascular lung water (EVLW) accumulation. The current study aimed to identify how the initial EVLW values and their change were associated with mortality. METHODS: This was a post hoc analysis of the PiCCO Pulmonary Edema Study, a multicenter prospective cohort study that included 23 institutions. Single-indicator transpulmonary thermodilution-derived EVLW index (EVLWi) and conventional prognostic factors were prospectively collected over 48 h after enrollment. Associations between 28-day mortality and each variable including initial (on day 0), mean, maximum, and Δ (subtracting day 2 from day 0) EVLWi were evaluated. RESULTS: We evaluated 192 ARDS patients (median age, 69 years (quartile, 24 years); Sequential Organ Failure Assessment (SOFA) score on admission, 10 (5); all-cause 28-day mortality, 31%). Although no significant differences were found in initial, mean, or maximum EVLWi, Δ-EVLWi was significantly higher (i.e., more reduction in EVLWi) in survivors than in non-survivors (3.0 vs. -0.3 mL/kg, p = 0.006). Age, maximum, and Δ-SOFA scores and Δ-EVLW were the independent predictors for survival according to the Cox proportional hazard model. Patients with Δ-EVLWi > 2.8 had a significantly higher incidence of survival than those with Δ-EVLWi ≤ 2.8 (log-rank test, χ (2) = 7.08, p = 0.008). CONCLUSIONS: Decrease in EVLWi during the first 48 h of ARDS may be associated with 28-day survival. Serial EVLWi measurements may be useful for understanding the pathophysiologic conditions in ARDS patients. A large multination confirmative trial is required.

Recombinant human soluble thrombomodulin prevents peripheral HMGB1-dependent hyperalgesia in rats.

BACKGROUND AND PURPOSE: High-mobility group box 1 (HMGB1), a nuclear protein, is actively or passively released during inflammation. Recombinant human soluble thrombomodulin (rhsTM), a medicine for treatment of disseminated intravascular coagulation (DIC), sequesters HMGB1 and promotes its degradation. Given evidence for involvement of HMGB1 in pain signalling, we determined if peripheral HMGB1 causes hyperalgesia, and then asked if rhsTM modulates the HMGB1-dependent hyperalgesia. EXPERIMENTAL APPROACH: Mechanical nociceptive threshold and swelling in rat hindpaw were determined by the paw pressure test and by measuring paw thickness, respectively, and HMGB1 levels in rat hindpaw plantar tissue, dorsal root ganglion (DRG) and serum were determined by Western blotting or elisa. KEY RESULTS: Intraplantar (i.pl.) administration of HMGB1 rapidly evoked paw swelling and gradually caused hyperalgesia in rats. Systemic administration of rhsTM abolished HMGB1-induced hyperalgesia, and partially blocked paw swelling. LPS, administered i.pl., rapidly produced mild paw swelling, and gradually caused hyperalgesia. The anti-HMGB1 neutralizing antibody abolished LPS-induced hyperalgesia, but partially inhibited paw swelling. rhsTM at a high dose, 10 mg kg(-1) , prevented both hyperalgesia and paw swelling caused by LPS. In contrast, rhsTM at low doses, 0.001-1 mg kg(-1) , abolished the LPS-induced hyperalgesia, but not paw swelling. HMGB1 levels greatly decreased in the hindpaw, but not DRG. Serum HMGB1 tended to increase after i.pl. LPS in rats pretreated with vehicle, but not rhsTM. CONCLUSION AND IMPLICATIONS: These data suggest that peripheral HMGB1 causes hyperalgesia, and that rhsTM abolishes HMGB1-dependent hyperalgesia, providing novel evidence for therapeutic usefulness of rhsTM as an analgesic.

Usefulness of presepsin in the diagnosis of sepsis in a multicenter prospective study.

The clinical usefulness of presepsin for discriminating between bacterial and nonbacterial infections (including systemic inflammatory response syndrome) was studied and compared with procalcitonin (PCT) and interleukin-6 (IL-6) in a multicenter prospective study. Suspected sepsis patients (n = 207) were enrolled into the study. Presepsin levels in patients with systemic bacterial infection and localized bacterial infection were significantly higher than in those with nonbacterial infections. In addition, presepsin, PCT, and IL-6 levels in patients with bacterial infectious disease were significantly higher than in those with nonbacterial infectious disease (P < 0.0001, P < 0.0001, and P < 0.0001, respectively). The area under the receiver operating characteristic curve was 0.908 for presepsin, 0.905 for PCT, and 0.825 for IL-6 in patients with bacterial infectious disease and those with nonbacterial infectious disease. The cutoff value of presepsin for discrimination of bacterial and nonbacterial infectious diseases was determined to be 600 pg/ml, of which the clinical sensitivity and specificity were 87.8 % and 81.4 %, respectively. Presepsin levels did not differ significantly between patients with gram-positive and gram-negative bacterial infections. The sensitivity of blood culture was 35.4 %; that for presepsin was 91.9 %. Also there were no significant differences in presepsin levels between the blood culture-positive and -negative groups. Consequently, presepsin is useful for the diagnosis of sepsis, and it is superior to conventional markers and blood culture.

Comparative study to elucidate the mechanism underlying the difference in airway hyperresponsiveness between two mouse strains.

The mechanism underlying airway hyperresponsiveness (AHR), a characteristic feature of asthma, remains obscure. We attempted to elucidate the mechanism responsible for the different degrees of AHR in two mouse strains, BALB/c and C57BL/6, following exposure to an anaphylactic trigger. When ovalbumin (OVA)-sensitized mice were challenged daily with OVA for up to three consecutive days, the BALB/c mice showed a higher degree of airway responsiveness to methacholine than did C57BL/6. Following the OVA challenge, eosinophils and macrophages in bronchoalveolar lavage fluid (BALF) from BALB/c increased significantly in number compared to those from C57BL/6. BALB/c mice also exhibited a higher serum IgE level than that of C57BL/6 after OVA challenge. The enhanced AHR and eosinophilic infiltration in BALF were significantly reduced by pretreatment with a selective cysteinyl-leukotriene type 1 receptor (cysLT(1)R) antagonist, montelukast. In the in vitro study, cysLT production was significantly lower in the dissected lung tissue from BALB/c than in tissue from C57BL/6 when both groups were stimulated with saline. The lungs from BALB/c generated significantly larger amounts of cysLTs on incubation with OVA rather than with saline, while the lungs from C57BL/6 did not show any significant increase in cysLTs with antigen stimulation. Significant upregulation of cysLT(1)R and cysLT(2)R mRNA expression was induced by OVA challenge in the lungs of BALB/c, but not in those of C57BL/6. It is suggested that, after an anaphylactic reaction, the degree of AHR is dependent on the genetic background and that cysLTs play an important role in the mechanism involved.

Effects of inducible nitric oxide synthase inhibitors on asthma depending on administration schedule.

The effectiveness of two inducible nitric oxide synthase (iNOS) inhibitors on allergic airway inflammation was investigated under different administration schedules. Rats sensitized to ovalbumin (OVA) were exposed to OVA for 3 consecutive days. Both iNOS inhibitors showed markedly different effects between two pretreatment schedules: pretreatment before each of three OVA exposures S1 and before the third exposure alone S2. S1 pretreatment resulted in higher pulmonary resistance than triple OVA alone. This potentiation was associated with increased eosinophil infiltration and malondialdehyde levels in the lungs, which were suppressed by superoxide dismutases (SODs) but not by methylprednisolone. However, the S2 administration of both iNOS inhibitors completely suppressed the airway response. Administration by schedule S1 completely suppressed plasma nitrite and nitrate levels, but that by S2 caused only a slight suppression. The triple OVA exposures resulted in the upregulation of iNOS in alveolar macrophages and arginase activity, Mn- and Cu/Zn-SOD expression, and nitrotyrosine and lipid peroxide deposition in the airway. However, inhibitors administered by schedule S1 suppressed this upregulation, but further potentiated nitrotyrosine, which in turn was inhibited by SOD. Although iNOS inhibitors may be beneficial for asthma, repeated administration may be detrimental because of extensive reduction of NO and downregulation of SOD.

Comparison of effects of nitric oxide synthase (NOS) inhibitors on plasma nitrite/nitrate levels and tissue NOS activity in septic organs.

An excessive production of nitric oxide (NO) by NO synthase (NOS) is considered to contribute to circulatory disturbance, tissue damage, and refractory hypotention, which are often observed in septic disorders. It is anticipated that a selective inducible NOS (iNOS) inhibitor with excellent pharmacokinetics may be potentially effective as a novel and potent therapeutic intervention in sepsis. We examined whether or not a selective iNOS inhibitor shows iNOS selectivity at the tissue level, when administered systemically. The effects of four NOS inhibitors on plasma nitrite/nitrate (NOx) and tissue NOS levels were compared in major organs (lungs, liver, heart, kidneys, and brain) 6 hr after the injection of E. coli lipopolysaccharide (LPS) into male Wistar-King rats. The rats treated with the three iNOS inhibitors (N-(3-(aminomethyl)benzyl)acetamidine (1400W), (1 S, 5 S, 6 R, 7 R )-2-aza-7-chloro-3-imino-5-methylbicyclo [4.1.0] heptane hydrochloride (ONO-1714), and aminoguanidine) administered 1 hr after LPS injection, showed dose-dependent decreases in plasma NOx levels and NOS activity in the lungs. The non-selective NOS inhibitor (N(G)-methyl-L-arginine (L-NMMA)) had an effect only at the maximum dose. The differences in in vitro iNOS selectivity among these drugs did not correlate with iNOS selectivity at the tissue level. The relationship between plasma NOx levels and NOS activity in the lungs showed a linear relationship with or without the NOS inhibitors. In conclusion, the iNOS selectivity of these drugs does not seem to differ at the tissue level. Plasma NOx levels may be a useful indicator of lung NOS activity.

Comparison study between the mechanisms of allergic asthma amelioration by a cysteinyl-leukotriene type 1 receptor antagonist montelukast and methylprednisolone.

We investigated the effects of cysteinyl-leukotriene (cysLT) type 1 receptor antagonist montelukast (MK) and compared them with those of methylprednisolone (MP) in an allergic asthma model. Rats sensitized to ovalbumin (OVA) received repeated intratracheal exposure to OVA for up to 3 consecutive days. Pretreatment with MK or MP before OVA exposure inhibited late airway response (LAR) and reduced cellular infiltration into the bronchial submucosa after the triple OVA. The amount of N-acetyl-leukotriene E(4) in the bile was significantly reduced by pretreatment with MK or MP, suggesting that both drugs reduced the production of cysLTs in the lungs. In the in vitro study, when the fragments of lungs that had been repeatedly pretreated with MK or MP and exposed to OVA were removed and incubated with OVA, the coaddition of either drug significantly reduced cysLT production. In contrast, the cysLT production following the addition of OVA to the lung fragments that had not received in vivo pretreatment with either drug was inhibited by MK but not by MP. These results indicate that MK and MP inhibit LAR by suppressing the infiltration of inflammatory cells into the bronchial submucosa, thereby inhibiting the production of cysLTs in the lungs, and that MK but not MP may inhibit cysLT production directly. The different effects on cysLT production between the two drugs may provide a rationale for the use of combination therapy with cysLT(1) receptor antagonists and steroids for the treatment of asthma.