Background: Sepsis often induces an immunosuppressive state, which is associated with high mortality rates. Immunostimulation may be beneficial for sepsis. We investigated the pharmacokinetics, pharmacodynamics, and safety of nivolumab, a human programmed death-1 immune checkpoint inhibitor approved for the treatment of several cancers. Methods: In this multicenter, open-label phase 1/2 study, a single 480 or 960 mg nivolumab dose was intravenously infused into Japanese patients with immunosuppressive sepsis. Doses were selected to mimic the exposure achieved with the approved dosage for cancer patients (3 mg/kg every 2 weeks [Q2W]). Results: Single 480 and 960 mg nivolumab doses were intravenously infused into five and eight patients, respectively. The maximum concentration after 480 mg (132 μg/mL) was similar to the predicted concentration at the end of infusion with 3 mg/kg Q2W (117 μg/mL). The concentration on Day 28 after 960 mg (33.1 μg/mL) was within the predicted trough concentration range for 3 mg/kg Q2W (90% prediction interval 19.0–163 μg/mL). Absolute lymphocyte counts and monocyte human leukocyte antigen-DR subtype expression levels appeared to increase over time. The incidences of adverse events (AEs) were 80% and 50% in the 480 mg and 960 mg groups, respectively. Drug-related AEs were observed in only one patient in the 480 mg group. No deaths related to nivolumab occurred. Conclusions: A single dose of 960 mg nivolumab appeared to be well tolerated and sufficient to maintain nivolumab blood concentrations. Both 480 mg and 960 mg nivolumab seemed to improve immune system indices over time. Trial registration: JAPIC, JapicCTI-173600.
IntroductionResults from the multicenter trial (J-Land study) of landiolol versus digoxin in atrial fibrillation (AF) and atrial flutter (AFL) patients with left ventricular (LV) dysfunction revealed that landiolol was more effective for controlling rapid HR than digoxin. The subgroup analysis for patient characteristics was conducted to evaluate the impact on the efficacy and safety of landiolol compared with digoxin.MethodsTwo hundred patients with AF/AFL, heart rate (HR) ≥ 120 beats/min, and LV ejection fraction (LVEF) 25–50% were randomized to receive either landiolol (n = 93) or digoxin (n = 107). Successful HR control was defined as ≥20% reduction in HR together with HR < 110 beats/min at 2 h after starting intravenous administration of landiolol or digoxin. The subgroup analysis for patient characteristics was to evaluate the impact on the effectiveness of landiolol in AF/AFL patients complicated with LV dysfunction.ResultsThe efficacy in patients with NYHA class III/NYHA class IV was 52.3%/35.3% in landiolol, and 13.8%/9.1% in digoxin (p < 0.001 and p = 0.172), lower LVEF (25–35%)/higher LVEF (35–50%) was 45.7%/51.1% in landiolol, and 14.0%/12.7% in digoxin (p < 0.001 and p < 0.001), CKD stage 1 (90 < eGFR)/CKD stage 2 (60 ≤ eGFR < 90)/CKD stage 3 (30 ≤ eGFR < 60)/CKD stage 4 (15 ≤ eGFR < 30) was 66.7%/59.1%/39.6%/66.7% in landiolol, and 0%/13.8%/17.0%/0% in digoxin (p = 0.003, p < 0.001, p = 0.015 and p = 0.040).ConclusionsThis subgroup analysis indicated that landiolol was more useful, regardless of patient characteristics, as compared with digoxin in AF/AFL patients complicated with LV dysfunction. Particularly, in patients with impaired renal function, landiolol should be preferred for the purpose of acute rate control of AF/AFL tachycardia.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-014-0111-2) contains supplementary material, which is available to authorized users.
Beta-blockers have been reported to improve prognosis for various cancers, but the usefulness of perioperative administration remains unclear. To assess the efficacy of perioperative administration of landiolol hydrochloride, an intravenous beta-blocker, for lung cancer, we conducted a single-center, retrospective study. This study included patients who participated in a research conducted by Nippon Medical School Hospital from August 2012 to November 2013. The main selection criteria were males and females younger than 85 years old who have undergone anatomic lung resection for lung malignancies. Fifty-seven patients, 28 in the landiolol group and 29 in the control group, were included. The postoperative relapse-free survival rate at 2 years was 0.89 (95% CI, 0.78–1.01) in the landiolol group and 0.76 (95% CI, 0.60–0.91) in the control group (Chi-squared test; P = 0.1828). The relapse-free survival rate tended to be higher in the landiolol group than in the control. Hazard ratio for relapse-free survival in the landiolol group compared to the control was 0.41 (95% CI, 0.13–1.34), demonstrating that relapse free survival was prolonged in the landiolol group (log-rank test; P = 0.1294). It was suggested that relapse-free survival was prolonged when landiolol hydrochloride was administered from the induction to completion of anesthesia. Further studies are needed to confirm our findings.
Background and Objective Anaphylactic shock is a serious adverse drug reaction that can occur in response to contrast media used during coronary computed tomography angiography. The imaging quality of coronary computed tomography angiography is improved by β-blockers, which decrease heart rate. In this study, we sought to analyze anaphylactic shock treatment in patients receiving short-acting β1-blockers. Methods We examined the influence of epinephrine and glucagon on hemodynamics during β-blocker treatment, using a dog histamine shock model; the β1-blocker landiolol hydrochloride was used. The effects of these drugs were assessed by recording changes relative to established baselines. Results Histamine and landiolol decreased mean blood pressure. Histamine exerted no apparent effect on heart rate, whereas landiolol decreased heart rate. Further, landiolol reduced histamine-mediated increases in the force of cardiac contraction. Increasing the doses of epinephrine and glucagon ameliorated anaphylactic shock-induced deterioration in hemodynamic parameters in subjects receiving landiolol. Conclusions In patients receiving landiolol for coronary computed tomography angiography, deterioration in hemodynamic parameters due to anaphylactic shock can be mitigated by increasing the doses of epinephrine and glucagon. Clinicians should thus prepare appropriate amounts of epinephrine and glucagon prior to coronary computed tomography angiography. Key PointsAnaphylactic shock should be treated with epinephrine The effects of epinephrine may be reduced in patients receiving β-blockers Shock symptoms can be ameliorated by increasing epinephrine and glucagon doses
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