Effect of Landiolol Hydrochloride on Hemodynamics in a Histamine-Induced Shock Model.

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 ß-blockers, which decrease heart rate. In this study, we sought to analyze anaphylactic shock treatment in patients receiving short-acting ß1-blockers. METHODS: We examined the influence of epinephrine and glucagon on hemodynamics during ß-blocker treatment, using a dog histamine shock model; the ß1-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.

Impact of patient characteristics on the efficacy and safety of landiolol in patients with sepsis-related tachyarrhythmia: Subanalysis of the J-Land 3S randomised controlled study.

BACKGROUND: The J-Land 3S trial demonstrated that landiolol is effective and tolerated for treating sepsis-related tachyarrhythmias. Patient characteristics (e.g. baseline heart rate [HR], type of tachyarrhythmia, and concomitant disorders) may impact the outcomes of landiolol therapy. We performed subanalyses of J-Land 3S to evaluate the impact of patient characteristics on the efficacy and safety of landiolol for treating sepsis-related tachyarrhythmia. METHODS: Patients (≥20 years old; N = 151) hospitalised with sepsis at 54 participating hospitals in Japan with HR ≥100 beats/min for ≥10 min accompanied by diagnosis of tachyarrhythmia were randomised 1:1 to conventional sepsis therapy alone (control group) or conventional sepsis therapy plus landiolol (landiolol group). The efficacy and safety of landiolol were assessed in prespecified analyses of patients divided into subgroups by baseline characteristics and in post hoc, multivariate analyses with adjustment for age and HR at baseline. FINDINGS: The percentage of patients with HR of 60-94 beats/min at 24 h after randomisation (primary endpoint) was greater in the landiolol group in most subgroups in univariate unadjusted analyses and in multivariate logistic regression. The incidence of new-onset arrhythmia by 168 h and mortality by 28 days were also lower in the landiolol group in most subgroups in univariate and multivariate Cox proportional hazards models. No subgroups showed a markedly higher incidence of adverse events in univariate or multivariate logistic regression analyses. INTERPRETATION: These results of the J-Land 3S study suggest that the efficacy and safety of landiolol are generally unaffected by key patient characteristics. FUNDING: Ono Pharmaceutical Co., Ltd.

Efficacy and safety of landiolol, an ultra-short-acting ß1-selective antagonist, for treatment of sepsis-related tachyarrhythmia (J-Land 3S): a multicentre, open-label, randomised controlled trial.

BACKGROUND: Tachycardia and atrial fibrillation frequently occur in patients being treated for sepsis or septic shock and have a poor prognosis. Treatments for tachyarrhythmias are often ineffective or contraindicated in this setting. We aimed to investigate the efficacy and safety of landiolol, an ultra-short-acting ß-blocker, for treating sepsis-related tachyarrhythmias. METHODS: We did a multicentre, open-label, randomised controlled trial at 54 hospitals in Japan. Patients admitted to the intensive care units who received conventional treatment for sepsis, according to clinical guidelines for the management of sepsis, and who subsequently developed a tachyarrhythmia, were enrolled. The main inclusion criteria were 20 years of age or older, diagnosis of sepsis according to Third International Consensus Definitions for Sepsis and Septic Shock criteria, administration of catecholamine necessary to maintain mean arterial pressure at 65 mm Hg or more for at least 1 h, and heart rate of 100 beats per min (bpm) or more maintained for at least 10 min without a change in catecholamine dose with diagnosis of atrial fibrillation, atrial flutter, or sinus tachycardia. Only patients who developed these symptoms and signs within 24 h before randomisation, and within 72 h after entering an intensive care unit, were prospectively assigned to receive conventional sepsis therapy alone (control group) or conventional sepsis therapy plus landiolol (landiolol group) in an open-label manner. Landiolol hydrochloride was intravenously infused at an initial dose of 1 µg/kg per min within 2 h after randomisation and the dose could be increased per study protocol to a maximum of 20 µg/kg per min. Patients in both groups received conventional therapy (Japanese Clinical Practice Guidelines for the Management of Sepsis and Septic Shock 2016), including respiratory and fluid resuscitation, antimicrobials, and catecholamines. The treating physicians were required to stabilise the patient's haemodynamic status before randomisation. Randomisation was done using a central randomisation system and dynamic allocation with the minimisation method by institution, heart rate at randomisation (≥100 to <120 bpm or ≥120 bpm), and age (<70 years or ≥70 years). The primary outcome was the proportion of patients with heart rate of 60-94 bpm at 24 h after randomisation. Patients without heart rate data at 24 h after randomisation were handled as non-responders. The primary outcome was analysed using the full analysis set on an as-assigned basis, while safety was analysed using the safety analysis set according to the treatment received. This study was registered with the Japan Pharmaceutical Information Center Clinical Trials Information database, number JapicCTI-173767. FINDINGS: Between Jan 16, 2018 and Apr 22, 2019, 151 patients were randomly assigned, 76 to the landiolol group and 75 to the control group. A significantly larger proportion of patients in the landiolol group had a heart rate of 60-94 bpm 24 h after randomisation than in the control group (55% [41 of 75] vs 33% [25 of 75]), with a between-group difference of 23·1% (95% CI 7·1-37·5; p=0·0031). Adverse events were observed in 49 (64%) of 77 patients in the landiolol group and in 44 (59%) of 74 in the control group, with serious adverse events (including adverse events leading to death) in nine (12%) of 77 and eight (11%) of 74 patients. Serious adverse events related to landiolol occurred in five (6%) of 77 patients, including blood pressure decreases in three patients (4%) and cardiac arrest, heart rate decrease, and ejection fraction decrease occurred in one patient each (1%). INTERPRETATION: Landiolol resulted in significantly more patients with sepsis-related tachyarrhythmia achieving a heart rate of 60-94 bpm at 24 h and significantly reduced the incidence of new-onset arrhythmia. Landiolol was also well tolerated, but it should be used under appropriate monitoring of blood pressure and heart rate owing to the risk of hypotension in patients with sepsis and septic shock. FUNDING: Ono Pharmaceutical Co.

Characterization of Actinobacillus pleuropneumoniae field strains antigenically related to the 3-6-8-15 group from diseased pigs in Japan and Argentina / Caracterización de cepas de Actinobacillus pleuropneumoniae antigénicamente relacionados al grupo 3-6-8-15 obtenidos de cerdos infectados naturalmente en Japón y Argentina

The objectives of this study were to determine the serovar of a collection of Actinobacillus pleuropneumoniae strains within the 3-6-8-15 cross-reacting group and to analyze their phenotypic and genetic properties. Based on the serological tests, forty-seven field strains of Actinobacillus pleuropneumoniae isolated from lungs with pleuropneumonia lesions in Japan and Argentina were found to be serovars belonging to the 3-6-8-15 cross-reacting group. By using a capsule loci-based PCR, twenty-nine (96.7%) and one (3.3%) from Japan were identified as serovars 15 and 8, respectively, whereas seventeen (100%) from Argentina were identified as serovar 8. The findings suggested that serovars 8 and 15 were prevalent within the 3-6-8-15 cross-reacting group, in Argentina and Japan, respectively. Phenotypic analyses revealed that the protein patterns observed on SDS-PAGE and the lipopolysaccharide antigen detected by immunoblotting of the reference and field strains of serovars 8 and 15 were similar to each other. Genetic (16S rDNA, apxIIA, apxIIIA, cps, cpx genes, apx and omlA patterns) analyses revealed that the apxIIA and apxIIIA genes of the field strains of serovars 8 and 15 were similar to those of the reference strains of serovars 3, 4, 6, 8 and 15. The results obtained in the present study may be useful for the development of more effective vaccines against disease caused by A. pleuropneumoniae by including the homologous antigens to the most prevalent serovars in specific geographical areas.

Los objetivos del presente estudio fueron determinar el serovar de una colección de cepas de Actinobacillus pleuropneumoniae pertenecientes al grupo 3, 6, 8, 15 de reacciones cruzadas y analizar sus propiedades fenotípicas y genéticas. En base a técnicas serológicas se determinó que cuarenta y siete cepas de A. pleuropneumoniae aisladas a partir de pulmones con lesiones de pleuroneumonía en Japón y Argentina pertenecen al grupo 3, 6, 8, 15. Mediante el uso de PCR basado en locus capsulares, veintinueve (96.7%) y una (3.3%) de los aislados japoneses fueron identificados como serovar 15 y 8 respectivamente, mientras que diecisiete (100%) de los aislados argentinos resultaron pertenecer al serotipo 8. Este hallazgo sugirió que los serovares 8 y 15 fueron los prevalentes dentro del grupo 3, 6, 8, 15 en Japón y Argentina, respectivamente. El análisis fenotípico reveló que los perfiles proteicos determinados por SDS-PAGE, y de antígenos lipopolisacáridos estudiados por inmunoblot, de las cepas de referencia y de campo de los serovares 8 y 15 fueron similares entre sí. El análisis genético (Í6S rDNA, apxIIA, apxIIA, cps, genes cpx, apx y los perfiles omlA) reveló que los genes apxIIA y apxIIIA de las cepas de campo de los serovares 8 y 15 fueron similares a sus homólogos de las cepas de referencia de los serovares 3, 4, 6, 8 y 15. Los resultados obtenidos en el presente estudio pueden ser útiles para el desarrollo de vacunas más efectivas contra la enfermedad causada por A. pleuropneumoniae, al posibilitar incluir antígenos homólogos a los serovares prevalentes en las áreas geográficas de interés.

Characterization of Actinobacillus pleuropneumoniae field strains antigenically related to the 3-6-8-15 group from diseased pigs in Japan and Argentina.

The objectives of this study were to determine the serovar of a collection of Actinobacillus pleuropneumoniae strains within the 3-6-8-15 cross-reacting group and to analyze their phenotypic and genetic properties. Based on the serological tests, forty-seven field strains of Actinobacillus pleuropneumoniae isolated from lungs with pleuropneumonia lesions in Japan and Argentina were found to be serovars belonging to the 3-6-8-15 cross-reacting group. By using a capsule loci-based PCR, twenty-nine (96.7%) and one (3.3%) from Japan were identified as serovars 15 and 8, respectively, whereas seventeen (100%) from Argentina were identified as serovar 8. The findings suggested that serovars 8 and 15 were prevalent within the 3-6-8-15 cross-reacting group, in Argentina and Japan, respectively. Phenotypic analyses revealed that the protein patterns observed on SDS-PAGE and the lipopolysaccharide antigen detected by immunoblotting of the reference and field strains of serovars 8 and 15 were similar to each other. Genetic (16S rDNA, apxIIA, apxIIIA, cps, cpx genes, apx and omlA patterns) analyses revealed that the apxIIA and apxIIIA genes of the field strains of serovars 8 and 15 were similar to those of the reference strains of serovars 3, 4, 6, 8 and 15. The results obtained in the present study may be useful for the development of more effective vaccines against disease caused by A. pleuropneumoniae by including the homologous antigens to the most prevalent serovars in specific geographical areas.

Efficacy of an avian colibacillosis live vaccine for layer breeder in Japan.

Colibacillosis is one of an economically significant disease in the poultry industry, especially for meat breed chickens. Recently it has become a serious problem for layer especially when the birds start laying and also at the later stage of laying. In Japan, the productivity of field laying hens improved when the Δcrp avian colibacillosis live vaccine ("Gall N tect CBL") was used. The survival rate and egg laying rate increased during almost all of the laying period when compared with the control group. The improvement in productivity was clearly demonstrated by comparing the number of eggs laid per day. The use of an avian colibacillosis live vaccine proved to be cost-effective in laying hens.

Study design for control of HEART rate in inFant and child tachyarrhythmia with heart failure Using Landiolol (HEARTFUL): A prospective, multicenter, uncontrolled clinical trial.

BACKGROUND: Persistent tachycardia in pediatric patients after congenital heart surgery further deteriorates their hemodynamic condition, and may become fatal. Therefore, immediate control of the tachycardia is mandatory in these patients. For this purpose, quick-acting, short-acting, titratable intravenous agents are required. However, there are no agents with such characteristics among the drugs approved for control of pediatric arrhythmias in Japan, and thus novel and effective medications for these patients are awaited. Landiolol, an ultrashort-acting ß-blocker, was approved in 2013 for tachyarrhythmias in adult patients with heart failure. However, its efficacy and safety in pediatric patients remain unclear. The aim of this prospective, multicenter, open-label phase IIb/III study is to investigate the efficacy and safety of landiolol in pediatric patients with tachyarrhythmias as well as heart failure. METHODS: Eligible patients are aged ≥ 3 months and <15 years, and have tachyarrhythmia (atrial fibrillation, atrial flutter, supraventricular tachycardia) as well as heart failure. The primary endpoint of the study is ≥20% reduction from baseline heart rate or return to normal sinus rhythm within 2h after starting intravenous administration of landiolol. Patients will receive intravenous infusion of landiolol, starting at 1µg/kg/min. The dose will be increased by 1µg/kg/min every 15-20min until the tachycardia rate has decreased by >20% or tachycardia has terminated, and the dose will then be maintained or further increased depending on the patient's condition. The study was started in April 2015 and will end within a few years. CONCLUSIONS: The study was designed and designated the "HEARTFUL study" in the hope of establishing a basis for control of HEART rate in inFant and child tachyarrhythmia Using Landiolol in children with heart failure.

Impacts of patient characteristics on the effectiveness of landiolol in AF/AFL patients complicated with LV dysfunction: Subgroup analysis of the J-Land study.

INTRODUCTION: Results 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. METHODS: Two 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. RESULTS: The 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). CONCLUSIONS: This 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.

Urgent management of rapid heart rate in patients with atrial fibrillation/flutter and left ventricular dysfunction: comparison of the ultra-short-acting ß1-selective blocker landiolol with digoxin (J-Land Study).

BACKGROUND: A rapid heart rate (HR) during atrial fibrillation (AF) and atrial flutter (AFL) in left ventricular (LV) dysfunction often impairs cardiac performance. The J-Land study was conducted to compare the efficacy and safety of landiolol, an ultra-short-acting ß-blocker, with those of digoxin for swift control of tachycardia in AF/AFL in patients with LV dysfunction. METHODS AND RESULTS: The 200 patients with AF/AFL, HR ≥120beats/min, and LV ejection fraction 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 <110beats/min at 2h after starting intravenous administration of landiolol or digoxin. The dose of landiolol was adjusted in the range of 1-10µg·kg(-1)·min(-1) according to the patient's condition. The mean HR at baseline was 138.2±15.7 and 138.0±15.0beats/min in the landiolol and digoxin groups, respectively. Successful HR control was achieved in 48.0% of patients treated with landiolol and in 13.9% of patients treated with digoxin (P<0.0001). Serious adverse events were reported in 2 and 3 patients in each group, respectively. CONCLUSIONS: Landiolol was more effective for controlling rapid HR than digoxin in AF/AFL patients with LV dysfunction, and could be considered as a therapeutic option in this clinical setting.

An attenuated mutant of avian pathogenic Escherichia coli serovar O78: a possible live vaccine strain for prevention of avian colibacillosis.

Here construction of an attenuated mutant of an avian pathogenic Escherichia coli serovar O78 using an allelic exchange procedure is described. The mutant AESN1331, which carries a deletion in the crp gene, lost tryptophan deaminase activity and therefore lacked the ability to produce indole. The mutant strain additionally lacked the ability to adsorb Congo red, no longer fermented sugars other than glucose and L-arabinose, did not harbor four known virulence-associated genes (iss, tsh, cvaA, papC), and was susceptible to many antimicrobials, with the exception of nalidixic acid. The lethal dose (LD(50) value) of the mutant strain on intravenous challenge in chickens was approximately 10-fold higher than that of the parent strain. Additionally, the mutant strain was rapidly eliminated from chickens, being detected in the respiratory tract only on the first day post-inoculation by fine spray. Administration of the mutant strain via various routes such as spray and eye drop for chickens, as well as in ovo inoculation for embryonated egg, evoked an effective immune response that protected against a virulent wild-type E. coli O78 strain. Specifically, after immunization with the mutant strain, chickens challenged intravenously with an E. coli O78 strain exhibited decreases in mortality, clinical scores, organ lesion scores, and recovery of the challenge strain from organs compared to non-immunized chickens. These findings suggest that AESN1331 is a suitable candidate for a live vaccine strain to protect chickens from colibacillosis caused by avian E. coli O78.

Characterization of Erysipelothrix rhusiopathiae strains isolated from recent swine erysipelas outbreaks in Japan.

The objective of the present study was to characterize Erysipelothrix sp. strains from recent erysipelas outbreaks in Japan. Eighty-three (100%) strains were identified as E. rhusiopathiae, based on serotyping and spaA PCR. Fifty (60.3%), 5 (6.0%), and 28 (33.7%) strains were isolated from animals with acute, subacute and chronic outbreaks, respectively, of which 79 (95.2%), 1 (1.2%), and 3 (3.6%) belonged to serotypes 1a, 2a, and untypeable, respectively. Fifteen strains (including 3, 2, and 10 from acute, subacute, and chronic cases, respectively) were sensitive to acriflavine, and showed high levels of virulence in mice; of which strains from acute cases, and from subacute and chronic cases killed 100%, and 80 to 100% mice, respectively at challenge doses of 10(2) CFU per mouse. Based on sequence analysis of a 432-bp hypervariable region in spaA gene, 83 strains could be divided into 3 groups: (i) group 1 (3 strains of serotype 1a) had Ala-195 and Ile-203; (ii) group 2 (76 strains of serotype 1a and 3 of untypeable) had Asp-195 and Met-203; and (iii) group 3 (one strain of serotype 2a) had Asn-195 and Ile-203. The results of the present study suggest that the serotype 1a strains belonging to the group 2 might be widespread in pig populations in Japan.

Immunization with truncated recombinant protein SpaC of Erysipelothrix rhusiopathiae strain 715 serovar 18 confers protective immunity against challenge with various serovars.

Previously, we showed that surface protective antigen (Spa) proteins of Erysipelothrix rhusiopathiae can be classified into three molecular species-SpaA, SpaB, and SpaC-and that SpaC is the most broadly cross-protective antigen among the three Spa proteins. In this study, we examined the ability of the α-helical domain, which comprises the N-terminal half of SpaC, to elicit cross-protective immunity in mice and pigs. Mice actively immunized with the full-length protein (rSpaC664) or the α-helical domain (rSpaC427), but not the C-terminal domain (rSpaC253), were protected against challenge with E. rhusiopathiae serovars 1a, 2, 6, 19, and 18 expressing heterologous (SpaA or SpaB) and homologous (SpaC) Spas. The α-helical domain seemed to provide better protection than rSpaC664, although the differences did not reach statistical significance. Similarly, mice passively immunized with rabbit anti-rSpaC664 or anti-rSpaC427 sera, but not anti-rSpaC253 serum, were protected from challenge with various serovars. Pigs immunized with SpaC427 also developed specific antibodies against Spa proteins and were protected from challenge with the highly virulent heterologous E. rhusiopathiae strain Fujisawa (serovar 1a). Taken together, these results demonstrate for the first time the striking protective efficacy of the α-helical domain-mediated immunization in both mice and pigs, thereby highlighting its utility as the most promising candidate for the development of a safe and effective vaccine against erysipelas.