Japanese Patients with Severe Asthma Identified as Responders to Omalizumab Treatment at 2 Years Based on the GETE Score Continued Treatment for an Extended Period.

Purpose: Omalizumab, the anti-IgE monoclonal antibody used to treat severe asthma, reduces asthma exacerbations, hospitalizations, and corticosteroid use. Although allergic asthma is a therapeutic target of omalizumab, omalizumab is not effective in all patients with severe allergic asthma and is not always available for long-term use. We retrospectively investigated factors related to long-term (≥2 years) use of omalizumab for severe asthma.

In vivo cardiovascular profile of ryanodine receptor 2 inhibitor M201-A: Utility as an anti-atrial fibrillatory drug for patients suffering from heart failure with preserved ejection fraction.

Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) often coexist; however, clinically available anti-AF drugs can exacerbate symptoms of HFpEF. M201-A suppressed ryanodine receptor-mediated diastolic Ca leakage, possibly inhibiting common pathological processes toward AF and HFpEF. To bridge the basic information to clinical practice, we assessed its cardiohemodynamic, anti-AF and ventricular proarrhythmic profile using halothane-anesthetized dogs (n = 4).

Drug-induced long QT syndrome: Concept and non-clinical models for predicting the onset of drug-induced torsade de pointes in patients in compliance with ICH E14/S7B guidance.

ICH established S7B and E14 guidelines in 2005 to prevent drug-induced torsade de pointes (TdP), effectively preventing the development of high-risk drugs. However, those guidelines unfortunately hampered the development of some potentially valuable drug candidates despite not being proven to be proarrhythmic. In response, Comprehensive In Vitro Proarrhythmia Assay (CiPA) and Exposure-Response Modeling were proposed in 2013 to reinforce proarrhythmic risk assessment.

Characterization of remodeling processes in the atria of atrioventricular block dogs: Utility as an early-stage atrial fibrillation model.

To characterize utility of atrioventricular block (AVB) dogs as atrial fibrillation (AF) model, we studied remodeling processes occurring in their atria in acute (<2 weeks) and chronic (>4 weeks) phases. Fifty beagle dogs were used. Holter electrocardiogram demonstrated that paroxysmal AF occurred immediately after the production of AVB, of which duration tended to be prolonged in chronic phase.

Analysis of cardiohemodynamic and electrophysiological effects of morphine along with its toxicokinetic profile using the halothane-anesthetized dogs.

Although morphine has been used for treatment-resistant dyspnea in end-stage heart failure patients, information on its cardiovascular safety profile remains limited. Morphine was intravenously administered to halothane-anesthetized dogs (n=4) in doses of 0.1, 1 and 10 mg/kg/10 min with 20 min of observation period.

Laparoscopic repair of concurrent direct and indirect inguinal, femoral, and obturator hernias on the same side: A case report.

Concurrent direct and indirect inguinal, femoral, and obturator hernias are rare. This case report describes a rare case treated using the laparoscopic approach. A 68-year-old female patient presented with a moving left inguinal lump and pain.

Analyses of the onset mechanisms of cardio-stimulatory action by aciclovir.

Cardio-stimulatory actions of aciclovir have been considered to primarily depend on the sympathetically-mediated reflex resulting from its hypotensive effect. To further clarify onset mechanisms of the cardio-stimulatory actions, we initially studied them using isoflurane-anesthetized dogs under thorough β-adrenoceptor blockade with atenolol (1 mg/kg, i.v.

Characterization of cardiovascular profile of anti-influenza drug peramivir: A reverse-translational study using the isoflurane-anesthetized dog.

An injectable anti-influenza drug peramivir has been reported to induce QT-interval prolongation in some phase III studies, although its thorough QT/QTc study was negative. We investigated the discrepancy among those clinical studies using isoflurane-anesthetized beagle dogs (n = 4). Peramivir in doses of 1 mg/kg/10 min (sub-therapeutic dose) followed by 10 mg/kg/10 min (clinically-relevant dose) was intravenously administered.

Cardiovascular safety pharmacology of ivermectin assessed using the isoflurane-anesthetized beagle dogs: ICH S7B follow-up study.

Antiparasitic ivermectin has been reported to induce cardiovascular adverse events, including orthostatic hypotension, tachycardia and cardiopulmonary arrest, of which the underlying pathophysiology remains unknown. Since its drug repurposing as an antiviral agent is underway at higher doses than those for antiparasitic, we evaluated the cardiovascular safety pharmacology of ivermectin using isoflurane-anesthetized beagle dogs (n=4). Ivermectin in doses of 0.

In vivo analysis of acute eletropharmacological effects of proton pump inhibitors using halothane-anesthetized dogs: a translational study of cardiovascular adverse events.

Long-term use of proton pump inhibitors (PPIs) is known to clinically induce hypomagnesemia, increasing the risk toward QT-interval prolongation and lethal ventricular arrhythmias, whereas PPIs can directly modulate cardiac ionic currents in the in vitro experiments. In order to fill the gap between those information, we assessed acute cardiohemodynamic and electrophysiological effects of sub- to supra-therapeutic doses (0.05, 0.

Characterization of electropharmacological profile of an anti-atrial fibrillatory drug vernakalant along with potential risk toward torsade de pointes: Translational studies using isoflurane-anesthetized dogs and isolated rat aortic preparations.

We simultaneously assessed electropharmacological effects of anti-atrial fibrillatory drug vernakalant and its potential risk toward torsade de pointes. Vernakalant hydrochloride in doses of 0.3 and 3 mg/kg/10 min was intravenously administered to isoflurane-anesthetized beagle dogs without (n = 5) and with (n = 4) α-adrenoceptor blockade.

Characterization of the electrocardiogram of microminipig in comparison with that of Clawn miniature swine: impacts of miniaturization of body size on electrocardiographic indices.

Effects of body size reduction on electrocardiographic indices were examined using microminipigs in comparison with Clawn miniature swine (Clawn). Electrocardiogram was recorded using Holter electrocardiograph in conscious state for 24 hr for microminipigs (male: 11.6 ± 0.

Both osmolality-dependent and independent mechanisms are associated with acute hyperglycemia-induced cardiovascular adverse reactions: Analysis of the mutual interactions leading to cardiovascular phenotypes in dogs.

Acute hyperglycemia causes various cardiovascular responses; however, the underlying pathophysiology in vivo is myriad and complex, of which mutual interactions remain poorly understood. We analyzed the cardiovascular effects of acute hyperglycemia in comparison with those of hyperosmolality alone. Three g/kg of D-glucose (n = 4) or D-mannitol (n = 4) was intravenously infused to isoflurane-anesthetized intact dogs.

Characterization of pathological remodeling in the chronic atrioventricular block cynomolgus monkey heart.

We studied time course of pathological remodeling occurring in the cynomolgus monkey hearts against persistent atrioventricular block condition ( = 10). The atrioventricular block induced the ventricular and atrial dilation followed by the ventricular hypertrophy. Interstitial fibrosis in the ventricle was also observed along with gradual increases in the plasma angiotensin II and aldosterone concentrations.

[A Case of Robotic Distal Pancreatectomy for Pancreatic Metastasis of Gastric Cancer].

A 78-year-old male who had received laparoscopic total gastrectomy for upper gastric cancer 30 months ago(pT3N0, pStage ⅡB)was referred for further treatment for a 30-mm in size mass at the splenic hilum. The mass was suspected of lymph node metastasis was suspected. Two courses of SOX therapy failed to achieve the tumor response.

[A Case of Curative Resection for Gastric Cancer with Single Giant Lymph Node Metastasis].

A 79-year-old male presented with epigastric discomfort and appetite loss. A type 1 advanced gastric tumor was detected by upper gastrointestinal endoscopy. Contrast-enhanced CT revealed a 7 cm mass with contrast effect at the greater curvature of the lower body of the stomach.

Docetaxel+Cisplatin+5-FU (DCF) Therapy as a Preoperative Chemotherapy to Advanced Esophageal Squamous Cell Carcinoma: A Single-center Retrospective Cohort Study.

Objective The aim of this study was to determine the safety and clinical efficacy of docetaxel+cisplatin+5-fluorouracil (DCF) as neoadjuvant chemotherapy (NAC). Methods In this single-center study, patient background and treatment outcomes (NAC efficacy assessment, NAC adverse events, short-term postoperative outcomes, and one-year postoperative outcomes) in patients treated with preoperative DCF and preoperative cisplatin+5-FU (CF) were compared retrospectively. Patients Seventeen patients diagnosed with esophageal squamous cell carcinoma (ESCC) and treated with preoperative DCF therapy and 50 patients treated with preoperative CF therapy between January 2013 and July 2019 were included in this study.

Site-directed deuteration of dronedarone preserves cytochrome P4502J2 activity and mitigates its cardiac adverse effects in canine arrhythmic hearts.

Cytochrome P4502J2 (CYP2J2) metabolizes arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic acids (EETs). Dronedarone, an antiarrhythmic drug prescribed for treatment of atrial fibrillation (AF) induces cardiac adverse effects (AEs) with poorly understood mechanisms. We previously demonstrated that dronedarone inactivates CYP2J2 potently and irreversibly, disrupts AA-EET pathway leading to cardiac mitochondrial toxicity rescuable EET enrichment.

Appraisal of ICH E14/S7B Q&As adopted in February 2022 using thorough QT/QTc study data for α4-integrin antagonist carotegrast methyl in Japanese healthy subjects.

We investigated how a lack of placebo control affects the interpretation of results of thorough QT/QTc (TQT) study. Results of TQT study in 48 healthy Japanese subjects assessing the effects of 480 and 960 mg of carotegrast methyl (test drug) and 400 mg of moxifloxacin (positive control) on the time-matched changes in corrected QT from baseline (ΔQTcF) and the placebo-adjusted ΔQTcF (ΔΔQTcF) were analyzed with central-tendency and concentration-response analyses. In central-tendency analysis, moxifloxacin prolonged ΔQTcF and ΔΔQTcF with the largest mean values (90% confidence interval) of 12.

Imatinib induces diastolic dysfunction and ventricular early-repolarization delay in the halothane-anesthetized dogs: Class effects of tyrosine kinase inhibitors.

Imatinib has been reported to induce heart failure and/or QTc prolongation. To better understand their underlying mechanisms, we assessed its effects on cardiohemodynamic, electrocardiographic and echocardiographic variables along with biomarkers of myocardial damage. Imatinib mesylate in doses of 1 and 10 mg/kg was intravenously administered to the halothane-anesthetized beagle dogs (n = 4).