Subacute stent thrombosis with spontaneously resolved secondary thrombi in paroxysmal nocturnal hemoglobinuria: a case report.

BACKGROUND: Stent thrombosis (ST) is a serious complication; however, a method to prevent ST in patients with thrombophilic diseases has not been established. CASE PRESENTATION: We report a case of subacute ST in a patient with paroxysmal nocturnal hemoglobinuria (PNH) who was receiving continuous heparin treatment in addition to the usual dual antiplatelet therapy for contrast defects at the proximal site of the occluded right coronary artery and the proximal site of the left circumflex artery. Despite the resolution of thrombi in secondary lesions, subacute ST occurred. After percutaneous coronary intervention for ST, triple therapy, including oral anticoagulation for PNH-related thrombosis, was initiated. The patient subsequently underwent craniotomy hematoma removal for hemorrhagic cerebral infarction. CONCLUSIONS: Reported cases of ST in patients with PNH are very few, and this case adds evidence with respect to antithrombotic therapy in patients with thrombotic tendencies. Both thrombosis and bleeding should be considered when administering antithrombotic therapy to patients with thrombotic diseases. If there are specific treatments for thrombophilic diseases, they should be initiated early.

Clinical effectiveness and adverse events associated with tolvaptan in patients above 90 years of age with acute decompensated heart failure.

With the aging society, the number of very-elderly (VE) patients with acute decompensated heart failure (ADHF) is increasing. Although tolvaptan is recommended for patients with ADHF in whom conventional diuretic therapy is ineffective, few reports exist on VE patients over 90 years of age. Therefore, we aimed to evaluate the clinical effectiveness and adverse events associated with tolvaptan in VE patients with ADHF. From January 2011 to December 2018, we retrospectively studied 180 patients with ADHF who were first administered tolvaptan during hospitalization. Patients were divided into two groups, namely, VE patients who were ≥ 90 years of age (n = 32) and not-VE patients (NVE) who were < 90 years of age (n = 148). The primary effective endpoints were the total urine volume and change in body weight. The safety endpoints evaluated were the incidence of hypernatremia (≥ 150 mEq/L) and worsening renal function (WRF) at any time during hospitalization. The median [interquartile range] patient age was 93 [91-94] years in the VE group and 80 [69-85] years in the NVE group. The mean dose of tolvaptan for the first week of administration was similar between groups (7.9 ± 5.0 mg, VE group; 7.3 ± 3.7 mg, NVE group; p = 0.52). There were no significant differences between the two groups in the total urine volume at 24 h (1901 ± 666 mL, VE group; 2101 ± 1167 mL, NVE group; p = 0.33) and that at 48 h (3707 ± 1274 mL, VE group; 4195 ± 1990 mL, NVE group; p = 0.19) and in the mean change in body weight (- 2.5 ± 2.0 kg, VE group; -2.7 ± 2.4 kg, NVE group; p = 0.70). The median duration of hospitalization was 24 [20-9] and 31 [20-42] days in the VE and NVE groups, respectively (p = 0.67). The incidence of hypernatremia (6.3% (2/32), VE group; 3.4% (5/148), NVE group; p = 0.61) and WRF (25.0% (8/32) VE group; 19.6% (29/148), NVE group; p = 0.31) was similar between the groups. In conclusion, tolvaptan has similar clinical effectiveness in increasing urine volume and decreasing body weight, without increased adverse events, in VE patients with ADHF who were ≥ 90 years of age compared to NVE patients with ADHF.

Delirium is associated with high mortality in older adult patients with acute decompensated heart failure.

BACKGROUND: Delirium is associated with high mortality after cardiac surgery. However, evidence on the epidemiology of delirium in patients with acute decompensated heart failure (ADHF) is limited. This study aimed to assess the incidence and prognostic impact of delirium in patients with ADHF. METHODS: This single-center prospective observational study enrolled 132 consecutive patients with ADHF. We utilized the Diagnostic and Statistical Manual of Mental Disorders, fifth edition and classified the patients into two groups according to the presence or absence of delirium. The primary endpoint was 90-day all-cause mortality. The prognostic impact and risk factors of delirium were evaluated using multivariable Cox and logistic regression analyses, respectively. RESULTS: The median patient age was 83 (interquartile range, 75-87) years. Approximately 51.5% were men. Delirium occurred in 36 (27.3%) patients, and hyperactive delirium was the most frequent type (86.1%). The 90-day all-cause mortality was higher in the patients with delirium than in those without (21.6% versus 3.9%, log-rank p = 0.002). Delirium was associated with higher mortality with an adjusted hazard ratio of 6.8 (95% confidence interval, 1.1-42.6, p = 0.042). The risk factors associated with delirium included advanced age, male sex, higher clinical frailty scale score, and dementia. CONCLUSIONS: Delirium was associated with a higher 90-day all-cause mortality in the older adult patients with ADHF. Hyperactive delirium was the most common subtype.

Permanent Pacing in a Patient with Left Ventricular Mid-Cavity Obstruction and Apical Aneurysm.

Hypertrophic cardiomyopathy with left ventricular (LV) mid-cavity obstruction and LV apical aneurysm is associated with high morbidity and mortality rates. However, consensus is lacking on the treatment modality for LV mid-cavity obstruction and LV apical aneurysm. Here, we report a case of reduced LV mid-cavity pressure gradient and symptoms, treated using permanent pacing. The effect of permanent pacing on pressure gradient and symptoms lasted for 4 years. As pacing is relatively non-invasive compared to surgical therapy, permanent pacing is a good option, especially in the elderly patients with LV mid-cavity obstruction and apical aneurysm.

Synthesis and pharmacological characterization of 1-benzyl-4-aminoindole-based thyroid hormone receptor ß agonists.

A series of 1-benzylindole-based TRß agonists were prepared and evaluated. Compounds 11b' and 11c' were found to have cholesterol-lowering in a rat model with marginal effects on cardiac function and HPT axis. The present work illustrates the potential use of indoles as inner ring isosteres.

In vivo evaluation of 1-benzyl-4-aminoindole-based thyroid hormone receptor ß agonists: importance of liver selectivity in drug discovery.

We recently reported that the novel thyroid hormone receptor ß (TRß) selective agonists SKL-12846 and SKL-13784 reduce blood cholesterol levels without affecting thyroid-stimulating hormone (TSH) in cholesterol-fed rats. Our aim in this study was to elucidate what sets apart these SKL-compounds as TRß agonists with no effect on TSH. To this end, we determined SKL-compounds pharmacokinetics and tissue distribution in normal rats and compared them to those of GC-1, a liver-selective TRß agonist with concomitant effect on TSH. The present study explains why SKL-12846 and SKL-13784 have beneficial effects on lowering lipids without affecting heart rate and TSH production at the therapeutic dose in cholesterol-fed rats. In addition, we found that SKL-13784 shows no sign of escape phenomenon in fructose-fed rats. These results demonstrate the advantages of extremely high liver specificity to TRß agonists. However, SKL-13784 has been found significantly to reduce endogenous T4 levels at doses lower than its lipid-lowering dose, which may raise concerns over this compound's ability to alter thyroid hormone metabolism in the liver. While the mechanism by which SKL-13784 reduces endogenous T4 levels is still unclear, our results would help design better liver-selective TRß modulators.

Left atrial remodeling and recurrence of congestive heart failure in patients initially diagnosed with heart failure.

BACKGROUND: Left atrial volumes (LAVs) have been suggested to represent long-term exposure to elevated pressures. This study examined the recurrence of heart failure (HF) based on LAV in patients initially diagnosed with congestive HF (CHF). METHODS: This study comprised 77 patients (age, 75 ± 8 years) with well-documented, clinically defined HF, and complete two-dimensional echocardiographic examinations. The echocardiographic examinations were performed on admission and after medical treatment (90 ± 43 days after initial examination). Patients with atrial fibrillation, flail mitral valve, or mitral valve replacement were excluded from this study. RESULTS: The initial left ventricular ejection fraction (LVEF) was 44 ± 17% and the indexed LAV (LAVI) was 61 ± 22 mL/m(2) . After medical treatment, a decreased LAVI was observed in 38 patients and an increased LAVI (LA remodeling) was observed in 39 patients. With median follow-up periods of 454 days, compared to patients with decreased LAVI, patients with LA remodeling had a significantly higher incidence of CHF recurrence (P = 0.008). Patients with LA remodeling had a CHF-free survival rate of 36 ± 13% vs. 81 ± 9% (those without LA remodeling). A multivariate analysis indicated that, follow-up LV end-systolic volume (P = 0.04), LVEF (P = 0.005) and LAVI (P = 0.04) independently predicted CHF recurrence. CONCLUSIONS: Patients initially diagnosed with CHF follow divergent courses based on their LAV. LA remodeling after medical treatment can be useful for predicting CHF recurrence during follow-up.

A case of ascending aortic dissection and rupture caused by giant cell arteritis.

Giant cell arteritis (GCA) is an autoimmune disease characterized by granulomatous inflammation in the wall of medium-sized and large-sized arteries, and it usually occurs in patients over 50 years of age.(1)) Symptoms are nonspecific, and include fatigue, fever, and headache.(2)) It is occasionally combined with aortic complications, and ruptures resulting in death. These complications occur as late events, usually several years after diagnosis and often after other symptoms have subsided.(3)) Physicians should therefore be alert for complications of the large arteries in GCA. Here we present a case of GCA combined with ascending aortic dissection and rupture 3 weeks after diagnosis.

Synthesis and SAR studies of bicyclic amine series GPR119 agonists.

We disclosed a novel series of G-protein coupled receptor 119 (GPR119) agonists based on a bicyclic amine scaffold. Through the optimization of hit compound 1, we discovered that the basic nitrogen atom of bicyclic amine played an important role in GPR119 agonist activity expression and that an indanone in various bicyclic rings was suitable in this series of compounds. The indanone derivative 2 showed the effect of plasma glucose control in oGTT and scGTT in the rodent model.

A novel C-C chemokine receptor 2 antagonist prevents progression of albuminuria and atherosclerosis in mouse models.

C-C chemokine ligand 2 (CCL2)/its receptor (CCR2) axis is considered as an important signaling pathway in inflammatory diseases. TLK-19705 is a novel CCR2 antagonist, (1-(1,3-dimethyl-1-H-pyrazolo[3,4-b]pyridine-5-carbonyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)urea), and the inhibitory activity was antagonized by the third extracellular loop peptide of CCR2. We examined in this study the effects of TLK-19705 on diabetic nephropathy and atherosclerosis in mouse models. Treatment with TLK-19705 (30 mg/kg/d) for 8 weeks ameliorated urinary albumin-creatinine ratio in db/db mice. In addition, TLK-19705, given at 10 mg/kg/d for 8 weeks, significantly reduced the areas of atherosclerotic lesion in apolipoprotein E knockout mice. In conclusion, the results of this study indicate not only considerable therapeutic potential of CCR2 antagonists for diabetic nephropathy and atherosclerosis, but also that TLK-19705 would serve as a powerful tool in mechanistic investigation of these inflammatory diseases.

Synthesis and pharmacological profile of a new selective G protein-coupled receptor 119 agonist; 6-((2-fluoro-3-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)propyl)amino)-2,3-dihydro-1H-inden-1-one.

6-((2-Fluoro-3-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)propyl)amino)-2,3-dihydro-1H-inden-1-one is a potent drug-like G protein-coupled receptor 119 (GPR119) agonist. It is hoped that this compound would be instrumental in probing the pharmacological potential of GPR119 agonists.

Differentiating Immune-Related Adrenal Insufficiency From Low Cardiac Output Syndrome: A Case Report.

We report a case of a 58-year-old woman with secondary adrenocortical insufficiency due to adrenocorticotropic hormone (ACTH) deficiency after pembrolizumab treatment that required differentiation from low cardiac output syndrome. The patient had chronic heart failure due to radiation cardiomyopathy and underwent implantation of cardiac resynchronization therapy defibrillator (CRT-D). One year ago, she was diagnosed with squamous cell lung cancer and started combination therapy with carboplatin, paclitaxel, and pembrolizumab. She was hospitalized for anorexia, nausea, and hypotension. A diagnosis of secondary hypoadrenocorticism due to isolated ACTH deficiency was made, and from the course of the disease, it was diagnosed as a side effect of immune checkpoint inhibitors (ICIs). As the indications for ICIs continue to expand, it is necessary to understand the screening and management of their side effects.

Practical preparation of ethyl 2-methylthiophene-3-carboxylate.

A safe and efficient process for the preparation of ethyl 2-methylthiophene-3-carboxylate (5) was devised. This process provides several advantages over the precedents, involving operational simplicity, avoidance of the use of strong bases such as n-butyllithium and application of noncryogenic conditions, and enabled to prepare 5 in 52% overall yield from commercially available 2-methylthiophene on a multikilogram scale.

A case of Wolff-Parkinson-White syndrome in which two-dimensional speckle-tracking echocardiography was useful for identifying the location of the accessory atrioventricular pathway.

BACKGROUND: In Wolff-Parkinson-White (WPW) syndrome, accessory atrioventricular pathways (AP) result in abnormal pre-excitation around the atrioventricular annuli and produce a dyssynchronous contraction of cardiac chambers. Identification of the AP affects the outcome of catheter ablation. CASE SUMMARY: We report a case of WPW syndrome and paroxysmal atrial fibrillation in a 65-year-old man. Wolff-Parkinson-White syndrome Type B was suspected from lead V1, but when two-dimensional speckle-tracking echocardiography (2D-STE) was performed, a decrease in regional strain was observed in the anterior basal wall of the left ventricle. We identified the earliest site of atrioventricular conduction, and improvement in the regional strain at the site of ablation was observed after successful AP ablation. DISCUSSION: Various echocardiographic techniques have been investigated as non-invasive alternatives for AP localization. Longitudinal 2D-STE accurately identified contractile abnormalities associated with the AP, allowing us to non-invasively estimate the localization of the AP in WPW syndrome.

Hydroxyzine-induced Torsade de Pointes in a Patient with Complete Atrioventricular Block.

An 82-year-old woman was admitted to our hospital because of dyspnea and bradycardia during exertion. Electrocardiography revealed complete atrioventricular block. During pacemaker implantation, a small dose (12.5 mg) of hydroxyzine was injected for sedation, and torsade de pointes (Tdp) occurred. The QT interval was prolonged after administration of hydroxyzine, and Tdp was observed after the R on T phenomenon occurred, indicating that hydroxyzine was capable of prolonging the QT interval and causing Tdp. Therefore, we must be cautious when administering hydroxyzine for sedation during surgery, especially in patients with bradycardia.

Asymptomatic Immune Checkpoint Inhibitor-associated Myocarditis.

We herein report the case of a 75-year-old man with asymptomatic immune checkpoint inhibitor (ICI)-associated myocarditis diagnosed on the basis of elevated levels of creatine kinase (CK), CK-myocardial band and troponin I (TNI). He was suspected of being complicated with myasthenia gravis (MG). High-dose prednisolone (PSL) is associated with a risk of MG exacerbation; therefore, PSL therapy was gradually increased from 5 mg/day to 20 mg/day, which resulted in the normalization of the TNI level, and no PSL-related side effects occurred. MG easily complicates myocarditis as an immune-related adverse event; thus, the treatment plan should be carefully considered.

Clarithromycin-induced Coronary Vasospasms Caused Acute Coronary Syndrome in a 19-year-old Male Patient.

A 19-year-old-man was admitted to our hospital with intermittent chest pain. The day before admission, he had been diagnosed with enteritis and prescribed clarithromycin. He had experienced severe chest pain three times after taking clarithromycin; thus, acute coronary syndrome (ACS) was suspected. Emergent coronary angiography showed normal coronary arteries; however, the result of a subsequent acetylcholine provocation test was positive. We diagnosed him to have ACS caused by coronary vasospasms and suspected clarithromycin-induced Kounis syndrome. Although more common in older patients, Kounis syndrome must be suspected and a thorough medication history should be taken whenever a patient complains of chest pain.

Severe Gastroparesis After Ablation for Atrial Fibrillation.

A 70-year-old man was treated with catheter ablation for symptomatic paroxysmal atrial fibrillation (AF). The treatment consisted of pulmonary vein isolation and radiofrequency ablation of the cavo-tricuspid isthmus line. However, the patient started vomiting two days after ablation. Abdominal radiography and plain abdominal computed tomography revealed gastric distension and massive accumulation of food residues. Esophagogastroduodenoscopy after fasting for two days revealed no organic stricture; food residues were retained in the stomach but not in the duodenum, suggesting gastroparesis. The most likely mechanism underlying gastroparesis associated with AF ablation is collateral periesophageal vagal nerve injury. Mosapride citrate is considered effective for symptoms.

Complete atrioventricular block and torsade de pointes due to dose-dense epirubicin and cyclophosphamide therapy.

The dose-dense epirubicin and cyclophosphamide (EC) therapy for breast cancer decreases the risk of cancer recurrence and death. However, epirubicin and cyclophosphamide also cause cardiotoxicity, and cardiomyopathy is the most well-known related adverse effect. A 58-year-old woman presented to our hospital with palpitations 2 weeks after her final dose-dense EC therapy for breast cancer. Holter electrocardiogram (ECG) showed transitory complete atrioventricular block (CAVB) and torsade de pointes. A 12-lead ECG showed QT prolongation in addition to CAVB. Patients receiving dose-dense EC therapy should be monitored more carefully with ECG due to their risk of fatal arrhythmias.

Pharmacokinetic Study of SKL-18287, a Novel Long-Acting Glucagon-Like Peptide-1 Receptor Agonist, in Rats, Monkeys and Mini-Pigs.

BACKGROUND: Long-acting glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used for treatment of type 2 diabetes (T2DM) in the United States, the European Union, and Japan. In our previous work, we designed and characterized a novel GLP-1 RA, SKL-18287. This RA consists of only natural L-amino acids, and is believed to exist in an oligomer form in systemic circulation. This unique feature may allow high biological stability and a long-lasting glucose lowering effect in T2DM treatment. In the present study, we investigated the pharmacokinetic properties of SKL-18287 in rats, monkeys, and mini-pigs. Tissue distributions of radioactivity were also studied in rats after subcutaneous administration of [3H]-SKL-18287. METHODS: Plasma concentrations of SKL-18287 were measured by LC-MS/MS after intravenous and subcutaneous administration of SKL-18287 in rats, monkeys, and mini-pigs. Pharmacokinetic parameters were then calculated and compared among these animal species. Tissue concentrations of radioactivity were determined by liquid scintillation counting following sample combustion, after subcutaneous administration of [3H]-SKL-18287 to rats. RESULTS: SKL-18287 showed an extended half-life of over 5 h, with good subcutaneous bioavailability, in all animal species. Prediction of the pharmacokinetic profiles of SKL-18287 in humans using an animal scale-up approach revealed an SKL-18287 half-life of 14.8 h. The radioactivity concentration in the pancreas, a target tissue of GLP-1RA, was relatively higher than in other tissues, until 12 h after [3H]-SKL-18287 administration. CONCLUSION: SKL-18287 might be sufficient to maintain an effective concentration for a once-daily treatment for T2DM, and is a unique GLP-1 RA with a pancreas-selective feature.