Fatal Systemic Capillary Leak Syndrome in a Patient with a COVID-19 Infection.

A 29-year-old Japanese woman was admitted to our hospital with a fever, cardiogenic shock, and cardiac arrest. Laboratory data indicated multiple organ failure in addition to hemoconcentration, hypoalbuminemia, and myocardial damage. The coronary angiography findings were normal, and fulminant myocarditis was suspected. Venoarterial peripheral extracorporeal membrane oxygenation and an Impella CP left ventricular assist device were initiated, along with the administration of positive inotropic agents. However, hypovolemic shock and hypoalbuminemia progressed along with severe anemia, and the patient died 18 hours after admission. The patient was diagnosed with systemic capillary leak syndrome associated with coronavirus disease 2019.

An Iron-chelating Agent Improved the Cardiac Function in a Patient with Severe Heart Failure Due to Hereditary Hemochromatosis.

A 24-year-old man was admitted to our hospital because of severe heart failure. Although he was treated with diuretics and positive inotropic agents, his heart failure progressed. An endomyocardial biopsy revealed iron deposition in his myocytes. Finally, he was diagnosed with hereditary hemochromatosis. After starting administration of an iron-chelating agent in addition to conventional treatment for heart failure, his condition improved. We should consider hemochromatosis in heart failure patients with severe right ventricular dysfunction in addition to left ventricular dysfunction.

Real-world Safety and Effectiveness of Edoxaban in Patients with Venous Thromboembolism with or without Preceding Parenteral Anticoagulants: A Single-center Retrospective Study.

Objective Edoxaban is an anticoagulant used for venous thromboembolism (VTE) treatment and requires pretreatment with parenteral anticoagulants. However, pretreatment is not always performed in the clinical setting. In this study, we investigated the safety and effectiveness of edoxaban treatment in patients with VTE with or without pretreatment. Methods We retrospectively enrolled 364 patients who received edoxaban for VTE treatment between September 2014 and March 2020 and investigated patient demographics, VTE recurrence, and major bleeding as clinical outcomes in patients with or without pretreatment. Furthermore, the factors contributing to pretreatment decisions were assessed. Results Patients without pretreatment (n=208) had more active cancer cases and fewer pulmonary embolism complications than those with pretreatment (n=156). Lower levels of hemoglobin and higher levels of white blood cell counts, C-reactive protein, and D-dimer at the diagnosis were found in patients who received pretreatment than in those without pretreatment. No symptomatic VTE recurrence was observed. After propensity score matching, the cumulative incidence of major bleeding was not significantly higher in patients with pretreatment than in those without it (log-rank test, p=0.136). The incidence of deteriorated VTE on imaging did not significantly differ between patients with and without pretreatment, even after propensity matching (log-rank test, p=0.414). Conclusion In a real-world clinical setting, where physicians determined the use of parenteral anticoagulant lead-in according to their experience, patient demographics, and VTE characteristics, no significant differences were found regarding safety and effectiveness in edoxaban-treated VTE patients with or without pretreatment with parenteral anticoagulants.

Fulminant Myocarditis and Acute Appendicitis after COVID-19 Vaccination.

A 19-year-old Japanese man was hospitalized for cardiogenic shock 28 days after receiving a second dose of the coronavirus disease 2019 (COVID-19) mRNA-1273 vaccine. He had had a high fever for three days with vomiting and abdominal pain before arriving at our hospital. The patient visited a local hospital and was diagnosed with heart failure and acute appendicitis. An endomyocardial biopsy specimen showed myocarditis. Thereafter, Impella CP left ventricular assist device implantation and venoarterial peripheral extracorporeal membranous oxygenation were initiated immediately along with inotropic support and steroid pulse therapy. Given these findings, he was finally diagnosed with multiple inflammatory syndrome and fulminant myocarditis.

Comparison of Effectiveness and Safety Among 3 Direct Oral Anticoagulants in Patients With Venous Thromboembolism　- A Single-Center Retrospective Study.

Background: Direct oral anticoagulants (DOACs), including edoxaban, rivaroxaban, and apixaban, are administered for the treatment of venous thromboembolism (VTE) in Japan. However, only a few reports have compared the effectiveness and safety of these DOACs. Methods and Results: We retrospectively enrolled 702 patients who received DOACs for VTE treatment between September 2014 and March 2020. We investigated patient demographics, VTE recurrence, major bleeding, and mortality until March 2021, and compared them among the 3 DOACs. Most patients (~70%; n=496) were prescribed edoxaban, followed by apixaban (n=107) and rivaroxaban (n=99). Age, body mass index, renal function, and the proportion of cancer patients did not differ significantly among the DOACs. Edoxaban was administered relatively more in women with low body weight and anemia. The rate of pulmonary embolism was significantly lower among patients receiving edoxaban than apixaban or rivaroxaban (24.4% vs. 41.1% and 53.5%, respectively). VTE reoccurred in 2 patients administered apixaban and 1 patient administered edoxaban. The cumulative incidence of major bleeding at 1 year was 11.7%, 18.5%, and 9.0% in the edoxaban, apixaban, and rivaroxaban groups, respectively. There were no significant differences in the cumulative incidence of major bleeding and all-cause death, estimated by Kaplan-Meier analysis, among the DOACs (log-rank P=0.316 and 0.722, respectively). Conclusions: The safety of the 3 DOACs did not differ significantly in clinical settings, despite differences in patient demographics.

Discovery of DS68702229 as a Potent, Orally Available NAMPT (Nicotinamide Phosphoribosyltransferase) Activator.

Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step of the nicotinamide adenine dinucleotide (NAD+) salvage pathway. Because NAD+ plays a pivotal role in energy metabolism and boosting NAD+ has positive effects on metabolic regulation, activation of NAMPT is an attractive therapeutic approach for the treatment of various diseases, including type 2 diabetes and obesity. Herein we report the discovery of 1-(2-phenyl-1,3-benzoxazol-6-yl)-3-(pyridin-4-ylmethyl)urea 12c (DS68702229), which was identified as a potent NAMPT activator. Compound 12c activated NAMPT, increased cellular NAD+ levels, and exhibited an excellent pharmacokinetic profile in mice after oral administration. Oral administration of compound 12c to high-fat diet-induced obese mice decreased body weight. These observations indicate that compound 12c is a promising anti-obesity drug candidate.

Novel mouse model for evaluating in vivo efficacy of xCT inhibitor.

xCT, a well-known cystine transporter, is reported to be involved in the proliferation of various cells, such as cancer cells, immune cells, and fibroblasts. xCT inhibitor is expected to be a promising drug for cancer or immune diseases. However, there are little studies reporting that xCT inhibitors improve disease progression in vivo. To invent potent xCT inhibitors in vivo, we established a new in vivo model for assessing efficacy of xCT inhibition. dl-propargylglycine (PPG) was administered intraperitoneally to wild-type C57BL/6J mice. Concentration of cystathionine, another substrate of xCT, in the thymus and spleen was measured by LC-MS/MS. PPG increased cystathionine amounts in the thymus and spleen in a dose- and time-dependent manner. At 7 h after PPG administration, the efficacy of erastin, a representative xCT inhibitor, was clearly shown. We synthesized a new compound, Compound A, which had much higher inhibitory effect on xCT than erastin both in vitro and in vivo. We established a mouse model of PPG-induced cystathionine accumulation for assessing xCT inhibition in vivo. By using this model, we discovered that Compound A was approximately 15 times more effective in vivo than erastin.

Coronary Artery Pseudoaneurysm due to Medial Mucoid Degeneration Mimicking an Intra-atrial Mass.

Coronary artery aneurysms are frequently asymptomatic and may be difficult to diagnose by cardiac imaging. We herein present a case of a coronary artery aneurysm of the right coronary artery due to medial mucoid degeneration mimicking an intra-atrial mass on echocardiography and magnetic resonance imaging, with the cause being diagnosed after surgery.

Synthesis and SAR studies of benzyl ether derivatives as potent orally active S1P1 agonists.

We report herein the synthesis and structure-activity relationships (SAR) of a series of benzyl ether compounds as an S1P1 receptor modulator. From our SAR studies, the installation of substituents onto the central benzene ring of 2a was revealed to potently influence the S1P1 and S1P3 agonistic activities, in particular, an ethyl group on the 2-position afforded satisfactory S1P1/S1P3 selectivity. These changes of the S1P1 and S1P3 agonistic activities caused by the alteration of substituents on the 2-position were reasonably explained by a docking study using an S1P1 X-ray crystal structure and S1P3 homology modeling. We found that compounds 2b and 2e had a potent in vivo immunosuppressive efficacy along with acceptable S1P1/S1P3 selectivity, and confirmed that these compounds had less in vivo bradycardia risk through the evaluation of heart rate change after oral administration of the compounds (30 mg/kg, p.o.) in rats.

Alpha-amylase inhibitor, CS-1036 binds to serum amylase in a concentration-dependent and saturable manner.

(2R,3R,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-3-yl 4-O-(6-deoxy-ß-D-glucopyranosyl)-α-D-glucopyranoside (CS-1036), which is an α-amylase inhibitor, exhibited biphasic and sustained elimination with a long t1/2 (18.4-30.0 hours) in rats and monkeys, but exhibited a short t1/2 (3.7-7.9 hours) in humans. To clarify the species differences in the t1/2, the plasma protein binding of CS-1036 was evaluated by ultrafiltration. A concentration-dependent and saturable plasma protein binding of CS-1036 was observed in rats and monkeys with the dissociation rate constant (KD) of 8.95 and 27.2 nM, and maximal binding capacity (Bmax) of 52.8 and 22.1 nM, respectively. By the assessments of the recombinant amylase and immunoprecipitation, the major binding protein of CS-1036 in rats was identified as salivary amylase (KD 5.64 nM). CS-1036 also showed concentration-dependent and saturable binding to human salivary and pancreatic amylase, with similar binding affinity in rats. However, the protein binding of CS-1036 was constant in human plasma (≤10.2%) due to the lower serum amylase level compared with rats and monkeys. From the calculation of the unbound fraction (fu) in plasma based on in vitro KD and Bmax, the dose-dependent increase in fu after oral administration is speculated to lead to a dose-dependent increase in total body clearance and a high area under the curve/dose at lower doses, such as 0.3 mg/kg in rats.

Tissue distribution and identification of radioactivity components at elimination phase after oral administration of [¹4C]CS-1036, an α-amylase inhibitor, to rats.

(2R,3R,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-3-yl 4-O-(6-deoxy-ß-D-glucopyranosyl)-α-D-glucopyranoside (CS-1036) is a potent inhibitor of pancreatic and salivary α-amylase. After oral administration of [¹4C]CS-1036 to rats, the radioactivity was still detectable up to 7-14 days after administration in various tissues, and its terminal phase in plasma could be explained neither by the exposure of CS-1036 nor its major metabolite M1. The slow elimination of radioactivity in various tissues was hypothesized to be caused by covalent binding to macromolecules or use for biogenic components. To assess the use for biogenic components, amino acid analysis of plasma proteins and lipid analysis of adipose tissue were conducted after repeated oral administration of [¹4C]CS-1036 by high-performance liquid chromatography and accelerated mass spectrometry and by thin layer chromatography and liquid chromatography/mass spectrometry, respectively. In amino acid analysis, glutamic acid, aspartic acid, alanine, and proline were identified as major radioactive amino acids, and radioactive nonessential amino acids occupied 76.0% of the radioactivity. In lipid analysis, a part of the radioactive lipids were identified as the fatty acids constituting the neutral lipids by lipase-hydrolysis. The radioactive fatty acids from neutral lipids were identified as palmitic acid, oleic acid, and 8,11,14-eicosatrienoic acid. Intestinal flora were involved in CS-1036 metabolism and are indicated to be involved in the production of small molecule metabolites, which are the sources for amino acids and fatty acids, from [¹4C]CS-1036. In conclusion, radioactivity derived from [¹4C]CS-1036 was incorporated as the constituents of amino acids of plasma proteins and fatty acids of neutral lipids.

Absorption, elimination, and metabolism of CS-1036, a novel α-amylase inhibitor in rats and monkeys, and the relationship between gastrointestinal distribution and suppression of glucose absorption.

The absorption, metabolism, and excretion of (2R,3R,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-3-yl 4-O-(6-deoxy-ß-d-glucopyranosyl)-α-d-glucopyranoside (CS-1036), a novel and potent pancreatic and salivary α-amylase inhibitor, were evaluated in F344/DuCrlCrlj rats and cynomolgus monkeys. The total body clearance and volume of distribution of CS-1036 were low (2.67-3.44 ml/min/kg and 0.218-0.237 l/kg for rats and 2.25-2.84 ml/min/kg and 0.217-0.271 l/kg for monkeys). After intravenous administration of [(14)C]CS-1036 to rats and monkeys, radioactivity was mainly excreted into urine (77.2% for rats and 81.1% for monkeys). After oral administration, most of the radioactivity was recovered from feces (80.28% for rats and 88.13% for monkeys) with a low oral bioavailability (1.73-2.44% for rats and 0.983-1.20% for monkeys). In rats, intestinal secretion is suggested to be involved in the fecal excretion as a minor component because fecal excretion after intravenous administration was observed (15.66%) and biliary excretion was almost negligible. Although intestinal flora was involved in CS-1036 metabolism, CS-1036 was the main component in feces (70.3% for rats and 48.7% for monkeys) and in the intestinal contents (33-68% for rats up to 2 hours after the dose) after oral administration. In Zucker diabetic fatty rats, CS-1036 showed a suppressive effect on plasma glucose elevation after starch loading with a 50% effective dose at 0.015 mg/kg. In summary, CS-1036 showed optimal pharmacokinetic profiles: low oral absorption and favorable stability in gastrointestinal lumen, resulting in suppression of postprandial hyperglycemia by α-amylase inhibition.

Purification and identification of activating enzymes of CS-0777, a selective sphingosine 1-phosphate receptor 1 modulator, in erythrocytes.

CS-0777 is a selective sphingosine 1-phosphate (S1P) receptor 1 modulator with potential benefits in the treatment of autoimmune diseases, including multiple sclerosis. CS-0777 is a prodrug that requires phosphorylation to an active S1P analog, similar to the first-in-class S1P receptor modulator FTY720 (fingolimod). We sought to identify the kinase(s) involved in phosphorylation of CS-0777, anticipating sphingosine kinase (SPHK) 1 or 2 as likely candidates. Unlike kinase activity for FTY720, which is found predominantly in platelets, CS-0777 kinase activity was found mainly in red blood cells (RBCs). N,N-Dimethylsphingosine, an inhibitor of SPHK1 and -2, did not inhibit CS-0777 kinase activity. We purified CS-0777 kinase activity from human RBCs by more than 10,000-fold using ammonium sulfate precipitation and successive chromatography steps, and we identified fructosamine 3-kinase (FN3K) and fructosamine 3-kinase-related protein (FN3K-RP) by mass spectrometry. Incubation of human RBC lysates with 1-deoxy-1-morpholinofructose, a competitive inhibitor of FN3K, inhibited ∼10% of the kinase activity, suggesting FN3K-RP is the principal kinase responsible for activation of CS-0777 in blood. Lysates from HEK293 cells overexpressing FN3K or FN3K-RP resulted in phosphorylation of CS-0777 and structurally related molecules but showed little kinase activity for FTY720 and no kinase activity for sphingosine. Substrate preference was highly correlated among FN3K, FN3K-RP, and rat RBC lysates. FN3K and FN3K-RP are known to phosphorylate sugar moieties on glycosylated proteins, but this is the first report that these enzymes can phosphorylate hydrophobic xenobiotics. Identification of the kinases responsible for CS-0777 activation will permit a better understanding of the pharmacokinetics and pharmacodynamics of this promising new drug.

Polymorphism of MDR1 gene in healthy japanese subjects: a novel SNP with an amino acid substitution (Glu108Lys).

We discovered a novel single nucleotide polymorphism (SNP) at position 325 (G325A) in exon 5 of the multidrug-resistance 1 (MDR1) gene in a study of 37 healthy Japanese subjects. Details are as follows. SNP, 020614Honda001; GENE NAME, human P-glycoprotein (MDR1); ACCESSION NUMBER, M29427; LENGTH, 25 bases; 5'-ATGAATCTGGAGG/AAAGACATGACCA-3'. This SNP is expected to cause an amino acid substitution (Glu108Lys). In this study, one homozygote and one heterozygote for G325A were identified.