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A 28-year-old man was diagnosed with acute myelomonocytic leukemia. He achieved complete remission (CR) after two cycles of induction therapy. However, after consolidation therapy, bone marrow aspiration performed to prepare for allogeneic hematopoietic stem cell transplantation revealed disease relapse. Companion diagnostics confirmed the presence of the FLT3-ITD mutation. The patient received gilteritinib monotherapy and achieved CR. Subsequently, he underwent unrelated allogeneic bone marrow transplantation. One year after transplantation, the patient relapsed, and gilteritinib was resumed. However, the leukemia progressed, and panel sequencing using a next-generation sequencer showed that the FLT3-ITD mutation disappeared. A mutation in PTPN11, which regulates the RAS/MAPK signaling pathway, was also detected. Gilteritinib was discontinued, and the patient achieved CR with salvage chemotherapy. He underwent related haploidentical peripheral blood stem cell transplantation but died of relapse. This was a case in which genetic analysis revealed clonal transition and acquisition of resistance to treatment.

Selexipag (Uptravi ® tablets) is a novel prostacyclin receptor (IP receptor) agonist designed and synthesized at Nippon Shinyaku Co., Ltd., and approved for the treatment of pulmonary arterial hypertension (PAH). Selexipag is converted to MRE-269 in vivo, and the plasma concentration of MRE-269 is maintained at a therapeutic level for a long time. MRE-269 has selective IP receptor agonist activity and exerts vasodilatory and anti-proliferative effects on pulmonary arterial smooth muscle cells. In a study to investigate its vasodilatory effect in isolated rat pulmonary arteries, MRE-269 showed potent vasodilatory effects not only in extralobar but also in small intralobar pulmonary arteries. In a Sugen 5416/hypoxia rat model of PAH, selexipag significantly improved pulmonary artery obstruction, decreased right ventricular systolic pressure, decreased right ventricular hypertrophy and improved survival rate. In a phase II clinical trial for treatment with PAH conducted in Europe, selexipag showed good tolerability with promising efficacy. In an open-label phase II study in 37 patients with PAH in Japan, selexipag significantly decreased pulmonary vascular resistance compared with baseline. In the GRIPHON (Prostacyclin (PGI 2 ) Receptor agonist In Pulmonary arterial HypertensiON) study in 1156 patients with PAH, the largest outcome study ever conducted in PAH, the selexipag treatment group showed a significant reduction in the risk of the primary composite endpoint of death or a complication related to PAH compared with placebo. Selexipag has been shown in clinical trials to prevent the progression of PAH, and is expected to contribute to the treatment of patients with PAH.

Gilteritinib fumarate (Xospata ® tablets 40 mg) is a novel, highly selective, oral FMS-like tyrosine kinase 3 (FLT3) inhibitor used for the treatment of patients with relapsed or refractory FLT3-mutated acute myeloid leukemia (AML), and it was approved in Japan in September 2018. Preclinical studies demonstrated that gilteritinib inhibited FLT3 and showed antiproliferative activity against Ba/F3 cells expressing mutated FLT3. In addition, gilteritinib inhibited tumor growth, induced tumor regression, and prolonged survival in mice xenografted with MV4-11 cells endogenously expressing FLT3-internal tandem duplication. In clinical trials conducted in the United States, Europe, and Japan, plasma concentrations after administration of gilteritinib 20 to 450 mg/day were generally dose proportional, and gilteritinib was well tolerated. Multiple clinical trials, including a global Phase III study, in patients with relapsed or refractory FLT3-mutated AML treated with gilteritinib demonstrated higher response rates of complete remission or complete remission with partial hematologic recovery and longer overall survival compared with patients treated with salvage chemotherapy. Some clinical trials are ongoing in patients with FLT3-mutated AML at various treatment stages, such as induction therapy, maintenance therapy, and treatment after hematopoietic stem cell transplantation. In conclusion, in vitro, in vivo, and clinical data indicate that gilteritinib fumarate is an effective treatment option in adult patients with relapsed or refractory FLT3-mutated AML in Japan.

We developed a method of video-rate bioluminescence imaging to visualize proteins secreted from living cells. A protein of interest was fused to Gaussia luciferase (GLase), and the luminescence signals of secreted GLase with coelenterazine (luciferin) were visualized at a video-rate of 30-500 ms/frame by using a water-cooled EM-CCD camera. We established a subclonal rat INS-1E cell line, named iGL cells, stably expressing the fusion protein of insulin and GLase (Insulin-GLase). By stimulation with high glucose, 3D-cultured iGL cells showed synchronized oscillatory secretion of insulin for over 1 h, as similarly observed in an isolated rat pancreatic islet. In 2D-cultured iGL cells, the luminescence images indicated that synchronized insulin secretion was localized in intercellular spaces between cells. Further, the relative amount of insulin secretion from iGL cells was easily determined with a luminometer, and we demonstrated that cell-cell interaction of beta cells is fundamental to increase glucose-stimulated insulin secretion by synchronization. Thus, iGL cells would be valuable for studying oscillatory insulin secretion and evaluating anti-diabetic drugs. Our bioluminescence imaging method with GLase could be generally used for investigating protein secretion in 2D and 3D cell culture systems.

Lung cancer is the leading cause of cancer-related death throughout the world including Japan. During the 1990s, new cytotoxic agents such as irinotecan, paclitaxel, docetaxel, vinorelbine, gemcitabine, and amrubicin showed impressive single-agent activity in patients with lung cancer. To date, clinical research has defined the current standard chemotherapy for advanced non-small cell lung cancer (NSCLC) as modern platinum-based doublets considered more efficacious than any single regimen and with no added benefit to triplet therapies. However, we have reached an efficacy plateau with these agents. Rearrangement of the drug combination or change of the drug doses and schedules will not result in significant further progress. New, less toxic agents that improve survival and quality of life are clearly needed. In the last three decades, we have gained a growing understanding of the molecular biologic changes and the complex series of cellular signals that allow cancer cells to manifest behavior. This provides an opportunity to develop novel therapies aimed at inhibiting some of these changes and signals. Targeted agents, primarily the epidermal growth factor receptor inhibitors, have led to a new era in the treatment of NSCLC. This paper will review the current status of cytotoxic agents and molecular targeted therapy in lung cancer potential useful in the treatment of the patients.

Depression of myocardial contractility plays an important role in the development of heart failure and many inotropic agents were developed to improve the contractile function of the failing heart. Agents that increase cyclic AMP, either by increasing its synthesis or reducing its degradation, exerted dramatic short-term hemodynamic benefits, but these acute effects were not extrapolated into long-term improvement of the clinical outcome of heart failure patients. Administration of these agents to an energy starved failing heart would be expected to increase myocardial energy use and could accelerate disease progression. The role of digitalis in the management of heart failure has been controversial, however, the recent large scale clinical trial has ironically proved that digoxin reduced the rate of hospitalization both overall and for worsening heart failure. More recently, attention was paid to other inotropic agents that have a complex and diversified mechanism. These agents have some phosphodiesterase-inhibitory action but also possess additional effects, including cytokine inhibitors, immunomodulators, or calcium sensitizers. In the Western Societies these agents were again shown to increase mortality of patients with severe heart failure in a dose dependent manner with the long-term administration. However, it may not be the case in the Japanese population in whom mortality is relatively low. Chronic treatment with inotropic agent may be justified in Japanese, as it allows optimal care in the context of relief of symptoms and an improved quality of life. Therefore, each racial group should obtain specific evidence aimed at developing its own guidelines for therapy rather than translating major guidelines developed for other populations.

The effects of vesnarinone (3,4-dihydro-6-[4(3,4-dimethoxybenzoyl)-1-piperanizyl]-2 (1H)-quinolinone) on the hematopoietic precursors in 5 healthy volunteers and leukemic blast progenitors in 11 acute myeloid leukemia (AML) patients, 1 chronic myelocytic leukemia patient (CML) in blast crisis, and 3 leukemic cell lines were studied in methylcellulose and suspension cultures. Normal erythroid precursors (colony-forming unit erythroid: CFU-E and burst-forming unit erythroid: BFU-E) and granulopoietic precursors (colony-forming unit granulocyte/macrophage: CFU-GM) were suppressed in methylcellulose culture by vesnarinone in a dose-dependent manner. Leukemic blast progenitors may replicate themselves and/or undergo terminal divisions with limited differentiation. The plating efficiency of primary blast colony formation (PE1) in methylcellulose, which is considered to reflect the terminal divisions of leukemic blast progenitors, was suppressed by vesnarinone in a dose-dependent manner in all cases tested. The plating efficiency of secondary blast colony-formation (PE2) in methylcellulose culture and the recovery of clonogenic cells in the suspension culture, which are considered to reflect the self-replication function of leukemic blast progenitors, were also suppressed by vesnarinone in a dose-dependent manner in all cases tested. The results suggest that vesnarinone inhibits the growth of normal and leukemic hematopoietic progenitors. To determine the mechanism by which vesnarinone inhibits hematopoiesis, the effect of the agent on apoptosis (programmed cell death) of leukemic cells was studied. DNA ladder formation was recognized in OCI/AML 1 a cells after exposure to 100 micrograms/ml vesnarinone for 18 hours; this means that vesnarinone induced apoptosis in this cell line. Therefore, vesnarinone is considered to be the cause of apoptosis of granulopoietic precursors.

The left ventricular (LV) end-systolic force-diameter (Fes-Des) relationship was used to examine the effect of a new positive inotropic agent (vesnarinone) on the contractility of the beta-blocked canine left ventricle. Seven adult mongrel dogs were implanted with ultrasonic crystals to measure the LV diameter and a micromanometer to measure LV pressure. Beta-adrenergic and vagal blockades were induced with intravenous propranolol (2 mg/kg) and atropine (0.2 mg/kg), respectively, and preload was decreased by inferior vena caval occlusion. The slope (Ec) and extrapolated diameter intercept (Do) of the LV Fes-Des relationship were derived from the end-systolic data obtained in the control, beta-blocked state, after sulfolane infusion, and after infusion of vesnarinone (3 mg/kg) dissolved in sulfolane. Ec was used as a new index of LV myocardial contractility. After vesarinone infusion, the LV Fes-Des relationship seemed to be nearly linear, and its Ec value was significantly increased by 18% (68.4 +/- 15.4 vs 80.4 +/- 21.8 g/cm, p < 0.05) without changes in heart rate, whereas Do did not change (1.74 +/- 0.44 vs. 1.70 +/- 0.42 cm). These results indicate that vesnarinone significantly enhances myocardial contractility in the beta-blocked canine left ventricle.

The crucial issues in the management of congestive heart failure (CHF) are improvement of depressed myocardial contractility and reduction of excessive load. For this purpose, positive inotropic agents and vasodilators have been developed as new oral drugs. The former include Denopamine which possesses beta 1 stimulating effect, Xamoterol which is a unique agent acting as a beta 1-partial agonist, and Ibopamine, Docarpamine and Phosphodiesterase Inhibitors which possess both inotropic and vasodilating effects and are called "Inodilators". The latter include Angiotensin Converting Enzyme Inhibitors. In addition, new vasodilators, such as, Vasopressin Antagonist have also been developed. However, careful long-term clinical trials are required with regard to the efficacy and adverse effects before these agents are widely used with safety in the management of CHF.

The possible chronotropic and arrhythmogenic effects of newly-developed oral inotropic agents were studied in 60 patients with idiopathic dilated cardiomyopathy (NYHA class II-IV). Changes in heart rates and the incidence of arrhythmias were evaluated using ambulatory electrocardiography. Denopamine 30 and 60 mg (beta 1 agonist), xamoterol 200 and 400 mg (beta 1 partial agonist) and OPC-8212 60, 90 and 120 mg (non-catecholamine) were sequentially administered for 10 +/- 2 months. Denopamine slightly increased heart rate throughout the day. Denopamine 60 mg caused excessive tachycardia in patients with atrial fibrillation, and could be used without digoxin. With xamoterol, maximum heart rate decreased during the daytime, while heart rate increased at night. Xamoterol was highly effective in patients with atrial fibrillation who not only had excessive tachycardia during exercise but marked bradycardia at night. Xamoterol increased the severity of heart failure in two patients who belonged to NYHA class IV, whose heart rates at rest had exceeded 100 beats/min. OPC-8212 did not affect heart rate, and was considered an ideal inotropic agent. None of these agents aggravated arrhythmias or caused sustained ventricular tachycardia. It was concluded that not only the severity of heart failure but the chronotropic and arrhythmogenic effects should be considered when choosing inotropic agents.