Computational Drug-repositioning Approach Identifying Sirolimus as a Potential Therapeutic Option for Inflammatory Dilated Cardiomyopathy.

OBJECTIVE: The aim of this study was to determine promising treatment options for human inflammatory dilated cardiomyopathy using a computational drug-repositioning approach (repurposing established drug compounds for new therapeutic indications). BACKGROUND: If the myocardial tissue is detected to be infiltrated with inflammatory cells, primarily of lymphocytes, and if the virus is confirmed using genetic examination (PCR) or immunostaining, the infection is suspected. However, there is no specific treatment (i. e., an antiviral drug) even if the virus is identified; therefore, we used Connectivity Map to identify compounds showing inverse drug-disease signatures, indicating activity against inflammatory dilated cardiomyopathy. RESULTS: Potential drug-repositioning candidates for the treatment of inflammatory dilated cardiomyopathy were explored through a systematic comparison of the gene expression profiles induced by drugs using Gene Expression Omnibus and Connectivity Map databases. CONCLUSION: Using a computational drug-repositioning approach based on the integration of publicly available gene expression signatures of drugs and diseases, sirolimus was suggested as a novel therapeutic option for inflammatory dilated cardiomyopathy.

Feasibility of High-dose Iodine-131-metaiodobenzylguanidine Therapy for High-risk Neuroblastoma Preceding Myeloablative Chemotherapy and Hematopoietic Stem Cell Transplantation: a Study Protocol.

OBJECTIVES: High-risk neuroblastoma is a childhood cancer with poor prognosis despite modern multimodality therapy. Internal radiotherapy using 131I-metaiodobenzylguanidine (MIBG) is effective for treating the disease even if it is resistant to chemotherapy. The aim of this study is to evaluate the safety and efficacy of 131I-MIBG radiotherapy combined with myeloablative high-dose chemotherapy and hematopoietic stem cell transplantation. METHODS: Patients with high-risk neuroblastoma will be enrolled in this study. A total of 8 patients will be registered. Patients will receive 666 MBq/kg of 131I-MIBG and after safety evaluation will undergo high-dose chemotherapy and hematopoietic stem cell transplantation. Autologous and allogeneic stem cell sources will be accepted. After engraftment or 28 days after hematopoietic stem cell transplantation, the safety and response will be evaluated. CONCLUSION: This is the first prospective study of 131I-MIBG with high-dose chemotherapy and hematopoietic stem cell transplantation in Japan. The results will be the basis of a future nationwide clinical trial.

A phase I clinical trial for [131I]meta-iodobenzylguanidine therapy in patients with refractory pheochromocytoma and paraganglioma: a study protocol.

Objective Pheochromocytoma and paraganglioma (PPGLs) are rare neuroendocrine tumors derived from the adrenal medulla or extra-adrenal paraganglioma from extra-adrenal chromaffin tissue. Although malignant PPGLs has miserable prognosis, the treatment strategy remains to be established. An internal radiation therapy using [131I]meta-iodobenzylguanidine (131I-mIBG) called MIBG therapy has been attempted as one of the systemic treatment of malignant PPGLs. The aim of this study is therefore to evaluate the safety and the efficacy of MIBG therapy for refractory PPGLs. Methods Patients with refractory PPGLs will be enrolled in this study. The total number of patients for registration is 20. The patients receive a fixed dose of 7,400 MBq of 131I-mIBG. Adverse events are surveyed during 20 weeks after 131I-mIBG injection and all severe adverse events will be documented and reported in detail in accordance with the Common Terminology Criteria for Adverse Events (CTCAE). Examination and imaging diagnosis are performed in 12 weeks after 131I-mIBG injection for the evaluation of therapeutic effect in accordance with the Response Evaluation in Solid Tumours (RECIST). Conclusion The current study is the first multi-institutional prospective study of MIBG therapy and thereby will play a significant role in improving the patients' prognosis of refractory PPGLs. J. Med. Invest. 64: 205-209, August, 2017.

Phase I/II study of alectinib in lung cancer with RET fusion gene: study protocol.

BACKGROUND: The rearranged during transfection (RET) fusion gene was discovered as a driver oncogene in 1-2% of non-small cell lung cancers (NSCLCs). Alectinib is an approved anaplastic lymphoma kinase (ALK) inhibitor that may also be effective for RET fusion-positive NSCLC. METHODS/DESIGN: RET fusion-positive NSCLC patients treated with at least one regimen of chemotherapy are being recruited. In step 1, alectinib (600 or 450 mg, twice daily) will be administered following a 3+3 design. The primary endpoint is safety. In step 2, alectinib will be administered at the recommended dose (RD) defined by step 1. The primary endpoint is the response rate of RET inhibitor treatment-naïve patients. CONCLUSION: This is the first study to investigate the safety and preliminary efficacy of alectinib in RET fusion-positive NSCLC patients. If successful, alectinib treatment may lead to substantial and important changes in the management of NSCLC with RET fusion genes. J. Med. Invest. 64: 317-320, August, 2017.

Calcitonin gene-related peptide released by capsaicin suppresses myoelectrical activity of gastric smooth muscle.

BACKGROUND: It is widely accepted that the inhibition of gastric motor activity as well as the maintenance of gastric mucosal blood flow and mucous secretion are important for the homeostasis of the gastric mucosa. The present study was performed to ascertain whether or not capsaicin, which can protect the stomach from noxious stimuli, affects gastric motor activity. METHODS: Male Sprague-Dawley rats were anesthetized with urethane, and the stomach was cannulated by two catheters from esophageal and duodenal sides. A biopolar electrode was fixed to the serosal surface of the antrum and myoelectrical activity was recorded during the instillation of a small volume of solutions. RESULTS: The myoelectrical activity of rat gastric smooth muscle was increased at intragastric pressures of >2 cmH(2)O. Replacement of intragastric physiological saline with 1.6 mmol/L capsaicin solution significantly suppressed this myoelectrical activity by 50%. Intragastric capsaicin administration caused a significant release of substance P (SP) and calcitonin gene-related peptide (CGRP). The maximum released levels of CGRP in the gastric perfusates were 100-fold those of SP. The myoelectrical activity observed at an intragastric pressure of 2 cmH(2)O was avoided by continuous infusion of CGRP (0.1-3.0 nmol/kg per min) into the gastric artery in a dose-dependent manner, but not by that of SP (1.0 nmol/kg per min). Continuous CGRP-(8-37) infusion into the gastric artery completely blocked the reduction by intragastric capsaicin of myoelectrical activity. CONCLUSION: These results suggest that the suppression of the myoelectrical activity of gastric smooth muscle by capsaicin is attributable to the endogenous CGRP released.