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Takarazuka, Japan

Hasegawa Y.,Osaka University | Hayashi H.,University of Tokyo | Naoi S.,University of Tokyo | Kondou H.,Osaka University | And 10 more authors.
Orphanet Journal of Rare Diseases | Year: 2014

Background: Progressive familial intrahepatic cholestasis type 1 (PFIC1), an inherited liver disease caused by mutations in ATP8B1, progresses to severe cholestasis with a sustained intractable itch. Currently, no effective therapy has been established for PFIC1. Decreased function of the bile salt export pump (BSEP) in hepatocytes is suggested to be responsible for the severe cholestasis observed in PFIC1. We found a previously unidentified pharmacological effect of 4-phenylbutyrate (4PB) that increases the expression and function of BSEP. Here, we tested 4PB therapy in three patients with PFIC1. Methods. The therapeutic potency of 4PB in these patients was tested by oral administration of this drug with gradually increasing dosage (200, 350, and 500 mg/kg/day) for 6 months. Biochemical, histological, and clinical data were collected. Results: 4PB therapy had no beneficial effect on the patients' liver functions, as assessed by biochemical and histological analyses, despite an increase in hepatic BSEP expression. However, therapy with 4PB at a dosage of 350 or 500 mg/kg/day significantly relieved the intractable itch. Serum levels of potential pruritogens in cholestasis were much higher than the reference ranges during the 4PB therapy. Conclusions: 4PB therapy may be a new medication for patients with intractable cholestatic pruritus and may improve quality of life for patients and their families. © 2014 Hasegawa et al.; licensee BioMed Central Ltd.


Taenaka N.,Takarazuka City Hospital | Kikawa S.,Ono Pharma United States Inc.
Clinical Drug Investigation | Year: 2013

Background: β-Adrenoceptor antagonists (β-blockers) have been reported to be effective for regulation of heart rate (HR) and restoring sinus rhythm in postoperative atrial fibrillation and atrial flutter, as well as in the prevention of those arrhythmias after open-heart surgery. Objectives: The objectives of this study were to evaluate the dose-dependent effects of landiolol, an ultra-short-acting β1-blocker, as well as the effectiveness and safety of the drug in suppressing supraventricular tachyarrhythmias (SVT) in postoperative patients. Methods: Landiolol was administered as a four-dose titration regimen (LL, L, M, and H doses) to postoperative patients who developed SVT. The titration sequence began with a 1-min loading infusion at a rate of 0.015 mg/kg/min, followed by a 10-min continuous infusion at 0.005 mg/kg/min (the LL dose). Infusions at progressively higher doses followed in sequence until 20 % reduction in HR was achieved. The L dose was a 1-min loading infusion at 0.03 mg/kg/min, followed by a 10-min continuous infusion at 0.01 mg/kg/min. The M dose was a 1-min loading infusion at 0.06 mg/kg/min, followed by a 10-min continuous infusion at 0.02 mg/kg/min. The H dose was a 1-min loading infusion at 0.125 mg/kg/min, followed by a 10-min continuous infusion at 0.04 mg/kg/min. The patient was then observed for 30 min to determine the cardiovascular responses to withdrawal of the medication. After completion of this follow-up period, additional maintenance infusion for up to 6 h was permitted if considered necessary by the investigator. Results: A total of 108 patients were enrolled in this study. The cumulative improvement rates (percentage of patients obtaining ≥20 % reduction in HR) were 11.4, 32.4, 63.1, and 87.3 % at the LL, L, M, and H doses, respectively, demonstrating the dose-dependent effectiveness of landiolol. Additional infusion for up to 6 h was conducted in 16 patients. HR was maintained between 95.5 and 116.8 beats/min during the maintenance period (mean 259.8 min). Landiolol was generally well tolerated, although one patient with sick sinus syndrome developed an approximately 5-s cardiac arrest. Conclusions: The overall results, including those pertaining to patient safety, demonstrate that landiolol is effective and useful for the treatment of postoperative SVT. © 2013 The Author(s).


Background: Persistent postoperative supraventricular tachyarrhythmias (SVTs) increase cardiac burden and aggravate cardiac hemodynamics. Therefore, for patients in unstable conditions after surgery, prompt and sustained control of heart rate is essential. The importance of β-adrenoceptor antagonists (β-blockers) in controlling such postoperative atrial fibrillation or atrial flutter has been established, and the usefulness of ultra-short-acting β1-blockers with high β1 selectivity has been suggested based on their safety and efficacy under such circumstances. Objectives: Our objectives were to evaluate the effectiveness and safety of landiolol hydrochloride, an ultra-short-acting β1-selective blocker, in the treatment of postoperative SVT in patients with a high risk of myocardial ischemia, or in patients after highly invasive surgery, in a multicenter, randomized, double-blind, placebo-controlled, group-comparative study. Methods: A total of 165 patients were randomly allocated to three groups and received LM or MH doses of landiolol hydrochloride or placebo. LM group: dose L (1-min loading dose at a rate of 0.03 mg/kg/min, followed by a 10-min infusion at 0.01 mg/kg/min) followed by dose M (1-min loading at a rate of 0.06 mg/kg/min, followed by a 10-min infusion at 0.02 mg/kg/min); MH group: dose M followed by dose H (1-min loading dose at a rate of 0.125 mg/kg/min, followed by a 10-min infusion at 0.04 mg/kg/min); placebo (PP) group: dose P (1-min loading dose at a rate of 0 mg/kg/min, followed by a 10-min infusion at 0 mg/kg/min) followed by another round of dose P. If the targeted heart-rate reduction was not obtained at the end of the first 10-min infusion, the higher dose was started. The primary endpoint was the percentage of patients who met the heart-rate reduction criteria (≥20 % reduction and <100 beats/min). The safety endpoint was the incidence of adverse events in each of the three groups. Results: The percentages of patients who met the heart-rate reduction criteria (≥20 % reduction and <100 beats/min) were 0.0, 60.4, and 42.0 % in the PP, LM, and MH groups, respectively. There were significant differences in the LM and MH groups relative to the PP group, but there was no significant difference between the LM and MH groups. No significant difference was observed in the incidence of adverse events among the three groups: 29.6 % in the PP group, 45.5 % in the LM group, and 43.1 % in the MH group. Conclusion: Landiolol hydrochloride is effective and safe for patients with postoperative SVT. © 2013 The Author(s).


Yorifuji T.,Childrens Medical Center | Kawakita R.,Childrens Medical Center | Hosokawa Y.,Childrens Medical Center | Fujimaru R.,Childrens Medical Center | And 6 more authors.
Clinical Endocrinology | Year: 2013

Objective To evaluate the efficacy of long-term, continuous, subcutaneous octreotide infusion for congenital hyperinsulinism caused by mutations in the KATP-channel genes, KCNJ11 and ABCC8. Patients Fifteen Japanese patients with diazoxide-unresponsive, KATP-channel hyperinsulinism. Methods Molecular diagnoses were made by sequencing and multiple ligation-dependent probe amplification analysis. In patients with paternally inherited, monoallelic mutations, 18F-DOPA PET scans were performed to determine the location of the lesion. The patients were treated with continuous, subcutaneous octreotide infusion at a dosage of up to 25 μg/kg/day, using an insulin pump to maintain blood glucose levels higher than 3·33 mmol/l. Additional treatments (IV glucose, glucagon or enteral feeding) were administered as needed. The efficacy of the treatment was assessed in patients who received octreotide for 4 months to 5·9 years. Results Three patients had biallelic mutations, and 12 had monoallelic, paternally inherited mutations. Four patients with monoallelic mutations showed diffuse 18F-DOPA uptake, whereas seven patients showed focal uptake. Octreotide was effective in all the patients. The patients with biallelic mutations required a higher dosage (17-25 μg/kg/day), and two patients required additional treatments. By contrast, the patients with monoallelic mutations required a lower dosage (0·5-21 μg/kg/day) irrespective of the PET results and mostly without additional treatments. Treatment was discontinued in three patients at 2·5, 3·3 and 5·9 years of age, without psychomotor delay. Except for growth deceleration at a higher dosage, no significant adverse effects were noted. Conclusions Long-term, continuous, subcutaneous octreotide infusion is a feasible alternative to surgery especially for patients with monoallelic KATP-channel mutations. © 2012 John Wiley & Sons Ltd.


Makiguchi T.,Gunma University | Terashi H.,Kobe University | Hashikawa K.,Kobe University | Yokoo S.,Gunma University | Kusaka J.,Takarazuka City Hospital
Journal of Craniofacial Surgery | Year: 2013

Lipoma is a benign tumor that often arises in the craniomaxillofacial region. Osteolipoma containing bone tissue is very rare and the developmental mechanism is unclear. Mesenchymal stem cells in adipose tissue that have potential to differentiate into fat, bone, cartilage, and vascular components may be involved in the development of osteolipoma, in which adipose and bone tissues coexist. We encountered a patient with osteolipoma that arose in the glabella. We describe the case and the results of an investigation of the presence in lipomas of mesenchymal stem cells with differentiation potential similar to that of normal adipose cells. The patient was a 66-year-old woman. Histopathologically, bone tissue surrounded by fibrous connective tissue was present in the nodular adipose tissue and was diagnosed as osteolipoma. Mesenchymal stem cells were collected by collagenase treatment of lipoma tissue, and their potential to differentiate into fat, bone, and cartilage was shown. On the basis of this study, we suggest that lipoma-derived mesenchymal stem cells are the basis of the pathogenesis of osteolipoma. The conditions that induce differentiation of mesenchymal stem cells into bone remain to be investigated. © 2013 by Mutaz B. Habal, MD.

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