Magnetic resonance evaluation of brain metastases from systemic malignances with two doses of gadobutrol 1.0 m compared with gadoteridol: A multicenter, Phase II/III study in patients with known or suspected brain metastases
Katakami N.,Institute of Biomedical Research and Innovation |
Inaba Y.,Aichi Cancer Center Hospital |
Sugata S.,Shikoku Cancer Center Hospital |
Tsurusaki M.,National Cancer Center |
And 7 more authors.
Investigative Radiology | Year: 2011
Objectives: To determine the efficacy and safety of 2 doses of gadobutrol 1.0 M (0.1 and 0.2 mmol/kg body weight [BW]), compared with gadoteridol 0.5 M (0.2 mmol/kg BW), in contrast-enhanced magnetic resonance imaging (CE-MRI) of brain metastases in patients with known or suspected brain metastases from systemic malignancies. The study also compared the usefulness of gadobutrol in treatment planning for stereotactic radiosurgery (SRS). Materials and Methods: This was a Phase II/III, multicenter, single-blind, randomized, controlled, crossover, intraindividual comparison study. Each patient underwent one MRI study examination with gadobutrol and the other with gadoteridol, each at a dose of 0.1 mmol/kg BW, administered twice, for a total dose of 0.2 mmol/kg BW. Image acquisition was carried out after the first and second doses of gadobutrol, but only after the second dose of gadoteridol. Contrast agents were assigned in a randomized order and their administration separated by an interval of 1 to 14 days. Images were evaluated through blinded readings by 3 independent experienced radiologists. Treatment planning for SRS was assessed in a blinded manner, as a consensus between a diagnostic neuroradiologist and a radiation oncologist, in addition to the clinical investigator's assessment. The safety and tolerability of gadobutrol and gadoteridol were evaluated in all patients who received the study drugs. The primary efficacy variable was the number of lesions detected in CE-MRI images; the secondary efficacy variables were the degree of contrast enhancement and border delineation of lesions, and experts' confidence in treatment planning for SRS. Results: A total of 175 patients were enrolled and randomized, with 164 (93.7%) included in the safety analysis set, and 151 (86.2%) evaluable in the efficacy analysis. The mean number of detected lesions per patient using the average of the 3 blinded readers was 6.28, 6.92, and 6.87 for gadobutrol 0.1 and 0.2 mmol/kg BW, and gadoteridol 0.2 mmol/kg BW, respectively. Noninferiority of gadobutrol (both doses) to gadoteridol 0.2 mmol/kg BW was demonstrated. The degree of contrast enhancement and the border delineation of each lesion were categorized as "good" or "excellent" for most lesions for both agents. Almost all enhanced images were rated as "confident" in treatment planning for SRS. Sixty-five (43%) and 62 (41%) patients in the gadobutrol 0.1 and 0.2 mmol/kg BW groups, respectively, were selected as eligible for SRS treatment. The percentage of images assessed as "gadobutrol was better than gadoteridol" was higher than that assessed as "gadoteridol was better than gadobutrol" for both doses of gadobutrol. Eight adverse events were reported as being related to the study drug in 7 patients (4.3%) in each group. Conclusion: In this study, a single dose of gadobutrol was shown to be noninferior to a double dose of gadoteridol at detecting brain metastases, and could be effectively used for treatment planning in patients eligible for SRS. A dose of gadobutrol 0.1 mmol/kg BW is recommended as the clinical dose for the detection of brain metastases. Copyright © 2011 Lippincott Williams & Wilkins.
Hayashi S.,University of Fukui |
Sakurai H.,University of Toyama |
Hayashi A.,Takarazuka City Hospital |
Tanaka Y.,University of Fukui |
And 2 more authors.
International Journal of Molecular Medicine | Year: 2010
We investigated the mechanisms of thermosensitization related to combination therapy with sesquiterpene lactone parthenolide (PTL), a nuclear factor-κB (NF-κB) inhibitor, and hyperthermia using human lung adenocarcinoma cells A549. The kinetics of apoptosis induction and cell cycle of cells treated with PTL, heating, and combined treatment were examined by flow cytometric analysis. The flow cytometric distribution was calculated and expressed as a percentage. The ratios of the sub-G1 division, used to determine the induction of apoptosis, increased significantly with the combination therapy. Furthermore, the ratios of G2/M division increased and the ratios of G0/G1 division decreased, indicating cell cycle arrest in G2/M. The cell phase response to PTL by A549 cells synchronized in the G1/S border with hydroxyurea was also analyzed. PTL showed remarkable cytotoxicity at the S phase of the cell cycle in A549 cells at all concentrations as well as with hyperthermia, thus PTL reduced the number of cells in the proliferation phase. Inhibition of intracellular transcription factor NF-κB activation in A549 cells with various incubation periods after treatments with PTL, heating and combined treatment was examined by Western blot analysis. Unexpectedly, PTL alone did not inhibit NF-κB activation in cells stimulated with TNF-α, while heating alone inhibited NF-κB early after treatment and that effect faded over time. In contrast, PTL combined with heating completely inhibited NF-κB activation. Our results demonstrated that PTL and heating in combination cause significant thermosensitization of A549 cells via induction of apoptosis or cell cycle arrest in G2/M by inhibiting NF-κB activation in a synergistic manner.
Yoshimuta T.,Kanazawa University |
Yokoyama H.,Japan National Cardiovascular Center Research Institute |
Okajima T.,Takarazuka City Hospital |
Tanaka H.,Japan National Cardiovascular Center Research Institute |
And 8 more authors.
Circulation Journal | Year: 2015
Background: Plasma d-dimer is known to be a useful clinical marker of thrombogenic status, and d-dimer is used as a diagnostic marker for acute aortic dissection (AAD). Little is known, however, regarding the clinical value of d-dimer for diagnosis of asymptomatic AAD in patients with ischemic stroke. We investigated whether d-dimer could be used for early diagnosis of AAD with isolated neurological symptoms in ischemic stroke patients. Methods and Results: We evaluated a total of 1,236 consecutive patients with symptomatic ischemic stroke without chest or back pain who underwent either head computed tomography or magnetic resonance imaging. d-Dimer was measured within 24 h after onset. There were 9 patients with Stanford type A AAD and they had significantly higher d-dimer than the patients without AAD (mean, 46.47 ±54.48 μg/ml; range, 6.9–167.1 μg/ml vs. 2.33±3.58 μg/ml, 0.3–57.9 μg/ml, P<0.001). When a cut-off of 6.9 μg/ml was adopted for d-dimer on the basis of receiver operating characteristics analysis, the sensitivity and specificity for AAD were 100% and 94.8%, respectively, while the positive and negative predictive values were 14.7% and 100%, respectively. Conclusions: d-Dimer might be a useful marker for the early diagnosis of AAD with isolated neurological symptoms in ischemic stroke patients. Whole-body contrast-enhanced computed tomography should be performed in ischemic stroke patients who have high d-dimer. © 2015, Japanese Circulation Society. All rights reserved.
PubMed | Oita University, Red Cross, Juntendo University, Saiseikai Yokohamashi Tobu Hospital and 11 more.
Type: | Journal: Molecular genetics and metabolism | Year: 2017
Citrin deficiency causes adult-onset type II citrullinemia (CTLN-2), which later manifests as severe liver steatosis and life-threatening encephalopathy. Long-standing energy deficit of the liver and brain may predispose ones to CTLN-2. Here, we compared the energy-driving tricarboxylic acid (TCA) cycle and fatty acid -oxidation cycle between 22 citrin-deficient children (age, 3-13years) with normal liver functions and 37 healthy controls (age, 5-13years). TCA cycle analysis showed that basal plasma citrate and -ketoglutarate levels were significantly higher in the affected than the control group (p<0.01). Conversely, basal plasma fumarate and malate levels were significantly lower than those for the control (p<0.001). The plasma level of 3-OH-butyrate derived from fatty acid -oxidation was significantly higher in the affected group (p<0.01). Ten patients underwent sodium pyruvate therapy. However, this therapy did not correct or attenuate such deviations in both cycles. Sodium pyruvate therapy significantly increased fasting insulin secretion (p<0.01); the fasting sugar level remained unchanged. Our results suggest that citrin-deficient children show considerable deviations of TCA cycle metabolite profiles that are resistant to sodium pyruvate treatment. Thus, long-standing and considerable TCA cycle dysfunction might be a pivotal metabolic background of CTLN-2 development.
Naoi S.,Tokyo Medical University |
Hayashi H.,Tokyo Medical University |
Inoue T.,Dokkyo Medical University |
Tanikawa K.,Kurume University |
And 8 more authors.
Journal of Pediatrics | Year: 2014
To examine the effects of 4-phenylbutyrate (4PB) therapy in a patient with progressive familial intrahepatic cholestasis type 2. A homozygous c.3692G>A (p.R1231Q) mutation was identified in ABCB11. In vitro studies showed that this mutation decreased the cell-surface expression of bile salt export pump (BSEP), but not its transport activity, and that 4PB treatment partially restored the decreased expression of BSEP. Therapy with 4PB had no beneficial effect for 1 month at 200 mg/kg/day and the next month at 350 mg/kg/day but partially restored BSEP expression at the canalicular membrane and significantly improved liver tests and pruritus at a dosage of 500 mg/kg/day. We conclude that 4PB therapy would have a therapeutic effect in patients with progressive familial intrahepatic cholestasis type 2 who retain transport activity of BSEP per se. © 2014 The Authors.
Yorifuji T.,Osaka City General Hospital |
Kawakita R.,Osaka City General Hospital |
Hosokawa Y.,Osaka City General Hospital |
Fujimaru R.,Osaka City General Hospital |
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.
Okano Y.,Hyogo College of Medicine |
Nagasaka H.,Takarazuka City Hospital
Molecular Genetics and Metabolism | Year: 2013
High serum phenylalanine in adult patients with phenylketonuria (PKU) causes neuropsychological and psychosocial problems that can be resolved by phenylalanine-restricted diet. Therefore, PKU patients must continue to adhere to phenylalanine-restricted diet for life, although the optimal serum phenylalanine level in later life has yet to be established. The purpose of this review was to establish the optimal serum phenylalanine level in later life of PKU patients. We evaluated oxidative stress status, nitric oxide metabolism, cholesterol-derived oxysterols, vitamin D and bone status, and magnetic resonance imaging (MRI) in adult PKU patients according to serum phenylalanine level. Oxidative stress increased markedly at serum phenylalanine of 700-800. μmol/L. Serum phenylalanine higher than 700-850. μmol/L correlated with the disturbance of nitric oxide regulatory system. Adult PKU patients had poor vitamin D status and exhibited predominance of bone resorption over bone formation. In the brain, the levels of 24S-hydroxycholesterol, a marker of brain cholesterol elimination, were low at serum phenylalanine levels exceeding 650. μmol/L. MRI studies showed high signal intensity in deep white matter on T2-weighted and FLAIR images of PKU patients with serum phenylalanine greater than 500. μmol/L, with decreased apparent diffusion coefficients. Changes in most parameters covering the entire body organs in adult PKU were almost acceptable below 700-800. μmol/L of phenylalanine level. However, the optimal serum phenylalanine level should be 500. μmol/L or less in later life for the brain to be safe. © 2013 Elsevier Inc.
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).
The Effectiveness and Safety of Landiolol Hydrochloride, an Ultra-Short-Acting β1-Blocker, in Postoperative Patients with Supraventricular Tachyarrhythmias: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study
Taenaka N.,Takarazuka City Hospital |
Kikawa S.,Ono Pharma United States Inc
American Journal of Cardiovascular Drugs | Year: 2013
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).
Imanaka H.,Takarazuka City Hospital
Japanese Journal of Chest Diseases | Year: 2016
Ventilator-associated pneumonia (VAP) refers to pneumonia that develops at least 48 hours after the initiation of mechanical ventilation. VAP is one of the most common complications during mechanical ventilation; increases along with period of mechanical ventilation, and it worsens the prognosis of patients. The risk factors for VAP are tracheal tube, a long duration of mechanical ventilation, reintubation, and aspiration. Most of the interventions to prevent VAP focus on reducing colonization and aspiration.