Kondo Y.,Kumamoto University |
Tokumaru H.,Kumamoto University |
Ishitsuka Y.,Kumamoto University |
Matsumoto T.,Kumamoto University |
And 8 more authors.
Molecular Genetics and Metabolism | Year: 2016
This study was conducted to evaluate the attenuating potential of 2-hydroxypropyl-β-cyclodextrin (HPBCD) against Niemann-Pick Type C (NPC) disease, as well as the physical and chemical properties, particularly the cholesterol-solubilizing ability, in an NPC disease model in vitro. As parameters of NPC abnormalities, intracellular free and esterified cholesterol levels and lysosome volume were measured in Npc1 null Chinese hamster ovary cells. HPBCD showed dose-dependent effects against dysfunctional intracellular cholesterol trafficking, such as the accumulation and shortage of free and esterified cholesterols, respectively, in Npc1 null cells. However, the effectiveness was gradually offset by exposure to ≥. 8 mM HPBCD. The same effect was also observed for increasing lysosome volume in Npc1 null cells. The degree of substitution of the hydroxypropyl group had little influence on the attenuating effects of HPBCD against the NPC abnormalities, at least in the range between 2.8 and 7.4. Next, we compared the effects of other hydroxyalkylated β-cyclodextrin derivatives with different cholesterol-solubilizing abilities, such as 2-hydroxyethyl-β-cyclodextrin (HEBCD) and 2-hydroxybutyl-β-cyclodextrin (HBBCD). The cholesterol solubilizing potential, attenuating effects against NPC abnormalities and cytotoxicity induction were HBBCD ≫ HPBCD > HEBCD, HBBCD = HPBCD > HEBCD and HBBCD ≫ HPBCD = HEBCD, respectively. HPBCD may be superior in terms of safety and efficacy in Npc1 null cells compared with HEBCD and HBBCD. The results of this study will provide a rationale for the optimization of HPBCD therapy for NPC disease. © 2016 Elsevier Inc.
Randomized teriparatide [human parathyroid hormone (PTH) 1-34] once-weekly efficacy research (TOWER) trial for examining the reduction in new vertebral fractures in subjects with primary osteoporosis and high fracture risk
Nakamura T.,University of Occupational and Environmental Health Japan |
Sugimoto T.,The University of Shimane |
Nakano T.,Tamana Central Hospital |
Kishimoto H.,Sanin Rosai Hospital |
And 8 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012
Context: Weekly teriparatide injection at a dose of 56.5 μg has been shown to increase bone mineral density. Objective: A phase 3 study was conducted to determine the efficacy of once-weekly teriparatide injection for reducing the incidence of vertebral fractures in patients with osteoporosis. Design and Setting: In this randomized, multicenter, double-blind, placebo-controlled trial conducted in Japan, the incidence of morphological vertebral fractures by radiographs was assessed. Patients: Subjects were 578 Japanese patients between the ages of 65 and 95 yr who had prevalent vertebral fracture. Intervention: Subjects were randomly assigned to receive once-weekly sc injections of teriparatide (56.5 μg) or placebo for 72 wk. Main Outcome Measure: The primary endpoint was the incidence of new vertebral fracture. Results: Once-weekly injections of teriparatide reduced the risk of new vertebral fracture with a cumulative incidence of 3.1% in the teriparatide group, compared with 14.5% in the placebo group (P < 0.01), and a relative risk of 0.20 (95% confidence interval, 0.09 to 0.45). At 72 wk, teriparatide administration increased bone mineral density by 6.4, 3.0, and 2.3% at the lumbar spine, the total hip, and the femoral neck, respectively, compared with the placebo (P < 0.01). Adverse events (AE) and the dropout rates by AE were more frequently experienced in the teriparatide group, but AE were generally mild and tolerable. Conclusion: Weekly sc administration of teriparatide at a dose of 56.5 μg may provide another option of anabolic treatments in patients with osteoporosis at higher fracture risk. Copyright © 2012 by The Endocrine Society.
Kuroda H.,Sanin Rosai Hospital
Kyobu geka. The Japanese journal of thoracic surgery | Year: 2013
We report a case of a 57-year-old woman who presented with cardiac tamponade 13 days after thoracoscopic excision of the diverticulum of the esophagus. Computed tomography and electrocardiogram revealed neither evidence of aortic dissection nor acute myocardial ischemia. Unstable hemodynamic condition continued even after 400 ml blood drainage through pericardiocentesis, and emergency open surgery was performed. Active arterial bleeding was seen at the marginal branch of the left circumflex coronary artery. The stump of the suture [4-0 polydioxanone (PDS) II], which had been used for closure of the overlying esophageal muscle layer, penetrated the pericardium and injured the coronary artery. Vessel injury caused by a stump of a suture seems to be extremely rare. Careful selection of the suture around the pericardium and management of its stump are necessary.
Castilla J.,Rovira i Virgili University |
Risquez R.,University of Seville |
Higaki K.,Tottori University |
Nanba E.,Tottori University |
And 6 more authors.
European Journal of Medicinal Chemistry | Year: 2014
Pyranoid-type glycomimetics having a cis-1,2-fused glucopyranose-2-alkylsulfanyl-1,3-oxazoline (Glc-PSO) structure exhibit an unprecedented specificity as inhibitors of mammalian β-glucosidase. Notably, their inhibitory potency against human β-glucocerebrosidase (GCase) was found to be strongly dependent on the nature of aglycone-type moieties attached at the sulfur atom. In the particular case of υ-substituted hexadecyl chains, an amazing influence of the terminal group was observed. A comparative study on a series of Glc-PSO derivatives suggests that hydrogen bond acceptor functionalities, e.g. fluoro or methyloxycarbonyl, significantly stabilize the Glc-PSO:GCase complex. The S-(16-fluorohexadecyl)-PSO glycomimetic turned out to be a more potent GCase competitive inhibitor than ambroxol, a non glycomimetic drug currently in pilot trials as a pharmacological chaperone for Gaucher disease. Moreover, the inhibition constant increased by one order of magnitude when shifting from neutral (pH 7) to acidic (pH 5) media, a favorable characteristic for a chaperone candidate. Indeed, the fluoro-PSO derivative also proved superior to ambroxol in mutant GCase activity enhancement assays in N370S/N370S Gaucher fibroblasts. The results presented here represent a proof of concept of the potential of exploiting long-range non-glycone interactions for the optimization of glycosidase inhibitors with chaperone activity. © 2014 Elsevier Masson SAS.
Mena-Barragan T.,University of Seville |
Narita A.,Tottori University |
Matias D.,University of Algarve |
Tiscornia G.,University of Algarve |
And 6 more authors.
Angewandte Chemie - International Edition | Year: 2015
A general approach is reported for the design of small-molecule competitive inhibitors of lysosomal glycosidases programmed to 1) promote correct folding of mutant enzymes at the endoplasmic reticulum, 2) facilitate trafficking, and 3) undergo dissociation and self-inactivation at the lysosome. The strategy is based on the incorporation of an orthoester segment into iminosugar conjugates to switch the nature of the aglycone moiety from hydrophobic to hydrophilic in the pH 7 to pH 5 window, which has a dramatic effect on the enzyme binding affinity. As a proof of concept, new highly pH-responsive glycomimetics targeting human glucocerebrosidase or α-galactosidase with strong potential as pharmacological chaperones for Gaucher or Fabry disease, respectively, were developed. pH-Responsive chaperones for rescuing mutant lysosomal glycosidases were developed by incorporating an acid-labile orthoester into sp2-iminosugar conjugates. In the endoplasmic reticulum (ER; pH 7), the chaperone binds to the mutant enzyme and promotes correct folding and trafficking. In the lysosome (pH 5), fast hydrolysis of the orthoester leads to inactivation of the chaperone. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.