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Patrick Yu-Wai-Man, Devorah Soiferman, David G Moore, Florence Burté, Ann Saada
Leber hereditary optic neuropathy (LHON) is an important cause of mitochondrial blindness among young adults. In this study, we investigated the potential of four quinone analogues (CoQ1, CoQ10, decylubiquinone and idebenone) in compensating for the deleterious effect of the m.11778G>A mitochondrial DNA mutation. The LHON fibroblast cell lines tested exhibited reduced cell growth, impaired mitochondrial bioenergetics and elevated levels of reactive oxygen species (ROS). Idebenone increased ATP production and reduced ROS levels, but the effect was partial and cell-specific...
January 16, 2017: Mitochondrion
Frederic Tort, Olatz Ugarteburu, Maria Angeles Torres, Judit García-Villoria, Marisa Girós, Angeles Ruiz, Antonia Ribes
We report the case of a 10-year-old Spanish girl with mutations in NADK2 Prenatal central nervous system abnormalities showed ventriculomegaly, colpocephaly, and hypoplasia of the corpus callosum. At birth, axial hypotonia, uncoordinated movements, microcephaly, and generalized cerebellar atrophy were detected. Metabolic investigations revealed high lysine, lactate, and pipecolic acid levels in blood and cerebrospinal fluid. Pyruvate carboxylase and pyruvate dehydrogenase activity in fibroblasts were normal...
November 2016: Pediatrics
Mario Contin, Fabián Buontempo, Cristian García Becerra, Cecilia Dobrecky, Silvia Lucangioli, Valeria Tripodi
A novel, simple and reliable method based on micellar electrokinetic chromatography with ultraviolet detection was developed to analyze idebenone in a pediatric formulation. Idebenone is a synthetic short chain benzoquinone that acts as an electron carrier in the mitochondrial electron transport chain facilitating the production of adenosine triphosphate. It can be found in two different redox states that differ in their physiological properties. Idebenone has been investigated as a treatment in several neurological disorders like Friedreich's ataxia, Leber's hereditary optic neuropathy, mitochondrial encephalomyopathies and senile dementia...
November 23, 2016: Journal of Chromatographic Science
Jared J Murray, Kaitlyn W Nolan, Collin McClelland, Michael S Lee
A 15-year-old boy experienced painless vision loss in the left eye of unknown duration. Leber hereditary optic neuropathy (LHON) was suspected, despite negative testing for the 3 most common pathogenic gene mutations and idebenone 300 mg 3 times daily was prescribed. Nine months later, the patient developed right eye involvement. Complete mitochondrial genome analysis revealed 2 rare variants-m.3890G>A of the MT-ND1 gene and m.8417C>A of the MT-ATP8 gene. The former has been described in severe infantile Leigh syndrome and LHON; the latter is of unknown significance...
October 27, 2016: Journal of Neuro-ophthalmology: the Official Journal of the North American Neuro-Ophthalmology Society
Ana Paula Terrasso, Ana Carina Silva, Augusto Filipe, Pedro Pedroso, Ana Lúcia Ferreira, Paula Marques Alves, Catarina Brito
INTRODUCTION: Central nervous system drug development has registered high attrition rates, mainly due to the lack of efficacy of drug candidates, highlighting the low reliability of the models used in early-stage drug development and the need for new in vitro human cell-based models and assays to accurately identify and validate drug candidates. 3D human cell models can include different tissue cell types and represent the spatiotemporal context of the original tissue (co-cultures), allowing the establishment of biologically-relevant cell-cell and cell-extracellular matrix interactions...
January 2017: Journal of Pharmacological and Toxicological Methods
Scott B Vafai, Emily Mevers, Kathleen W Higgins, Yevgenia Fomina, Jianming Zhang, Anna Mandinova, David Newman, Stanley Y Shaw, Jon Clardy, Vamsi K Mootha
Deficiency of mitochondrial complex I is encountered in both rare and common diseases, but we have limited therapeutic options to treat this lesion to the oxidative phosphorylation system (OXPHOS). Idebenone and menadione are redox-active molecules capable of rescuing OXPHOS activity by engaging complex I-independent pathways of entry, often referred to as "complex I bypass." In the present study, we created a cellular model of complex I deficiency by using CRISPR genome editing to knock out Ndufa9 in mouse myoblasts, and utilized this cell line to develop a high-throughput screening platform for novel complex I bypass factors...
2016: PloS One
Joël Schlatter, Elodie Bourguignon, Elyes Majoul, Sofiane Kabiche, Issa-Bella Balde, Salvatore Cisternino, Jean-Eudes Fontan
Adapted forms for administration to infants are limited. The proposed study was performed to propose oral liquid formulations of idebenone in Ora-Plus and either Ora-Sweet or Ora-Sweet SF, Ora-Blend, Ora-Blend SF and Inorpha. Each formulation was stored in 30 ml amber glass bottle at 5 or 25 °C for 90 days. Idebenone contents in these suspensions, determined by a stability-indicating high-performance liquid chromatography method, remained stable at least 90 days in Inorpha when stored at the two temperatures...
March 2017: Pharmaceutical Development and Technology
Mary Kearney, Richard W Orrell, Michael Fahey, Ruth Brassington, Massimo Pandolfo
BACKGROUND: Friedreich ataxia is a rare inherited autosomal recessive neurological disorder, characterised initially by unsteadiness in standing and walking, slowly progressing to wheelchair dependency usually in the late teens or early twenties. It is associated with slurred speech, scoliosis, and pes cavus. Heart abnormalities cause premature death in 60% of people with the disorder. There is no easily defined clinical or biochemical marker and no known treatment. This is the second update of a review first published in 2009 and previously updated in 2012...
August 30, 2016: Cochrane Database of Systematic Reviews
Gunnar M Buyse, Thomas Voit, Ulrike Schara, Chiara S M Straathof, Maria Grazia D'Angelo, Günther Bernert, Jean-Marie Cuisset, Richard S Finkel, Nathalie Goemans, Christian Rummey, Mika Leinonen, Oscar H Mayer, Paolo Spagnolo, Thomas Meier, Craig M McDonald
Assessment of dynamic inspiratory function may provide valuable information about the degree and progression of pulmonary involvement in patients with Duchenne muscular dystrophy (DMD). The aims of this study were to characterize inspiratory function and to assess the efficacy of idebenone on this pulmonary function outcome in a large and well-characterized cohort of 10-18 year-old DMD patients not taking glucocorticoid steroids (GCs) enrolled in the phase 3 randomized controlled DELOS trial. We evaluated the effect of idebenone on the highest flow generated during an inspiratory FVC maneuver (maximum inspiratory flow; V'I,max(FVC)) and the ratio between the largest inspiratory flow during tidal breathing (tidal inspiratory flow; V'I,max(t)) and the V'I,max(FVC)...
August 29, 2016: Pediatric Pulmonology
Yue Guan, Juan Li, Tao Zhan, Jian-Wen Wang, Jian-Bo Yu, Lan Yang
No abstract text is available yet for this article.
August 20, 2016: Chinese Medical Journal
Filomena Lauro, Sara Ilari, Luigino Antonio Giancotti, Cinzia Anna Ventura, Chiara Morabito, Micaela Gliozzi, Valentina Malafoglia, Ernesto Palma, Donatella Paolino, Vincenzo Mollace, Carolina Muscoli
Considerable evidence demonstrated that the central role of reactive oxygen species and reactive nitrogen species (ROS and RNS) in the development of thermal hyperalgesia is associated to acute and chronic inflammation. Idebenone (IDE), a synthetic analogue of the endogenous cellular antioxidant coenzyme Q10 (CoQ10), is an active drug in the central nervous system which shows a protection in a variety of neurological disorders. Since it is lipophilic, poorly water soluble and highly bound to plasma proteins, different technological approaches have been explored to increase its solubility and new pharmaceutical properties...
September 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Victoria Gómez-Murcia, Alejandro Torrecillas, Ana M deGodos, Senena Corbalán-García, Juan C Gómez-Fernández
Here we present some of our data about the interaction of idebenone and idebenol with dipalmitoyl-phosphatidylcholine (DPPC). In particular, we include data of small angle X-ray diffraction (SAXD) and wide angle X-ray diffraction experiments, obtention of electronic profiles of the membranes, (2)H-NMR and (31)P-NMR, as part of the research article: "Both idebenone and idebenol are localized near the lipid-water interface of the membrane and increase its fluidity" (Gomez-Murcia et al., 2016) [1]. These data were obtained from model membranes that included different proportions of idebenone and idebenol, at temperatures both above and below of the gel to fluid phase...
June 2016: Data in Brief
Kamel Djaout, Vinayak Singh, Yap Boum, Victoria Katawera, Hubert F Becker, Natassja G Bush, Stephen J Hearnshaw, Jennifer E Pritchard, Pauline Bourbon, Peter B Madrid, Anthony Maxwell, Valerie Mizrahi, Hannu Myllykallio, Sean Ekins
There is an urgent need to identify new treatments for tuberculosis (TB), a major infectious disease caused by Mycobacterium tuberculosis (Mtb), which results in 1.5 million deaths each year. We have targeted two essential enzymes in this organism that are promising for antibacterial therapy and reported to be inhibited by naphthoquinones. ThyX is an essential thymidylate synthase that is mechanistically and structurally unrelated to the human enzyme. DNA gyrase is a DNA topoisomerase present in bacteria and plants but not animals...
2016: Scientific Reports
Craig M McDonald, Thomas Meier, Thomas Voit, Ulrike Schara, Chiara S M Straathof, M Grazia D'Angelo, Günther Bernert, Jean-Marie Cuisset, Richard S Finkel, Nathalie Goemans, Christian Rummey, Mika Leinonen, Paolo Spagnolo, Gunnar M Buyse
In Duchenne muscular dystrophy (DMD), progressive loss of respiratory function leads to restrictive pulmonary disease and places patients at significant risk for severe respiratory complications. Of particular concern are ineffective cough, secretion retention and recurrent respiratory tract infections. In a Phase 3 randomized controlled study (DMD Long-term Idebenone Study, DELOS) in DMD patients 10-18 years of age and not taking concomitant glucocorticoid steroids, idebenone (900 mg/day) reduced significantly the loss of respiratory function over a 1-year study period...
August 2016: Neuromuscular Disorders: NMD
N Gueven
Idebenone is a rapidly absorbed, safe and well-tolerated drug and is currently the only clinically proven treatment option for Leber's hereditary optic neuropathy (LHON) patients. Idebenone (Raxone®) is approved by the European Medicines Agency for the treatment of LHON and has been available on the European market since 2015. Due to its molecular mode of action of bypassing the defective mitochondrial complex I, idebenone leads to improved energy supply and a functional recovery of retinal ganglion cells during the acute stage of the disease, thereby preventing further vision loss and promoting recovery of vision...
March 2016: Drugs of Today
Katherine A Lyseng-Williamson
Idebenone (Raxone(®)), a short-chain benzoquinone, is the only disease-specific drug approved to treat visual impairment in adolescents and adults with Leber's hereditary optic neuropathy (LHON), a rare genetic mitochondrial disease that causes rapid and progressive bilateral vision loss. The mechanism of action of idebenone involves its antioxidant properties and ability to act as a mitochondrial electron carrier. Idebenone overcomes mitochondrial complex I respiratory chain deficiency in patients with LHON by transferring electrons directly to mitochondrial complex III (by-passing complex I), thereby restoring cellular energy (ATP) production and re-activating inactive-but-viable retinal ganglion cells, which ultimately prevents further vision loss and promotes vision recovery...
May 2016: Drugs
Sandra Elincx-Benizri, Amir Glik, Drorit Merkel, Michael Arad, Dov Freimark, Evgenia Kozlova, Ioav Cabantchik, Sharon Hassin-Baer
Friedreich ataxia is an inherited disorder characterized by degeneration of the peripheral and central nervous system and hypertrophic cardiomyopathy. Homozygous mutations in the frataxine (FXN) gene reduce expression of frataxin and cause accumulation of iron in the mitochondria. Deferiprone, an oral iron chelator, has been shown effective in cell and animal models of Friedreich ataxia. The results of a 6-month randomized, double blind placebo-controlled study suggested that deferiprone 20 mg/kg/day may reduce disease progression...
July 2016: Journal of Child Neurology
Victoria Gómez-Murcia, Alejandro Torrecillas, Ana M de Godos, Senena Corbalán-García, Juan C Gómez-Fernández
Idebenone is a synthetic analog of coenzyme Q; both share a quinone moiety but idebenone has a shorter lipophilic tail ending with a hydroxyl group. Differential scanning calorimetry experiments showed that both idebenone and idebenol widened and shifted the phase transition of 1,2-dipalmitoylphosphatidylcholine (DPPC) to a lower temperature and a phase separation with different concentrations of these molecules was observed. Also small angle X-ray diffraction and wide angle X-ray diffraction revealed that both, idebenone and idebenol, induced laterally separated phases in fluid membranes when included in DPPC membranes...
June 2016: Biochimica et Biophysica Acta
Carl R Thornfeldt, Ronald L Rizer
INTRODUCTION: Research has shown that a disrupted stratum corneum permeability barrier coupled with chronic inflammation induce signs of extrinsic aging (photoaging). An novel herbal-based three product cosmeceutical regimen used to reverse these two anomalies that does not contain retinol, soy, niacinamide, tea, L-ascorbic acid or esters, hydroxy acids, tocopherol, or growth factors was tested in six human clinical trials to determine effectiveness and safety in reversing photoaging...
February 2016: Journal of Drugs in Dermatology: JDD
T G Smith, S Seto, P Ganne, M Votruba
Dominant optic atrophy (DOA) arises from mutations in the OPA1 gene that promotes fusion of the inner mitochondrial membrane and plays a role in maintaining ATP levels. Patients display optic disc pallor, retinal ganglion cell (RGC) loss and bilaterally reduced vision. We report a randomized, placebo-controlled trial of idebenone at 2000 mg/kg/day in 56 Opa1 mutant mice (B6;C3-Opa1(Q285STOP)), with RGC dendropathy and visual loss, and 63 wildtype mice. We assessed cellular responses in the retina, brain and liver and RGC morphology, by diolistic labeling, Sholl analysis and quantification of dendritic morphometric features...
April 5, 2016: Neuroscience
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