1,721,793 research outputs found
Discovery and characterization of ORM-11372, a unique and positively inotropic sodium-calcium exchanger/inhibitor
Get PDFBackground and purpose
The lack of selective sodium-calcium exchanger (NCX) inhibitors has hampered the exploration of
physiological and pathophysiological roles of cardiac NCX 1.1. We aimed to discover more potent and
selective drug like NCX 1.1. inhibitor.
Experimental approach
A flavan series-based pharmacophore model was constructed. Virtual screening helped us identify a
novel scaffold for NCX inhibition. A distinctively different NCX 1.1 inhibitor, ORM-11372, was
discovered after lead optimization. Its potency against human and rat NCX 1.1 and selectivity against
other ion channels was assessed. The cardiovascular effects of ORM-11372 were studied in normal
and infarcted rats, and rabbits. Human cardiac safety was studied ex-vivo using human ventricular
trabeculae.
Key results
ORM-11372 inhibited human NCX 1.1 reverse and forward currents; IC50 values were 5 and 6 nM,
respectively. ORM-11372 inhibited human cardiac sodium 1.5 (INa) and hERG KV11.1 currents (IhERG) in
a concentration-dependent manner; IC50 values were 23.2 and 10.0 µM. ORM-11372 caused no changes
in action potential duration; short term variability and triangulation were observed for
concentrations of upto 10 µM.
ORM-11372 induced positive inotropic effects in 18 ± 6% and 35 ± 8% anesthetized rats with myocardial
infarctions and rabbits, respectively; no other haemodynamic effects were observed, except
improved relaxation at the lowest dose
Effect of strontium ranelate on hydrogen peroxide-induced apoptosis of CRL-11372 cells
No full textIn vitro and in vivo studies have proven strontium to be an osteoinductive trace element. The effect of strontium ranelate (SR) on H2O2-induced apoptosis of CRL-11372 cells and optimization of its anti-apoptotic dose were the aims of this study. After 1 h of pretreatment with SR 1 mu M, 50 mu M, 100 mu M, 500 mu M, and 1,000 mu M concentrations, CRL-11372 osteoblasts were exposed to 100 mu M H2O2 for periods of 6-12 h. The same experiments were repeated without H2O2. The apoptotic index and viability of cells were assessed quantitatively with a fluorescent dye and qualitatively with agarose gel electrophoresis. Concentrations of 1-100 mu M of SR with a 6-h treatment and only 1 mu M concentration with a 12-h treatment inhibited the apoptotic effect of H2O2 on cultured osteoblasts significantly (P < 0.05). SR was shown to inhibit H2O2-induced apoptosis of CRL-11372 cells in a dose-dependent manner
Discovery and Characterization of ORM‐11372, a Novel Inhibitor of the Sodium‐Calcium Exchanger with Positive Inotropic Activity
Get PDFBackground and purpose
The lack of selective sodium‐calcium exchanger (NCX) inhibitors has hampered the exploration of physiological and pathophysiological roles of cardiac NCX 1.1. We aimed to discover more potent and selective drug like NCX 1.1. inhibitor.
Experimental approach
A flavan series‐based pharmacophore model was constructed. Virtual screening helped us identify a novel scaffold for NCX inhibition. A distinctively different NCX 1.1 inhibitor, ORM‐11372, was discovered after lead optimization. Its potency against human and rat NCX 1.1 and selectivity against other ion channels was assessed. The cardiovascular effects of ORM‐11372 were studied in normal and infarcted rats, and rabbits. Human cardiac safety was studied ex‐vivo using human ventricular trabeculae.
Key results
ORM‐11372 inhibited human NCX 1.1 reverse and forward currents; IC50 values were 5 and 6 nM, respectively. ORM‐11372 inhibited human cardiac sodium 1.5 (INa) and hERG KV11.1 currents (IhERG) in a concentration‐dependent manner; IC50 values were 23.2 and 10.0 μM. ORM‐11372 caused no changes in action potential duration; short term variability and triangulation were observed for concentrations of upto 10 μM.
ORM‐11372 induced positive inotropic effects in 18 ± 6% and 35 ± 8% anesthetized rats with myocardial infarctions and rabbits, respectively; no other haemodynamic effects were observed, except improved relaxation at the lowest dose.
Conclusion and implications
ORM‐11372, a unique, novel, and potent inhibitor of human and rat NCX 1.1, is a positive inotropic compound. NCX inhibition can induce clinically relevant improvements in left ventricular contractions without affecting relaxation, heart rate, or blood pressure, without pro‐arrhythmic risk
Italian Content Words v2
No full textThis resource is the second version of an Italian morphological dictionary for content words, encoded in a JSON Lines format text file. It contains correspondences between surface form and lexical forms of words followed by standard grammatical properties. Compared to the first release, this version has a better JSON structure. The surface word forms have been generated algorithmically by using stable phonological and morphological rules of the Italian language. Particular attention has been given to the generation of verbs for which rules have been extracted from A.L e G. Lepschy, La Lingua Italiana. The dictionary with its remarkable coverage is particularly useful used together with the Italian Function Words v2 (http://hdl.handle.net/11372/LRT-2629) for tasks such as pos-tagging or syntactic parsing
Italian Content Words
No full textThis resource is an Italian morphological dictionary for content words, encoded in a JSON Lines format text file. It contains correspondences between surface form and lexical forms of words followed by grammatical features. The surface word forms have been generated algorithmically by using stable phonological and morphological rules of the Italian language. Particular attention has been given to the generation of verbs for which rules have been extracted from the famous A.L e G. Lepschy, La lingua italiana. The dictionary with its remarkable coverage is particularly useful used together with the Italian Function Words (http://hdl.handle.net/11372/LRT-2288) for tasks such as POS-Tagging or Syntactic Parsing
Biocompatibility of different barrier membranes in cultures of human CRL 11372 osteoblast-like cells: an immunohistochemical study
No full textThe aim of this study was to evaluate the biocompatibility of two different barrier materials in cultures of human osteoblast-like cells (CRL 11372) in vitro
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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