23 research outputs found
Exploring the Electrophysiologic and Hemodynamic Effects of Cardiac Resynchronization Therapy: From Bench to Bedside and Vice Versa
Cardiac resynchronization therapy (CRT) is an important therapy for heart failure patients with prolonged QRS duration. In patients with left bundle branch block the altered left ventricular electrical activation results in dyssynchronous, inefficient contraction of the left ventricle. CRT aims to reverse these changes and to improve cardiac function. This article explores the electrophysiologic and hemodynamic changes that occur during CRT in patient and animal studies. It also addresses how novel techniques, such as multipoint and endocardial pacing, can further improve the electromechanical response.</p
Exploring the Electrophysiologic and Hemodynamic Effects of Cardiac Resynchronization Therapy: From Bench to Bedside and Vice Versa
Cardiac resynchronization therapy (CRT) is an important therapy for heart failure patients with prolonged QRS duration. In patients with left bundle branch block the altered left ventricular electrical activation results in dyssynchronous, inefficient contraction of the left ventricle. CRT aims to reverse these changes and to improve cardiac function. This article explores the electrophysiologic and hemodynamic changes that occur during CRT in patient and animal studies. It also addresses how novel techniques, such as multipoint and endocardial pacing, can further improve the electromechanical response
Carbohydrate-response-element-binding protein (ChREBP) and not the liver X receptor α (LXRα) mediates elevated hepatic lipogenic gene expression in a mouse model of glycogen storage disease type 1
GSD-1 (glycogen storage disease type 1) is caused by an inherited defect in glucose-6-phosphatase activity, resulting in a massive accumulation of hepatic glycogen content and an induction of de novo lipogenesis. The chlorogenic acid derivative S4048 is a pharmacological inhibitor of the glucose 6-phosphate transporter, which is part of glucose-6-phosphatase, and allows for mechanistic studies concerning metabolic defects in GSD-1. Treatment of mice with S4048 resulted in an ~60% reduction in blood glucose, increased hepatic glycogen and triacylglycerol (triglyceride) content, and a markedly enhanced hepatic lipogenic gene expression. In mammals, hepatic expression of lipogenic genes is regulated by the co-ordinated action of the transcription factors SREBP (sterol-regulatory-element-binding protein)-1c, LXRα (liver X receptor α) and ChREBP (carbohydrate-response-element-binding protein). Treatment of Lxra-/- mice and Chrebp-/- mice with S4048 demonstrated that ChREBP, but not LXRα, mediates the induction of hepatic lipogenic gene expression in this murine model of GSD-1. Thus ChREBP is an attractive target to alleviate derangements in lipid metabolism observed in patients with GSD-1
Interaction of Digitalis-Like Compounds with Liver Uptake Transporters NTCP, OATP1B1, and OATP1B3
Digitalis-like compounds (DLCs) such
as digoxin, digitoxin, and
ouabain, also known as cardiac glycosides, are among the oldest pharmacological
treatments for heart failure. The compounds have a narrow therapeutic
window, while at the same time, DLC pharmacokinetics is prone to drug–drug
interactions at the transport level. Hepatic transporters organic
anion transporting polypeptide (OATP) 1B1, OATP1B3, and Na<sup>+</sup>-dependent taurocholate co-transporting polypeptide (NTCP) influence
the disposition of a variety of drugs by mediating their uptake from
blood into hepatocytes. The interaction of digoxin, digitoxin, and
ouabain with hepatic uptake transporters has been studied before.
However, here, we systematically investigated a much wider range of
structurally related DLCs for their capability to inhibit or to be
transported by these transporters in order to better understand the
relation between the activity and chemical structure of this compound
type. We studied the uptake and inhibitory potency of a series of
14 structurally related DLCs in Chinese hamster ovary cells expressing
NTCP (CHO-NTCP) and human embryonic kidney cells expressing OATP1B1
and OATP1B3 (HEK-OATP1B1 and HEK-OATP1B3). The inhibitory effect of
the DLCs was measured against taurocholic acid (TCA) uptake in CHO-NTCP
cells and against uptake of β-estradiol 17-β-d-glucuronide (E<sub>2</sub>17βG) in HEK-OATP1B1 and HEK-OATP1B3
cells. Proscillaridin A was the most effective inhibitor of NTCP-mediated
TCA transport (IC<sub>50</sub> = 22 μM), whereas digitoxin and
digitoxigenin were the most potent inhibitors of OATP1B1 and OAPTP1B3,
with IC<sub>50</sub> values of 14.2 and 36 μM, respectively.
Additionally, we found that the sugar moiety and hydroxyl groups of
the DLCs play different roles in their interaction with NTCP, OATP1B1,
and OATP1B3. The sugar moiety decreases the inhibition of NTCP and
OATP1B3 transport activity, whereas it enhances the inhibitory potency
against OATP1B1. Moreover, the hydroxyl group at position 12 reinforces
the inhibition of NTCP but decreases the inhibition of OATP1B1 and
OATP1B3. To investigate whether DLCs can be translocated, we quantified
their uptake in transporter-expressing cells by LC–MS. We demonstrated
that convallatoxin, ouabain, dihydroouabain, and ouabagenin are substrates
of OATP1B3. No transport was observed for the other compounds in any
of the studied transporters. In summary, this work provides a step
toward an improved understanding of the interaction of DLCs with three
major hepatic uptake transporters. Ultimately, this can be of use
in the development of DLCs that are less prone to transporter-mediated
drug–drug interactions
Supplementary data for the article: Cyclists’ eye movements and crossing judgments at uncontrolled intersections: An eye-tracking study using animated video clips
This dataset includes, animated video clips, Matlab scripts, raw data, data for statistical analyses, forms (consent form, instructions) and questionnaires provided to participants for the paper: Kovácsová, N., Cabrall, C. D. D., Antonisse, S. J., De Haan, T., Van Namen, R., Nooren, J. L., Schreurs, R., Hagenzieker, M. P., & De Winter, J. C. F. (2018). Cyclists’ eye movements and crossing judgments at uncontrolled intersections: An eye-tracking study using animated video clips. Accident Analysis and Prevention, 120, 270–28
<i>In Silico</i> Identification and <i>in Vitro</i> Validation of Potential Cholestatic Compounds through 3D Ligand-Based Pharmacophore Modeling of BSEP Inhibitors
Drug-induced
cholestasis is a frequently observed side effect of
drugs and is often caused by an unexpected interaction with the bile
salt export pump (BSEP/ABCB11). BSEP is the key membrane transporter
responsible for the transport of bile acids from hepatocytes into
bile. Here, we developed a pharmacophore model that describes the
molecular features of compounds associated with BSEP inhibitory activity.
To generate input and validation data sets, <i>in vitro</i> experiments with membrane vesicles overexpressing human BSEP were
used to assess the effect of compounds (50 μM) on BSEP-mediated <sup>3</sup>H-taurocholic acid transport. The model contains two hydrogen
bond acceptor/anionic features, two hydrogen bond acceptor vector
features, four hydrophobic/aromatic features, and exclusion volumes.
The pharmacophore was validated against a set of 59 compounds, including
registered drugs. The model recognized 9 out of 12 inhibitors (75%),
which could not be identified based on general parameters, such as
molecular weight or SlogP, alone. Finally, the model was used to screen
a virtual compound database. A number of compounds found via virtual
screening were tested and displayed statistically significant BSEP
inhibition, ranging from 13 ± 1% to 67 ± 7% of control (<i>P</i> < 0.05). In conclusion, we developed and validated
a pharmacophore model that describes molecular features found in BSEP
inhibitors. The model may be used as an <i>in silico</i> screening tool to identify potentially harmful drug candidates at
an early stage in drug development
Baseline surgical status and short-term mortality after extracorporeal membrane oxygenation for post-cardiotomy shock:a meta-analysis
Objective: While reported mortality rates on post-cardiotomy extracorporeal membrane oxygenation vary from center to center, impact of baseline surgical status (elective/urgent/emergency/salvage) on mortality is still unknown. Methods: A systematic search was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement using PubMed/Medline databases until March 2018 using the keywords "postcardiotomy," "cardiogenic shock," "extracorporeal membrane oxygenation," and "extracorporeal life support." Relevant articles were scrutinized and included in the meta-analysis only if reporting in-hospital/30-day mortality and baseline surgical status. The correlations between mortality and percentage of elective/urgent/emergency cases were investigated. Inference analysis of baseline status and extracorporeal membrane oxygenation complications was conducted as well. Results: Twenty-two studies (conducted between 1993 and 2017) enrolling N = 2,235 post-cardiotomy extracorporeal membrane oxygenation patients were found. Patients were mostly of non-emergency status (65.2%). Overall in-hospital/30-day mortality event rate (95% confidence intervals) was 66.7% (63.3-69.9%). There were no differences in in-hospital/30-day mortality with respect to baseline surgical status in the subgroup analysis (test for subgroup differences; p = 0.406). Similarly, no differences between mortality in studies enrolling 50% of emergency/salvage cases was found: respective event rates were 66.9% (63.1-70.4%) versus 64.4% (57.3-70.8%); p = 0.525. Yet, there was a significant positive association between increasing percentage of emergency/salvage cases and rates of neurological complications (p <0.001), limb complications (p <0.001), and bleeding (p = 0.051). Incidence of brain death (p = 0.099) and sepsis (p = 0.134) was increased as well. Conclusion: Other factors than baseline surgical status may, to a higher degree, influence the mortality in patients treated with extracorporeal membrane oxygenation for post-cardiotomy cardiogenic shock. Baseline status, however, strongly influences the complication occurrence while on extracorporeal membrane oxygenation