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La Tunisie Medicale Feb 2020Cardiac arrest (CA) is a public health problem, with various etiologies and a fatal issue in 90-95% of cases. Toxin-induced cardiac arrests (TICA) are poorly described....
BACKGROUND
Cardiac arrest (CA) is a public health problem, with various etiologies and a fatal issue in 90-95% of cases. Toxin-induced cardiac arrests (TICA) are poorly described. Scarcity of national data prompted us to carry-out this study.
AIM
To determine TICA frequency in a Tunisian reference center in toxicology and its hospital prognosis, and to describe its clinical and therapeutic aspects Methods : Data were collected retrospectively over an 8-years period. We included patients admitted for post-CA care with highly suspected or confirmed TICA. Clinical and toxicological data were recorded.
RESULTS
We recorded 21 cases of TICA, which represented 48.8% of CA. A single toxic agent was incriminated in 90% of cases. Main causative agents identified in our series were pesticides and betablockers: chloralosed (n = 6), carbamate inhibitor of cholinesterase (n = 5), acebutolol (n = 4) and organophosphate (n = 2). One case of opiates and cocaine poisoning was reported. Median duration of "no flow" was 0 minutes. Mean duration of "low flow" was 13.74±9.15 minutes. An initial shockable rhythm was noted only in three patients. Mortality rate was 76% (16/21). Four of the five survivors had a Cerebral Performance Category Scale (CPC) 1, only one patient survived with a CPC 3. Factors associated with mortality were : the duration of "low flow" (p=0.02) and APACHE II score (p=0.014). APACHE II≥29 was the only independent factor (OR=2.0, 95%CI [1.07;3.71]).
CONCLUSION
TICA were most frequently provoked by pesticides, mortality was high and was independently predicted by APACHE II score.
Topics: Adrenergic beta-Antagonists; Cardiotoxicity; Cocaine; Drug-Related Side Effects and Adverse Reactions; Heart Arrest; Hospital Mortality; Hospitalization; Humans; Incidence; Mortality; Organophosphates; Pesticides; Retrospective Studies; Risk Factors; Toxins, Biological; Treatment Outcome; Tunisia
PubMed: 32395801
DOI: No ID Found -
Current Computer-aided Drug Design 2021The aim of the study was to develop new SIRT1 activator compounds, for this aim, we used virtual screening and molecular dynamics methods, which have been important...
AIM
The aim of the study was to develop new SIRT1 activator compounds, for this aim, we used virtual screening and molecular dynamics methods, which have been important tools for new hit compound searches.
BACKGROUND
Recently, with the progress of computing technology, it has been possible to obtain higher efficiency and lower costs for drug discovery. With in silico research and drug design, there is a reduction in time-consuming and expensive experimental work. An NAD+ dependent histone deacetylase enzyme, Sirtuin 1 (SIRT1), is involved in a variety of human disorders such as type II diabetes, cancer, obesity, and aging. Activation of SIRT1 could be useful for longevity and treating metabolic disorders.
OBJECTIVE
We used computational methods to develop new SIRT1 activator compounds.
METHODS
Firstly, virtual screening studies on the human SIRT1 enzyme were carried out. We used approximately 150.000 commercially available compounds from the Zinc database, which include FDA-approved drugs. According to virtual screening results, we selected seven potent activators. Then we compared these hit compounds with known activators by using docking methods. One of these hit compounds, acebutolol, is an FDA-approved drug, and was selected for additional studies using molecular dynamics simulations.
RESULTS
Seven hit compounds were identified with database screening. Each showed strong interactions with SIRT1, and acebutolol formed H-bonds with the important active site residues, Asn226 and/or Glu230 during the dynamics simulation.
CONCLUSION
Based on our in silico studies, the seven most promising compounds, especially acebutolol, showed promising SIRT1 activator potency. The results may be used to design new selective and more potent SIRT1 activator drugs.
Topics: Acebutolol; Age Factors; Aging; Drug Design; Drug Discovery; Enzyme Activators; Humans; Longevity; Molecular Docking Simulation; Molecular Dynamics Simulation; Sirtuin 1
PubMed: 32321406
DOI: 10.2174/1573409916666200422074441 -
Biochemical Pharmacology Jan 2020Stereoselectivity is well described for receptor binding and enzyme catalysis, but so far has only been scarcely investigated in carrier-mediated membrane transport. We...
Stereoselectivity is well described for receptor binding and enzyme catalysis, but so far has only been scarcely investigated in carrier-mediated membrane transport. We thus studied transport kinetics of racemic (anti)adrenergic drugs by the organic cation transporters OCT1 (wild-type and allelic variants), OCT2, OCT3, MATE1, and MATE2-K with a focus on stereospecificity. OCT1 showed stereoselective uptake with up to 2-fold higher v over their corresponding counterpart enantiomers for (R,R)-fenoterol, (R,R)-formoterol, (S)-salbutamol, (S)-acebutolol, and (S)-atenolol. Orciprenaline and etilefrine were also transported stereoselectively. The K was 2.1-fold and 1.5-fold lower for the (S,S)-enantiomers of fenoterol and formoterol, while no significant difference in K was seen for the other aforementioned drugs. Common OCT1 variants showed similar enantiopreference to wild-type OCT1, with a few notable exceptions (e.g. a switch in enantiospecificity for fenoterol in OCT1*2 compared to the wild-type). Other cation transporters showed strong differences to OCT1 in stereoselectivity and transport activity: The closely related OCT2 displayed a 20-fold higher v for (S,S)-fenoterol compared to (R,R)-fenoterol and OCT2 and OCT3 showed 3.5-fold and 4.6-fold higher v for the pharmacologically active (R)-salbutamol over (S)-salbutamol. MATE1 and MATE2-K generally mediated transport with a higher capacity but lower affinity compared to OCT1, with moderate stereoselectivity. Our kinetic studies showed that significant stereoselectivity exists in solute carrier-mediated membrane transport of racemic beta-adrenergic drugs with surprising, and in some instances even opposing, preferences between closely related organic cation transporters. This may be relevant for drug therapy, given the strong involvement of these transporters in hepatic and renal drug elimination.
Topics: Acebutolol; Adrenergic Agonists; Adrenergic Antagonists; Atenolol; Biological Transport; Fenoterol; Formoterol Fumarate; HEK293 Cells; Humans; Kinetics; Organic Cation Transport Proteins; Organic Cation Transporter 1; Organic Cation Transporter 2; Stereoisomerism
PubMed: 31783011
DOI: 10.1016/j.bcp.2019.113731 -
Molecules (Basel, Switzerland) Oct 2019A wooden stick coated with a novel graphene-based nanocomposite (Graphene oxide/polyethylene glycol (GO/PEG)) is introduced and investigated for its efficacy in solid...
A wooden stick coated with a novel graphene-based nanocomposite (Graphene oxide/polyethylene glycol (GO/PEG)) is introduced and investigated for its efficacy in solid phase microextraction techniques. The GO/PEG-stick was prepared and subsequently applied for the extraction of β-blockers, acebutolol, and metoprolol in human oral fluid samples, which were subsequently detected by liquid chromatography tandem mass spectrometry (LC-MS/MS). Experimental parameters affecting the extraction protocol including sample pH, extraction time, desorption time, appropriate desorption solvent, and salt addition were optimized. Method validation for the detection from oral fluid samples was performed following FDA (Food and Drug Administration) guidelines on bioanalytical method validation. Calibration curves ranging from 5.0 to 2000 nmol L for acebutolol and 25.0 to 2000 nmol L for metoprolol were used. The values for the coefficient of determination (R) were found to be 0.998 and 0.996 ( = 3) for acebutolol and metoprolol, respectively. The recovery of analytes during extraction was 80.0% for acebutolol and 62.0% for metoprolol, respectively. The limit of detections (LODs) were 1.25, 8.00 nmol L for acebutolol and metoprolol and the lower limit of quantifications (LLOQ) were 5.00 nmol L for acebutolol and 25.0 nmol L for metoprolol. Validation experiments conducted with quality control (QC) samples demonstrated method accuracy between 80.0% to 97.0% for acebutolol and from 95.0% to 109.0% for metoprolol. The inter-day precision for QC samples ranged from 3.6% to 12.9% for acebutolol and 9.5% to 11.3% for metoprolol. Additionally, the GO/PEG-stick was demonstrated to be reusable, with the same stick observed to be viable for more than 10 extractions from oral fluid samples.
Topics: Acebutolol; Adrenergic beta-Antagonists; Body Fluids; Chromatography, Liquid; Graphite; Humans; Limit of Detection; Metoprolol; Mouth; Nanocomposites; Polyethylene Glycols; Solid Phase Microextraction; Tandem Mass Spectrometry
PubMed: 31614604
DOI: 10.3390/molecules24203664 -
The Cochrane Database of Systematic... Sep 2019Randomized controlled trials (RCTs) have yielded conflicting results regarding the ability of beta-blockers to influence perioperative cardiovascular morbidity and...
BACKGROUND
Randomized controlled trials (RCTs) have yielded conflicting results regarding the ability of beta-blockers to influence perioperative cardiovascular morbidity and mortality. Thus routine prescription of these drugs in unselected patients remains a controversial issue. A previous version of this review assessing the effectiveness of perioperative beta-blockers in cardiac and non-cardiac surgery was last published in 2018. The previous review has now been split into two reviews according to type of surgery. This is an update and assesses the evidence in cardiac surgery only.
OBJECTIVES
To assess the effectiveness of perioperatively administered beta-blockers for the prevention of surgery-related mortality and morbidity in adults undergoing cardiac surgery.
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase, CINAHL, Biosis Previews and Conference Proceedings Citation Index-Science on 28 June 2019. We searched clinical trials registers and grey literature, and conducted backward- and forward-citation searching of relevant articles.
SELECTION CRITERIA
We included RCTs and quasi-randomized studies comparing beta-blockers with a control (placebo or standard care) administered during the perioperative period to adults undergoing cardiac surgery. We excluded studies in which all participants in the standard care control group were given a pharmacological agent that was not given to participants in the intervention group, studies in which all participants in the control group were given a beta-blocker, and studies in which beta-blockers were given with an additional agent (e.g. magnesium). We excluded studies that did not measure or report review outcomes.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed studies for inclusion, extracted data, and assessed risks of bias. We assessed the certainty of evidence with GRADE.
MAIN RESULTS
We included 63 studies with 7768 participants; six studies were quasi-randomized and the remaining were RCTs. All participants were undergoing cardiac surgery, and in most studies, at least some of the participants were previously taking beta-blockers. Types of beta-blockers were: propranolol, metoprolol, sotalol, esmolol, landiolol, acebutolol, timolol, carvedilol, nadolol, and atenolol. In twelve studies, beta-blockers were titrated according to heart rate or blood pressure. Duration of administration varied between studies, as did the time at which drugs were administered; in nine studies this was before surgery, in 20 studies during surgery, and in the remaining studies beta-blockers were started postoperatively. Overall, we found that most studies did not report sufficient details for us to adequately assess risk of bias. In particular, few studies reported methods used to randomize participants to groups. In some studies, participants in the control group were given beta-blockers as rescue therapy during the study period, and all studies in which the control was standard care were at high risk of performance bias because of the open-label study design. No studies were prospectively registered with clinical trials registers, which limited the assessment of reporting bias. We judged 68% studies to be at high risk of bias in at least one domain.Study authors reported few deaths (7 per 1000 in both the intervention and control groups), and we found low-certainty evidence that beta-blockers may make little or no difference to all-cause mortality at 30 days (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.47 to 1.90; 29 studies, 4099 participants). For myocardial infarctions, we found no evidence of a difference in events (RR 1.05, 95% CI 0.72 to 1.52; 25 studies, 3946 participants; low-certainty evidence). Few study authors reported cerebrovascular events, and the evidence was uncertain (RR 1.37, 95% CI 0.51 to 3.67; 5 studies, 1471 participants; very low-certainty evidence). Based on a control risk of 54 per 1000, we found low-certainty evidence that beta-blockers may reduce episodes of ventricular arrhythmias by 32 episodes per 1000 (RR 0.40, 95% CI 0.25 to 0.63; 12 studies, 2296 participants). For atrial fibrillation or flutter, there may be 163 fewer incidences with beta-blockers, based on a control risk of 327 incidences per 1000 (RR 0.50, 95% CI 0.42 to 0.59; 40 studies, 5650 participants; low-certainty evidence). However, the evidence for bradycardia and hypotension was less certain. We found that beta-blockers may make little or no difference to bradycardia (RR 1.63, 95% CI 0.92 to 2.91; 12 studies, 1640 participants; low-certainty evidence), or hypotension (RR 1.84, 95% CI 0.89 to 3.80; 10 studies, 1538 participants; low-certainty evidence).We used GRADE to downgrade the certainty of evidence. Owing to studies at high risk of bias in at least one domain, we downgraded each outcome for study limitations. Based on effect size calculations in the previous review, we found an insufficient number of participants in all outcomes (except atrial fibrillation) and, for some outcomes, we noted a wide confidence interval; therefore, we also downgraded outcomes owing to imprecision. The evidence for atrial fibrillation and length of hospital stay had a moderate level of statistical heterogeneity which we could not explain, and we, therefore, downgraded these outcomes for inconsistency.
AUTHORS' CONCLUSIONS
We found no evidence of a difference in early all-cause mortality, myocardial infarction, cerebrovascular events, hypotension and bradycardia. However, there may be a reduction in atrial fibrillation and ventricular arrhythmias when beta-blockers are used. A larger sample size is likely to increase the certainty of this evidence. Four studies awaiting classification may alter the conclusions of this review.
Topics: Adrenergic beta-Antagonists; Arrhythmias, Cardiac; Bradycardia; Cardiac Surgical Procedures; Cerebrovascular Disorders; Humans; Hypotension; Morbidity; Myocardial Infarction; Myocardial Ischemia; Perioperative Care; Postoperative Complications; Randomized Controlled Trials as Topic
PubMed: 31544227
DOI: 10.1002/14651858.CD013435 -
Ultrasonics Sonochemistry Dec 2019This work reports the sonochemical exfoliation of graphite (bath sonication with the frequency of 37/80 kHz and power of 60 W) and its electrocatalytic properties to...
This work reports the sonochemical exfoliation of graphite (bath sonication with the frequency of 37/80 kHz and power of 60 W) and its electrocatalytic properties to the β-blocker drug. The pencil graphite (PG) was exfoliated by the ultrasound emulsification with the support of ethyl cellulose (EC). Herein, EC act as an emulsifier which aids to the exfoliation and also stabilizing the exfoliated graphite. This EC assisted PG (ECPG) was characterized by various analytical techniques which showed that ECPG has high crystalline graphene sheets. In some places, EC submerged to the graphene sheets which improve the dispersibility of graphene in water. The performance of ECPG was evaluated to the electrocatalysis of acebutolol (ACE) which exhibited good electrochemical signal. Therefore, the ECPG was utilized to the detection of ACE as the electrochemical sensor electrode. It showed notable sensitivity (2.87 µA μM cm) appreciable linear range (0.01-200 µM) and satisfactory detection limit (4 nM). Furthermore, it displays acceptable anti-interference properties with other interfering ions.
PubMed: 31479887
DOI: 10.1016/j.ultsonch.2019.104720 -
European Journal of Nuclear Medicine... Nov 2019Targeting fibroblast activation protein (FAP) is a new diagnostic approach allowing the visualization of tumor stroma. Here, we applied FAP-specific PET imaging to...
PURPOSE
Targeting fibroblast activation protein (FAP) is a new diagnostic approach allowing the visualization of tumor stroma. Here, we applied FAP-specific PET imaging to gliomas. We analyzed the target affinity and specificity of two FAP ligands (FAPI-02 and FAPI-04) in vitro, and the pharmacokinetics and biodistribution in mice in vivo. Clinically, we used Ga-labeled FAPI-02/04 for PET imaging in 18 glioma patients (five IDH-mutant gliomas, 13 IDH-wildtype glioblastomas).
METHODS
For binding studies with Lu-radiolabeled FAPI-02/04, we used the glioblastoma cell line U87MG, FAP-transfected fibrosarcoma cells, and CD26-transfected human embryonic kidney cells. For pharmacokinetic and biodistribution studies, U87MG-xenografted mice were injected with Ga-labeled compounds followed by small-animal PET imaging and Lu-labeled FAPI-02/04, respectively. Clinical PET/CT scans were performed 30 min post intravenous administration of Ga-FAPI-02/04. PET and MRI scans were co-registrated. Immunohistochemistry was done on 14 gliomas using a FAP-specific antibody.
RESULTS
FAPI-02 and FAPI-04 showed high binding specificity to FAP. FAPI-04 demonstrated higher tumor accumulation and delayed elimination compared with FAPI-02 in preclinical studies. IDH-wildtype glioblastomas and grade III/IV, but not grade II, IDH-mutant gliomas showed elevated tracer uptake. In glioblastomas, we observed spots with increased uptake in projection on contrast-enhancing areas. Immunohistochemistry showed FAP-positive cells with mainly elongated cell bodies and perivascular FAP-positive cells in glioblastomas and an anaplastic IDH-mutant astrocytoma.
CONCLUSIONS
Using FAP-specific PET imaging, increased tracer uptake in IDH-wildtype glioblastomas and high-grade IDH-mutant astrocytomas, but not in diffuse astrocytomas, may allow non-invasive distinction between low-grade IDH-mutant and high-grade gliomas. Therefore, FAP-specific imaging in gliomas may be useful for follow-up studies although further clinical evaluation is required.
Topics: Acebutolol; Adult; Animals; Biological Transport; Brain Neoplasms; Cell Line, Tumor; Endopeptidases; Female; Gelatinases; Glioblastoma; Humans; Isocitrate Dehydrogenase; Ligands; Membrane Proteins; Mice; Middle Aged; Mutation; Naphthols; Neoplasm Grading; Positron Emission Tomography Computed Tomography; Radioactive Tracers; Serine Endopeptidases; Triazines; Young Adult
PubMed: 31388723
DOI: 10.1007/s00259-019-04444-y -
Environmental Science and Pollution... Sep 2019Production, distribution, and disposal of pharmaceutical products, including beta-blockers, have become a global issue. Beta-blockers are known to persist in the...
Production, distribution, and disposal of pharmaceutical products, including beta-blockers, have become a global issue. Beta-blockers are known to persist in the environment months after their release and may result in the disruption of the homeostatic system in non-target organisms. Here, we study the bioconcentration of three of the most commonly used beta-blockers and their effect on the regeneration of Girardia dorotocephala, a freshwater brown planarian. Acute toxicity tests determined LCs for acebutolol, metoprolol, and propranolol to be 778 mg/L, 711 mg/L, and 111 mg/L, respectively. The quantification and analysis of beta-blocker bioconcentration during acute exposure were performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). After 4 days of exposure to beta-blockers, the bioconcentration drastically decreased for all three beta-blockers at all exposure levels, suggesting that an effective mechanism to reduce uptake or excrete beta-blockers could be present. Additionally, Girardia dorotocephala were cut proximal to the head and the quality of regeneration was documented from each fragment daily. No significant difference was visually observed after 2 weeks of regeneration between the brown planarians placed in beta-blocker solution and those placed in control solution.
Topics: Adrenergic beta-Antagonists; Animals; Chromatography, Liquid; Ecotoxicology; Lethal Dose 50; Planarians; Regeneration; Tandem Mass Spectrometry; Toxicity Tests, Acute; Water Pollutants, Chemical
PubMed: 31327142
DOI: 10.1007/s11356-019-05960-y -
International Journal of Biological... Sep 2019We present a computational analysis coupled with experimental studies, focusing on the binding-interaction between beta-adrenoreceptor blocking agents (acebutolol and...
We present a computational analysis coupled with experimental studies, focusing on the binding-interaction between beta-adrenoreceptor blocking agents (acebutolol and propranolol) with fibrinogen protein (E-region). Herein, computational modeling on structural validation and flexibility properties of fibrinogen E-region showed that the E-region interacting residues, which form the funnel-shaped hydrophobic cavity for ligand-binding, can be efficiently modeled. The obtained free energy of binding (FEB) values for the docking complexes, namely acebutolol/fibrinogen E-region and propranolol/fibrinogen E-region, were very close and amounted to - 6.9 kcal/mol and - 6.8 kcal/mol, respectively. They were supported by a high binding-accuracy (R.M.S.D < 2 Å) for the best crystallographic binding-poses in both cases. In this regard, we identify a docking-mechanism of interaction for the propranolol and acebutolol mainly based on non-covalent hydrophobic contacts with the fibrinogen E-region binding-site. Besides, the beta-adrenoreceptor blocking agents are able to induce local perturbations affecting particularly the fibrinogen E-region allosteric residues linked to significant changes in the inter-residue communication and flexibility properties of residue network. In this sense, we show that the key biophysical parameters like frequency and collectivity degree may be compromised in different ways by the interaction with acebutolol and propranolol. Isothermal titration calorimetry, zeta potential and small angle X-ray scattering (SAXS) measurements were performed to complete and corroborate computational analysis. The combined experimental results point out that acebutolol acts to a lesser extent to fibrinogen structure than propranolol.
Topics: Adrenergic beta-Antagonists; Fibrinogen; Glycine; Molecular Docking Simulation; Propranolol; Protein Binding; Protein Domains; Thermodynamics
PubMed: 31265849
DOI: 10.1016/j.ijbiomac.2019.06.229 -
International Journal of Legal Medicine Jan 2020The published version of this article unfortunately contained a mistake. In Figure 1 on the molecular network of acebutololol, two molecular structures are not displayed...
The published version of this article unfortunately contained a mistake. In Figure 1 on the molecular network of acebutololol, two molecular structures are not displayed ("acebutolol glucuronide "and "impurity J"). The Figure is corrected here.
PubMed: 31127372
DOI: 10.1007/s00414-019-02073-6