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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 -
Mikrochimica Acta Mar 2021Molybdenum disulfide (MoS) surface functionalization was performed with a catechol-containing polymer sodium alginate (SA) and dopamine (DA) through simultaneous MoS...
Molybdenum disulfide (MoS) surface functionalization was performed with a catechol-containing polymer sodium alginate (SA) and dopamine (DA) through simultaneous MoS exfoliation and self-polymerization of DA. The MoS/SA-PDA nanocomposite was characterized using spectroscopic, microscopic, and electroanalytical techniques to evaluate its electrocatalytic performance. The electrocatalytic behavior of the MoS/SA-PDA nanocomposite modified electrode for the detection of acebutolol (ACE), a cardio-selective β-blocker drug was explored through cyclic voltammetric and differential pulse voltammetric techniques. The influence of scan rate, concentration, and pH value on the oxidation peak current of ACE was investigated to optimize the deducting condition. The electrochemical activity of the MoS/SA-PDA nanocomposite electrode was attributed to the existence of reactive functional groups being contributed from SA, PDA, and MoS exhibiting a synergic effect. The MoS/SA-PDA nanocomposite modified electrode exhibits admirable electrocatalytic activity with a wide linear response range (0.009 to 520 μM), low detection limit (5 nM), and high sensitivity (0.354 μA μM cm) also in the presence of similar (potentially interfering) compounds. The fabricated MoS/SA-PDA nanocomposite modified electrode can be useful for the detection of ACE in pharmaceutical analysis.
Topics: Acebutolol; Adrenergic beta-1 Receptor Antagonists; Alginates; Biosensing Techniques; Disulfides; Electrochemical Techniques; Electrodes; Humans; Indoles; Limit of Detection; Molybdenum; Nanocomposites; Oxidation-Reduction; Polymers; Reproducibility of Results
PubMed: 33646401
DOI: 10.1007/s00604-021-04717-0 -
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 -
Electrophoresis Jun 2015A series of eight chiral β-blocker drugs, acebutolol, atenolol, carazolol, carteolol, carvedilol, propranolol, sotalol, and talinolol, have been enantioseparated using... (Comparative Study)
Comparative Study
A series of eight chiral β-blocker drugs, acebutolol, atenolol, carazolol, carteolol, carvedilol, propranolol, sotalol, and talinolol, have been enantioseparated using two single-component anionic β-CD derivatives, namely heptakis (2,3-di-O-methyl-6-sulfo)-β-CD (HDMS-β-CD) and heptakis (2,3-di-O-acetyl-6-sulfo)-β-CD (HDAS-β-CD), in aqueous CE and NACE. The influence of the nature of substituents (methyl or acetyl) in positions 2 and 3 on the CD derivatives and of the electrophoretic medium (water or methanol) on the enantioselectivity and enantiomer affinity pattern (EAP) of these structurally related compounds was systematically studied. All eight β-blockers could be enantioseparated at least partially in the four CE systems, except sotalol with HDMS-β-CD in NACE. In general, lower affinity and enantioselectivity were obtained in the presence of HDMS-β-CD compared to HDAS-β-CD. Reversals of EAPs were observed for all compounds. EAPs toward these two CDs were found to be opposite to each other in NACE for all compounds except carvedilol and in aqueous CE for atenolol, carteolol, talinolol, and sotalol. It is particularly noteworthy that opposite EAPs were also observed using the same CD derivative when the aqueous BGE was replaced with the methanolic one: for carazolol, carvedilol, and propranolol in the presence of HDMS-β-CD and for acebutolol and carvedilol with HDAS-β-CD.
Topics: Adrenergic beta-Antagonists; Anions; Cyclodextrins; Electrophoresis, Capillary; Stereoisomerism
PubMed: 25401523
DOI: 10.1002/elps.201400462 -
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 -
The Journal of Pharmacy and Pharmacology May 2015The purpose of this study was to analyse P-glycoprotein (P-gp) expression in different human in-vitro cornea models (HCE-T epithelial model and Hemicornea construct)...
OBJECTIVES
The purpose of this study was to analyse P-glycoprotein (P-gp) expression in different human in-vitro cornea models (HCE-T epithelial model and Hemicornea construct) after stimulation with P-gp substrates (rhodamine 123, levofloxacin and acebutolol).
METHODS
The influence of P-gp substrates on mRNA expression was analysed using reverse transcriptase polymerase chain reaction (PCR) and real-time PCR. The effect of stimulation on the transporter functionality was estimated with a digoxin efflux assay. The Caco-2 cell line was used as positive control.
KEY FINDINGS
The reverse transcriptase PCR results showed an increase in band intensity compared with the control medium for all substrates. The real-time PCR for the Caco-2 and HCE-T epithelial model yielded a similar outcome, in which all tested substrates upregulated P-gp. In contrast, the Hemicornea construct showed no significant increase in the mRNA expression after stimulation. Both in-vitro models possessed similar drug transport profiles after stimulation. A significantly increased efflux of digoxin was measured after 24 and 72 h of stimulation with levofloxacin and acebutolol.
CONCLUSIONS
The expression and functionality of the P-gp in corneal tissue can be influenced through time exposure with specific substrates. However, the exact mechanism still requires further elucidation.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Acebutolol; Cells, Cultured; Cornea; Humans; In Vitro Techniques; Levofloxacin; Ophthalmic Solutions; Rhodamine 123; Up-Regulation
PubMed: 25643948
DOI: 10.1111/jphp.12357 -
Journal of Labelled Compounds &... Aug 2014Acebutolol was successfully labeled with (125) I via direct electrophilic substitution reaction. Radioiodinated acebutolol was prepared with a maximum radiochemical...
Acebutolol was successfully labeled with (125) I via direct electrophilic substitution reaction. Radioiodinated acebutolol was prepared with a maximum radiochemical yield of 96.5 ± 0.3% and in vitro stability up to 72 h. The in vivo biological distribution of radioiodinated acebutolol showed high heart uptake of 37.8 ± 0.14% injected activity/g organ with low lungs and liver uptakes at 5 min post-injection. In vivo receptor blocking study was carried out in mice to evaluate its selectivity to heart. Radioiodinated acebutolol showed fast heart accumulation with high heart/liver ratio, which provides the ability for fast myocardial imaging with significant decrease in the radiation hazards risk on patients. So, radioiodinated acebutolol could be displayed as a radiotracer drug of choice in case of emergency patients for myocardial perfusion imaging.
Topics: Acebutolol; Animals; Iodine Radioisotopes; Male; Mice; Myocardial Perfusion Imaging; Radiopharmaceuticals; Tissue Distribution
PubMed: 25196119
DOI: 10.1002/jlcr.3223 -
European Journal of Pharmaceutics and... Aug 2014Since pharmacokinetic and pharmacodynamic activities of drugs are often related to their interactions with biomembranes, it is of high interest to establish an approach...
Interactions of beta-blockers with model lipid membranes: molecular view of the interaction of acebutolol, oxprenolol, and propranolol with phosphatidylcholine vesicles by time-dependent fluorescence shift and molecular dynamics simulations.
Since pharmacokinetic and pharmacodynamic activities of drugs are often related to their interactions with biomembranes, it is of high interest to establish an approach for the characterization of these interactions at the molecular level. For the present study, beta-blockers (oxprenolol, propranolol, and acebutolol) were selected due to their well described nonspecific membrane effects (NME). Their interactions with model lipid membranes composed of palmitoyloleoylphosphatidylcholine (POPC) were studied using Time-Dependent Fluorescence Shift (TDFS) and Generalized Polarization (GP) as well as molecular dynamics (MD) simulations. Liposomal vesicles were labeled with fluorescent membrane polarity probes (Laurdan, Prodan, and Dtmac). Increasing beta-blocker concentrations (0-10 mM for acebutolol and oxprenolol, and 0-1.5 mM for propranolol) significantly rigidifies the lipid bilayer at the glycerol and headgroup level, which was detected in the steady-state and in the time-resolved fluorescence data. The effects of propranolol were considerably stronger than those of the two other beta-blockers. The addition of fluorescent probes precisely located at different levels within the lipid bilayer revealed the insertion of the beta-blockers into the POPC bilayer at the glycerol backbone level, which was further confirmed by MD simulations in the case of propranolol.
Topics: Acebutolol; Adrenergic beta-Antagonists; Fluorescence; Fluorescent Dyes; Glycerol; Lipid Bilayers; Liposomes; Membrane Lipids; Molecular Dynamics Simulation; Oxprenolol; Phosphatidylcholines; Propranolol
PubMed: 24681296
DOI: 10.1016/j.ejpb.2014.03.013 -
European Journal of Drug Metabolism and... Jun 2017The US Food and Drug Administration, World Health Organization and European Medicines Agency have allowed biowaiver for some BCS class III drugs, but shortened the...
BACKGROUND AND OBJECTIVES
The US Food and Drug Administration, World Health Organization and European Medicines Agency have allowed biowaiver for some BCS class III drugs, but shortened the requisite dissolution time of BCS class III drugs from 30 to 15 min, considering their site-specific absorption and others risk. The objective of this study was to assess the effects of site-specific absorption, low absorbed fraction (F ) and gastric emptying rate on the biowaiver extension of BCS class III drugs.
METHODS
The oral absorption of BCS class III drugs nadolol, acebutolol and atenolol which were P-gp substrates, was simulated using GastroPlus software with physiological parameters reflecting site-specific and site-independent absorption. Then, the simulation results were compared with the experimental data in literature. Simulation with different dissolution rates (>85 % solubility, T = 15-180 min) was performed to predict absorption (maximum concentration, C and area under the concentration-time curve from time 0 to infinity, AUC) of the above model/virtual drugs (F 3.81-80.14 %).
RESULTS
The results of this study indicated that the site-specific absorption and low F magnified the effect of dissolution rate on C and AUC. However, the oral absorption of model drugs was not sensitive to the change of gastric emptying rate from 0.1, 0.25, 0.5 to 1 h.
CONCLUSIONS
Based on the results of this study, we suggest that for BCS class III drug with high F (about >80 %), the biowaiver should extend to rapid dissolution (T = 30 min), and 30 % of F as the boundary of intermediate permeability class (30 % < F < 85 %).
Topics: Computer Simulation; Gastrointestinal Tract; Humans; Intestinal Absorption; Models, Biological; Permeability; Phenoxypropanolamines; Software
PubMed: 27447171
DOI: 10.1007/s13318-016-0361-2 -
Arhiv Za Higijenu Rada I Toksikologiju Mar 2020Beta-blockers are chiral compounds with enantiomers that have different bioactivity, which means that while one is active, the other can be inactive or even harmful. Due...
Beta-blockers are chiral compounds with enantiomers that have different bioactivity, which means that while one is active, the other can be inactive or even harmful. Due to their high consumption and incomplete degradation in waste water, they may reach surface waters and affect aquatic organisms. To address this issue we developed a chromatographic method suitable for determining beta-blocker enantiomers in surface waters. It was tested on five beta-blockers (acebutolol, atenolol, bisoprolol, labetalol and metoprolol) and validated on bisoprolol enantiomers. Good enantioseparation of all analysed beta-blockers was achieved on the Chirobiotic V column with the mobile phase composed of methanol/acetic acid/triethylamine (100/0.20/0.15 v/v/v) at a flow rate of 0.5 mL/min and column temperature of 45 °C. Method proved to be linear in the concentration range from 0.075 µg/mL to 5 µg/mL, and showed good recovery. The limits of bisoprolol enantiomer detection were 0.025 µg/mL and 0.026 µg/mL and of quantification 0.075 µg/mL and 0.075 µg/mL. Despite its limitations, it seems to be a promising method for bisoprolol enantiomer analysis in surface water samples. Further research could focus on waste water analysis, where enantiomer concentrations may be high. Furthermore, transferring the method to a more sensitive one such as liquid chromatography coupled with tandem mass spectrometry and using ammonium acetate as the mobile phase additive instead of acetic acid and triethylamine would perhaps yield much lower limits of detection and quantification.
Topics: Acebutolol; Adrenergic beta-Antagonists; Atenolol; Bisoprolol; Chromatography, High Pressure Liquid; Labetalol; Metoprolol; Water
PubMed: 32597137
DOI: 10.2478/aiht-2020-71-3318