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Environmental Pollution (Barking, Essex... Jul 2020The importance of stereochemistry on the behaviour and effects of chiral pharmaceutical and illicit drugs in amended agricultural soils has been over looked to date....
The importance of stereochemistry on the behaviour and effects of chiral pharmaceutical and illicit drugs in amended agricultural soils has been over looked to date. Therefore, this study was aimed at investigating the enantiospecific behaviour of a chemically diverse range of chiral drugs including naproxen, ibuprofen, salbutamol, bisoprolol, metoprolol, propranolol, acebutolol, atenolol, chlorpheniramine, amphetamine, fluoxetine and citalopram in soil microcosms. Considerable changes of the enantiomeric composition of ibuprofen, naproxen, atenolol, acebutolol and amphetamine were observed within 56 d. This is significant as enantiomer enrichment can favour the pharmacologically active (e.g., S(-)-atenolol) or less/non-active forms of the drug (e.g., R(-)-amphetamine). Single enantiomer microcosms showed enantiospecific degradation was responsible for enantiomer enrichment of atenolol and amphetamine. However, naproxen and ibuprofen enantiomers were subject to chiral inversion whereby one enantiomer converts to its antipode. Interestingly, chiral inversion was bidirectional and this is the first time it is reported in soil. Therefore, introduction of the less active enantiomer to soil through irrigation with reclaimed wastewater or biosolids as fertiliser can result in the formation of its active enantiomer, or vice versa. This phenomenon needs considered in risk assessment frameworks to avoid underestimating the risk posed by chiral drugs in amended soils.
Topics: Ibuprofen; Illicit Drugs; Soil; Stereoisomerism; Wastewater
PubMed: 32443211
DOI: 10.1016/j.envpol.2020.114364 -
Journal of Pharmaceutical Analysis Dec 2018The aim of the present investigation was to demonstrate an approach involving use of liquid chromatography (LC) and liquid chromatography-mass spectrometry (LC-MS) to...
The aim of the present investigation was to demonstrate an approach involving use of liquid chromatography (LC) and liquid chromatography-mass spectrometry (LC-MS) to separate, identify and characterize very small quantities of degradation products (DPs) of acebutolol without their isolation from the reaction mixtures. The drug was subjected to oxidative, hydrolytic, thermal and photolytic stress conditions as per International Conference on Harmonization (ICH) guideline Q1A(R2). Among all the stress conditions the drug was found to be labile in hydrolytic (acidic & basic) and photolytic stress conditions, while it was stable in water-induced hydrolysis, oxidative and thermal stress conditions. A total of four degradation products were formed. A C column was employed for the separation of all the DPs on a gradient mode by using high-performance liquid chromatography (HPLC). All the DPs were characterized with the help of their fragmentation pattern and the masses obtained upon LC-MS/MS and MS analysis. All the hitherto unknown degradation products were identified as 1-(2-(2-hydroxy-3-(isopropylamino)propoxy)-5-(amino)phenyl)ethanone (DP-I), N-(4-(2-hydroxy-3-(isopropylamino)propoxy)-3-acetylphenyl)acrylamide (DP-II), 1-(2-(2-hydroxy-3-(isopropylamino)propoxy)-5-(hydroxymethylamino)phenyl)ethanone (DP-III) and 1-(6-(2-hydroxy-3-(isopropylamino)propoxy)-2,3-dihydro-2-propylbenzo[d]oxazol-5-yl)ethanone (DP-IV). Finally the in-silico carcinogenicity and hepatotoxicity predictions of the drug and all the DPs were performed by using toxicity prediction softwares viz., TOPKAT, LAZAR and Discovery Studio ADMET. The results of in-silico toxicity studies revealed that acebutolol (0.967) and DP-I (0.986) were found to be carcinogenic, while acebutolol (0.490) and DP-IV (0.437) were found to be hepatotoxic.
PubMed: 30595941
DOI: 10.1016/j.jpha.2018.03.001 -
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 -
Ecotoxicology and Environmental Safety Apr 2021MoS/montmorillonite (MoS/Mt) composite was successfully synthesized through a simple hydrothermal method, and its adsorption performance for two emerging...
The adsorption performance and micro-mechanism of MoS/montmorillonite composite to atenolol and acebutolol: Adsorption experiments and a novel visual study of interaction.
MoS/montmorillonite (MoS/Mt) composite was successfully synthesized through a simple hydrothermal method, and its adsorption performance for two emerging contaminants-atenolol (ATE) and acebutolol (ACE) was researched. The batch experiments revealed that the adsorption process can be described by the Pseudo-second order model and Langmuir model, and the adsorption capacity of MoS/Mt, MoS and Mt for ATE were 132.08 mg/g, 60.68 mg/g and 74.23 mg/g, for ACE were 113.82 mg/g, 33.01 mg/g and 36.05 mg/g, respectively. Besides, Fourier-transform infrared spectroscopy (FTIR), BET specific surface area measurement and X-ray photoelectron spectroscopy (XPS) were also employed to analyze the adsorption mechanism. Moreover, quantitative molecular surface analysis and weak intermolecular interaction analysis with independent gradient model were combined to probe the microscopic interaction between the adsorbent and adsorbate. The results indicated the interactions included hydrogen bonding and vdW interaction. Mt and MoS interacted more strongly with ATE than ACE, which revealed the reason MoS/Mt, Mt and MoS possessed higher adsorption capacity for ATE.
Topics: Acebutolol; Adsorption; Atenolol; Bentonite; Hydrogen Bonding; Hydrogen-Ion Concentration; Kinetics; Molybdenum; Photoelectron Spectroscopy; Spectroscopy, Fourier Transform Infrared; Water Pollutants, Chemical
PubMed: 33578102
DOI: 10.1016/j.ecoenv.2021.111993 -
Environmental Pollution (Barking, Essex... Jul 2016Adsorption of weakly basic compounds by sludge is poorly understood, although it has important implications on the distribution and fate of such micropollutants in...
Adsorption of weakly basic compounds by sludge is poorly understood, although it has important implications on the distribution and fate of such micropollutants in wastewater effluent and sludge. Additionally, many of these compounds are chiral, and it is likely that their interactions with sludge is stereoselective and that the process may be further modified by surfactants that coexist in these systems. Adsorption of (R) and (S)-enantiomers of five commonly used β-blockers, i.e., acebutolol, atenolol, metoprolol, pindolol and propranolol, on sludge was characterized through batch experiments. Stereoselectivity in adsorption increased with decreases in hydrophobicity of the β-blockers. The enantiomeric fraction (EF) of the amount of acebutolol, atenolol and metoprolol sorbed on sludge were 0.27, 0.55 and 0.32, respectively. Thus, Kd values of the (S)-enantiomers of acebutolol and metoprolol were approximately twice that of the (R)-enantiomer, that is, 109 ± 11 and 57 ± 8 L/kg compared to 52 ± 13 and 22 ± 8 L/kg, respectively. There was no statistically significant difference in Kd values of the enantiomers of pindolol and propranolol, suggesting stereoselectivity in adsorption was likely driven by specific polar interactions rather than hydrophobic interactions. The EF value of atenolol decreased from 0.55 ± 0.03 to 0.44 ± 0.04 after modifying the sludge with Triton X 100. These results suggested that surfactants altered adsorption of β-blockers to sludge, likely by forming ion pair complexes that promote hydrophobic interactions with the solid surfaces.
Topics: Adrenergic beta-Antagonists; Adsorption; Models, Chemical; Sewage; Stereoisomerism; Surface-Active Agents; Wastewater; Water Pollutants, Chemical; Water Purification
PubMed: 27155096
DOI: 10.1016/j.envpol.2016.04.091 -
Neurological Research Apr 2023This present study was undertaken to determine whether beta-blockers produce the cutaneous analgesic effect, comparing them with the long-acting local anesthetic...
BACKGROUND
This present study was undertaken to determine whether beta-blockers produce the cutaneous analgesic effect, comparing them with the long-acting local anesthetic bupivacaine.
METHODS
Using a rat model of infiltrative cutaneous analgesia, the effect of 5 beta-blockers (oxprenolol, carteolol, butaxamine, metoprolol, and acebutolol) and bupivacaine was compared and eventually combined with epinephrine.
RESULTS
Among 5 beta-blockers, oxprenolol exhibited the most potent and the longest duration of cutaneous analgesia. In dose-response studies, the rank order of efficacy (ED [50% effective dose]) was bupivacaine (0.40 [0.35-0.47] μmol) > oxprenolol (2.33 [2.06-2.64] μmol) > carteolol (4.86 [4.27-5.53] μmol) (< 0.01). Carteolol provoked a longer duration of analgesia (< 0.01) than oxprenolol or bupivacaine on an equipotent basis (ED, ED, and ED). Adding epinephrine 1:200,000 to drug preparations (carteolol, oxprenolol, and bupivacaine) at ED had a peripheral action in prolonging the duration of action.
CONCLUSIONS
Oxprenolol and carteolol had greater potencies and longer durations of cutaneous analgesia than butaxamine, metoprolol, and acebutolol. Oxprenolol produced a similar duration of action when compared to bupivacaine, while carteolol had a greater duration of action than bupivacaine. Cutaneous analgesia of oxprenolol (or carteolol) plus adrenaline was greater than that of bupivacaine plus adrenaline.
Topics: Rats; Animals; Oxprenolol; Carteolol; Acebutolol; Metoprolol; Butoxamine; Rats, Sprague-Dawley; Pain; Anesthetics, Local; Analgesia; Bupivacaine; Epinephrine; Dose-Response Relationship, Drug
PubMed: 36403147
DOI: 10.1080/01616412.2022.2148511 -
International Journal of Legal Medicine Jan 2020Acebutolol is a β1-selective adrenergic receptor antagonist with moderate membrane-stabilizing activity and intrinsic sympathomimetic activity; accordingly, the drug is...
Acebutolol is a β1-selective adrenergic receptor antagonist with moderate membrane-stabilizing activity and intrinsic sympathomimetic activity; accordingly, the drug is indicated in hypertension, angina pectoris, and arrhythmia. However, acebutolol's beta-blocking properties also extend the QRS and QTc intervals, and may predispose the patient to ventricular tachydysrhythmia. Here, we report autopsy and toxicological findings on a fatal case of acebutolol self-poisoning in a 70-year-old woman. Toxicological analyses of post-mortem samples (using a liquid chromatography high-resolution mass spectrometry (LC-HR-MS) method) highlighted high concentrations of acebutolol and its metabolite diacetolol in femoral blood (92.8 mg/L and 21.2 mg/L, respectively) and other matrices (cardiac blood, urine, bile, and gastric contents). A molecular networking approach provided useful information on acebutolol's metabolism and revealed the existence of an unknown phase II metabolite of acebutolol. Molecular networking also facilitated visualization of the complex LC-HR-MS/MS datasets and the sample-to-sample comparisons that confirmed massive acebutolol intoxication by ingestion.
Topics: Acebutolol; Aged; Autopsy; Chromatography, Liquid; Female; Humans; Molecular Imaging; Suicide; Tandem Mass Spectrometry
PubMed: 30997571
DOI: 10.1007/s00414-019-02062-9 -
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 -
Journal of Translational Medicine Aug 2018Major differences exist between men and women in both physiology and pathophysiology. Dissecting the underlying processes and contributing mechanisms of sex differences...
BACKGROUND
Major differences exist between men and women in both physiology and pathophysiology. Dissecting the underlying processes and contributing mechanisms of sex differences in health and disease represents a crucial step towards precision medicine. Considering the significant differences between men and women in the response to pharmacotherapies, our aim was to develop an in silico model able to predict sex-specific drug responses in a large-scale.
METHODS
For this purpose, we focused on cardiovascular effects because of their high morbidity and mortality. Our model predicted several drugs (including acebutolol and tacrine) with significant differences in the heart between men and women. To validate the sex-specific drug responses identified by our model, acebutolol was selected to lower blood pressure in spontaneous hypertensive rats (SHR), tacrine was used to assess cardiac injury in mice and metformin as control for a non-sex-specific response.
RESULTS
As our model predicted, acebutolol exhibited a stronger decrease in heart rate and blood pressure in female than male SHRs. Tacrine lowered heart rate in male but not in female mice, induced higher plasma cTNI level and increased cardiac superoxide (DHE staining) generation in female than male mice, indicating stronger cardiac toxicity in female than male mice. To validate our model in humans, we employed two Chinese cohorts, which showed that among patients taking a beta-receptor blocker (metoprolol), women reached significantly lower diastolic blood pressure than men.
CONCLUSIONS
We conclude that our in silico model could be translated into clinical practice to predict sex-specific drug responses, thereby contributing towards a more appropriate medical care for both men and women.
Topics: Acebutolol; Animals; Blood Pressure; China; Computer Simulation; Drug Therapy; Female; Heart; Heart Injuries; Heart Rate; Humans; Hypertension; Male; Metformin; Mice; Mice, Inbred C57BL; Middle Aged; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Sex Factors; Tacrine
PubMed: 30157868
DOI: 10.1186/s12967-018-1612-6 -
British Journal of Clinical Pharmacology Aug 2016Peripheral vasoconstriction has long been described as a vascular adverse effect of β-adrenoceptor blockers. Whether β-adrenoceptor blockers should be avoided in... (Comparative Study)
Comparative Study Meta-Analysis Review
AIM
Peripheral vasoconstriction has long been described as a vascular adverse effect of β-adrenoceptor blockers. Whether β-adrenoceptor blockers should be avoided in patients with peripheral vascular disease depends on pharmacological properties (e.g. preferential binding to β1 -adrenoreceptors or intrinsic sympathomimetic activity). However, this has not been confirmed in experimental studies. We performed a network meta-analysis in order to assess the comparative risk of peripheral vasoconstriction of different β-adrenoceptor blockers.
METHOD
We searched for randomized controlled trials (RCTs) including β-adrenoceptor blockers that were published in core clinical journals in the Pubmed database. All RCTs reporting peripheral vasoconstriction as an adverse effect of β-adrenoceptor blockers and controls were included. Sensitivity analyses were conducted including possibly confounding covariates (latitude, properties of the β-adrenoceptor blockers, e.g. intrinsic sympathomimetic activity, vasodilation, drug indication, drug doses). The protocol and the detailed search strategy are available online (PROSPERO registry CRD42014014374).
RESULTS
Among 2238 records screened, 38 studies including 57 026 patients were selected. Overall, peripheral vasoconstriction was reported in 7% of patients with β-adrenoceptor blockers and 4.6% in the control groups (P < 0.001), with heterogeneity among drugs. Atenolol and propranolol had a significantly higher risk than placebo, whereas pindolol, acebutolol and oxprenolol had not.
CONCLUSION
Our results suggest that β-adrenoceptor blockers have variable propensity to enhance peripheral vasoconstriction and that it is not related to preferential binding to β1 -adrenoceptors. These findings challenge FDA and European recommendations regarding precautions and contra-indications of use of β-adrenoceptor blockers and suggest that β-adrenoceptor blockers with intrinsic sympathomimetic activity could be safely used in patients with peripheral vascular disease.
Topics: Adrenergic beta-Antagonists; Dose-Response Relationship, Drug; Humans; Randomized Controlled Trials as Topic; Sympathomimetics; Vasoconstriction; Vasodilation
PubMed: 27085011
DOI: 10.1111/bcp.12980