SU-101 for the removal of pharmaceutical active compounds by the combination of adsorption/photocatalytic processes.

Pharmaceutical active compounds (PhACs) are some of the most recalcitrant water pollutants causing undesired environmental and human effects. In absence of adapted decontamination technologies, there is an urgent need to develop efficient and sustainable alternatives for water remediation. Metal-organic frameworks (MOFs) have recently emerged as promising candidates for adsorbing contaminants as well as providing photoactive sites, as they possess exceptional porosity and chemical versatility. To date, the reported studies using MOFs in water remediation have been mainly focused on the removal of a single type of PhACs and rarely on the combined elimination of PhACs mixtures. Herein, the eco-friendly bismuth-based MOF, SU-101, has been originally proposed as an efficient adsorbent-photocatalyst for the elimination of a mixture of three challenging persistent PhACs, frequently detected in wastewater and surface water in ng L-1 to mg·L-1 concentrations: the antibiotic sulfamethazine (SMT), the anti-inflammatory diclofenac (DCF), and the antihypertensive atenolol (At). Adsorption experiments of the mixture revealed that SU-101 exhibited a great adsorption capacity towards At, resulting in an almost complete removal (94.1 ± 0.8% for combined adsorption) in only 5 h. Also, SU-101 demonstrated a remarkable photocatalytic activity under visible light to simultaneously degrade DCF and SMT (99.6 ± 0.4% and 89.2 ± 1.4%, respectively). In addition, MOF-contaminant interactions, the photocatalytic mechanism and degradation pathways were investigated, also assessing the toxicity of the resulting degradation products. Even further, recycling and regeneration studies were performed, demonstrating its efficient reuse for 4 consecutive cycles without further treatment, and its subsequent successful regeneration by simply washing the material with a NaCl solution.

Synthesis of Enantiopure (S)-Atenolol by Utilization of Lipase-Catalyzed Kinetic Resolution of a Key Intermediate.

(S)-Atenolol ((S)-2-(4-(2-Hydroxy-3-(isopropylamino)propoxy)phenyl)acetamide) has been synthesized in >99% enantiomeric excess (ee) with the use of Candida antarctica lipase B from Syncozymes (Shanghai, China), in a kinetic resolution of the corresponding racemic chlorohydrin. A catalytic amount of base was used in deprotonation of the phenol building block. The enantiopurity of the chlorohydrin building block remained unchanged upon subsequent amination to yield the final drug. All four steps in the synthesis protocol have been optimized compared to previously reported methods, which makes this new protocol more sustainable and in accordance with green chemistry principles. The overall yield of (S)-atenolol was 9.9%, which will be further optimized.

Construction of An Oral Bioavailability Prediction Model Based on Machine Learning for Evaluating Molecular Modifications.

OBJECTIVE: This study aims to explore the impact of ADME on the Oral Bioavailability (OB) of drugs and to construct a machine learning model for OB prediction. The model is then applied to predict the OB of modified berberine and atenolol molecules to obtain structures with higher OB. METHODS: Initially, a drug OB database was established, and corresponding ADME characteristics were obtained. The relationship between ADME and OB was analyzed using machine learning, with Morgan fingerprints serving as molecular descriptors. Compounds from the database were input into Random Forest, XGBoost, CatBoost, and LightGBM machine learning models to train the OB 7prediction model and evaluate its performance. Subsequently, berberine and atenolol were modified using Chemdraw software with ten different substituents for mono-substitution, and chlorine atoms for a full range of double substitutions. The modified molecular structures were converted into the same format as the training set for OB prediction. The predicted OB values of the modified structures of berberine and atenolol were compared. RESULTS: An OB database of 386 drugs was obtained. It was found that smaller molecular weight and a higher number of rotatable bonds (ten or less) could potentially lead to higher OB. The four machine learning models were evaluated using MSE, R2 score, MAE, and MFE as metrics, with Random Forest performing the best. The models' predictions for the test set were particularly accurate when OB ranged from 30% to 90%. After mono-substitution and double substitution of berberine and atenolol, the OB of both drugs was significantly improved. CONCLUSIONS: This study found that some ADME properties of molecules do not have an absolute impact on OB. The database played a decisive role in the process of the machine learning OB prediction model, and the performance of the model was evaluated based on predictions within a range of strong generalization ability. In most cases, mono-substitution and double substitution were beneficial for enhancing the OB of berberine and atenolol. In summary, this study successfully constructed a machine learning regression prediction model that can accurately predict drug OB, which can guide drug design to achieve higher OB to some extent.

Modeling Free Nitrous Acid Inhibition on the Removal of Nitrogen and Atenolol during Sidestream Partial Nitritation Processes.

Sidestream serves as an important reservoir collecting pharmaceuticals from sludge. However, the knowledge on sidestream pharmaceutical removal is still insufficient. In this work, atenolol biodegradation during sidestream partial nitritation (PN) processes characterized by high free nitrous acid (FNA) accumulation was modeled. To describe the FNA inhibition on ammonia oxidation and atenolol removal, Vadivelu-type and Hellinga-type inhibition kinetics were introduced into the model framework. Four inhibitory parameters along with four biodegradation kinetic parameters were calibrated and validated separately with eight sets of batch experimental data and 60 days' PN reactor operational data. The developed model could accurately reproduce the dynamics of nitrogen and atenolol. The model prediction further revealed that atenolol biodegradation efficiencies by ammonia-oxidizing bacteria (AOB)-induced cometabolism, AOB-induced metabolism, and heterotrophic bacteria-induced biodegradation were 0, ∼ 60, and ∼35% in the absence of ammonium and FNA; ∼ 14, ∼ 29, and ∼28% at 0.03 mg-N L-1 FNA; and 7, 15, and 5% at 0.19 mg-N L-1 FNA. Model simulation showed that the nitritation efficiency of ∼99% and atenolol removal efficiency of 57.5% in the PN process could be achieved simultaneously by controlling pH at 8.5, while 89.2% total nitrogen and 57.1% atenolol were removed to the maximum at pH of 7.0 in PN coupling with the anammox process. The pH-based operational strategy to regulate FNA levels was mathematically demonstrated to be effective for achieving the simultaneous removal of nitrogen and atenolol in PN-based sidestream processes.

Legacy benefits of blood pressure treatment on cardiovascular events are primarily mediated by improved blood pressure variability: the ASCOT trial.

BACKGROUND AND AIMS: Visit-to-visit systolic blood pressure variability (BPV) is an important predictor of cardiovascular (CV) outcomes. The long-term effect of a period of blood pressure (BP) control, but with differential BPV, is uncertain. Morbidity and mortality follow-up of UK participants in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure-Lowering Arm has been extended for up to 21 years to determine the CV impact of mean systolic blood pressure (SBP) control and BPV during the trial, and amongst those allocated to amlodipine- and atenolol-based treatment. METHODS: Eight thousand five hundred and eighty hypertensive participants (4305 assigned to amlodipine ± perindopril-based and 4275 to atenolol ± diuretic-based treatment during the in-trial period (median 5.5 years) were followed for up to 21 years (median 17.4 years), using linked hospital and mortality records. A subgroup of participants (n = 2156) was followed up 6 years after the trial closure with a self-administered questionnaire and a clinic visit. In-trial mean SBP and standard deviation of visit-to-visit SBP as a measure of BPV, were measured using >100 000 BP measurements. Cox proportional hazard models were used to estimate the risk [hazard ratios (HRs)], associated with (i) mean with SBP and BPV during the in-trial period, for the CV endpoints occurring after the end of the trial and (ii) randomly assigned treatment to events following randomization, for the first occurrence of pre-specified CV outcomes. RESULTS: Using BP data from the in-trial period, in the post-trial period, although mean SBP was a predictor of CV outcomes {HR per 10 mmHg, 1.14 [95% confidence interval (CI) 1.10-1.17], P < .001}, systolic BPV independent of mean SBP was a strong predictor of CV events [HR per 5 mmHg 1.22 (95% CI 1.18-1.26), P < .001] and predicted events even in participants with well-controlled BP. During 21-year follow-up, those on amlodipine-based compared with atenolol-based in-trial treatment had significantly reduced risk of stroke [HR 0.82 (95% CI 0.72-0.93), P = .003], total CV events [HR 0.93 (95% CI 0.88-0.98), P = .008], total coronary events [HR 0.92 (95% CI 0.86-0.99), P = .024], and atrial fibrillation [HR 0.91 (95% CI 0.83-0.99), P = .030], with weaker evidence of a difference in CV mortality [HR 0.91 (95% CI 0.82-1.01), P = .073]. There was no significant difference in the incidence of non-fatal myocardial infarction and fatal coronary heart disease, heart failure, and all-cause mortality. CONCLUSIONS: Systolic BPV is a strong predictor of CV outcome, even in those with controlled SBP. The long-term benefits of amlodipine-based treatment compared with atenolol-based treatment in reducing CV events appear to be primarily mediated by an effect on systolic BPV during the trial period.

Mental Health of School-Aged Children Treated with Propranolol or Atenolol for Infantile Hemangioma and Their Parents.

BACKGROUND: Infants with infantile hemangioma (IH) have been effectively treated with propranolol or atenolol. Concerns were raised about the mental health of these children at school age, due to central nervous system effects of propranolol and visible nature of IH. OBJECTIVE: This study aimed to compare the mental health at school age of children treated with propranolol to children treated with atenolol for IHs and their parents. METHODS: This two-centered cross-sectional study included children aged ≥6 years and treated with either propranolol or atenolol for IH during infancy. Children's outcomes were performance-based affect recognition (Dutch version of the Developmental Neuropsychological Assessment-II [NEPSY-II-NL]), parent-reported emotional and behavioral functioning (Child Behavioral Checklist [CBCL]), and health-related quality of life (KIDSCREEN-27). Parents' outcome was parenting stress (Parenting Stress Questionnaire [OBVL]). RESULTS: Data of 105 children (36 propranolol, 69 atenolol; 6.0-11.8 years) were analyzed. Mental health outcomes did not differ between both ß-blocker groups. Although overall functioning was in line with norms, children presented specific problems concerning affect recognition, parent-reported attention, and social quality of life. Parents showed increased physical symptoms, depressive symptoms, and parent-child relationship problems. CONCLUSION: No difference in mental health at school age was found between children treated with propranolol or atenolol for IH. Although few overall mental health problems were found, specific problems require follow-up. Follow-up of children should be directed toward affect recognition, attention, and social functioning in daily life. Problems reported by parents could be ameliorated by mental health support during and after their infant's ß-blocker treatment.

ASPAD dynamic simulation and artificial neural network for atenolol adsorption in GGSWAC packed bed column.

This study aimed to assess the dynamic simulation models provided by Aspen adsorption (ASPAD) and artificial neural network (ANN) in understanding the adsorption behavior of atenolol (ATN) on gasified Glyricidia sepium woodchips activated carbon (GGSWAC) within fixed bed columns for wastewater treatment. The findings demonstrated that increasing the bed height from 1 to 3 cm extended breakthrough and exhaustion times while enhancing adsorption capacity. Conversely, higher initial ATN concentrations resulted in shorter breakthrough and exhaustion times but increased adsorption capacity. Elevated influent flow rates reduced breakthrough and exhaustion times while maintaining constant adsorption capacity. The ASPAD software demonstrated competence in accurately modeling the crucial exhaustion points. However, there is room for enhancement in forecasting breakthrough times, as it exhibited deviations ranging from 6.52 to 239.53% when compared to the actual experimental data. ANN models in both MATLAB and Python demonstrated precise predictive abilities, with the Python model (R2 = 0.985) outperforming the MATLAB model (R2 = 0.9691). The Python ANN also exhibited superior fitting performance with lower MSE and MAE. The most influential factor was the initial ATN concentration (28.96%), followed by bed height (26.39%), influent flow rate (22.43%), and total effluent time (22.22%). The findings of this study offer an extensive comprehension of breakthrough patterns and enable accurate forecasts of column performance.

Common teratogenic medication exposures-a population-based study of pregnancies in the United States.

BACKGROUND: Risk mitigation for most teratogenic medications relies on risk communication via drug label, and prenatal exposures remain common. Information on the types of and risk factors for prenatal exposures to medications with teratogenic risk can guide strategies to reduce exposure. OBJECTIVE: This study aimed to identify medications with known or potential teratogenic risk commonly used during pregnancy among privately insured persons. STUDY DESIGN: We used the Merative™ MarketScan® Commercial Database to identify pregnancies with live or nonlive (ectopic pregnancies, spontaneous and elective abortions, stillbirths) outcomes among persons aged 12 to 55 years from 2011 to 2018. Start/end dates of medication exposure and pregnancy outcomes were identified via an adapted algorithm based on validation studies. We required continuous health plan enrollment from 90 days before conception until 30 days after the pregnancy end date. Medications with known or potential teratogenic risk were selected from TERIS (Teratogen Information System) and drug monographs based on the level of risk and quality of evidence (138 with known and 60 with potential risk). We defined prenatal exposure on the basis of ≥1 outpatient pharmacy claim or medical encounter for medication administration during target pregnancy periods considering medication risk profiles (eg, risk only in the first trimester or at a certain dose threshold). Sex hormones and hormone analogs, and abortion and postpartum/abortion hemorrhage treatments were not considered as teratogenic medications because of challenges in separating pregnancy-related indications, nor were opioids (because of complex risk-benefit considerations) or antiobesity medications if their only teratogenic mechanism was weight loss. RESULTS: Among all pregnancies, the 10 medications with known teratogenic risk and the highest prenatal exposures were sulfamethoxazole/trimethoprim (1988 per 100,000 pregnancy-years), high-dose fluconazole (1248), topiramate (351), lisinopril (144), warfarin (57), losartan (56), carbamazepine (50), valproate (49), vedolizumab (28 since 2015), and valsartan (25). Prevalence of exposure to sulfamethoxazole/trimethoprim decreased from 2346 to 1453 per 100,000 pregnancy-years from 2011 to 2018, but prevalence of exposure to vedolizumab increased 6-fold since its approval in 2015. Prenatal exposures in the first trimester were higher among nonlive pregnancies than among live-birth pregnancies, with the largest difference observed for warfarin (nonlive 370 vs live birth 78), followed by valproate (258 vs 86) and topiramate (1728 vs 674). Prenatal exposures to medications with potential teratogenic risk were most prevalent for low-dose fluconazole (6495), metoprolol (1325), and atenolol (448). The largest first-trimester exposure differences between nonlive and live-birth pregnancies were observed for lithium (242 vs 89), gabapentin (1639 vs 653), and duloxetine (1914 vs 860). Steady increases in hydralazine and gabapentin exposures were observed during the study years, whereas atenolol exposure decreased (561 to 280). CONCLUSION: Several medications with teratogenic risk for which there are potentially safer alternatives continue to be used during pregnancy. The fluctuating rates of prenatal exposure observed for select teratogenic medications suggest that regular reevaluation of risk mitigation strategies is needed. Future research focusing on understanding the clinical context of medication use is necessary to develop effective strategies for reducing exposures to medications with teratogenic risk during pregnancy.

Oral atenolol compared to oral propranolol for infantile hemangioma. / Atenolol oral comparado con propranolol oral para hemangioma infantil.

Introduction: Infantile hemangioma is the most frequent benign vascular tumor in childhood, with an incidence of 3 to 10%. When patients require treatment, oral propranolol, a non-selective lipophilic beta-blocker, is usually considered the therapy of choice. However, its use has been associated with several adverse events related to its ß-2 action and its ability to cross the blood-brain barrier. Because of this, oral atenolol, a hydrophilic ß-1 receptor-selective beta-blocker, may represent a valid treatment alternative. Nonetheless, there is still controversy regarding the efficacy and safety of atenolol when compared with propranolol as monotherapy for this condition. Methods: We searched Epistemonikos, the largest database of systematic reviews in health science, which is maintained by screening multiple sources of information, including MEDLINE/PubMed, EMBASE, and Cochrane, among others. Data were extracted from the identified reviews, data from the primary studies were analyzed, a meta-analysis was performed, and a summary table of the results was prepared using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method. Results: Nine systematic reviews were identified, including 10 primary studies and three randomized trials. The three randomized trials were included in the analysis of this investigation. Conclusion: The use of oral atenolol compared with oral propranolol as monotherapies may result in little or no difference in terms of likelihood of complete remission, decrease in Hemangioma Activity Score, likelihood of post-treatment relapse, and risk of adverse events and severe adverse events, in infantile hemangioma (low certainty of evidence).

Introducción: El hemangioma infantil corresponde al tumor vascular benigno más frecuente de la infancia, con una incidencia de 3 a 10%. Entre los pacientes que requieren tratamiento el uso oral de propranolol, un betabloqueador no selectivo de tipo lipofílico, es usualmente considerado como la terapia de elección. Sin embargo, su uso se ha asociado a diversos efectos adversos, relacionados con su acción ß-2, y a su capacidad de cruzar la barrera hematoencefálica. Debido a esto, el uso oral de atenolol, un betabloqueador selectivo de receptores ß-1, de tipo hidrofílico, podría representar una alternativa válida de tratamiento. Sin embargo, aún existe controversia en relación con la eficacia y seguridad del tratamiento con atenolol como monoterapia, en comparación con el uso de propranolol como monoterapia para esta condición. Métodos: Se realizó una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el tamizaje de múltiples fuentes de información, incluyendo MEDLINE/PubMed, EMBASE, Cochrane, entre otras. Se extrajeron los datos desde las revisiones identificadas, se analizaron los datos de los estudios primarios, se realizó un metanálisis y se preparó una tabla de resumen de los resultados utilizando el método GRADE. Resultados: Se identificaron nueve revisiones sistemáticas, que en conjunto incluyeron 10 estudios primarios y tres ensayos aleatorizados. Se incluyeron los tres ensayos aleatorizados en el análisis del presente trabajo. Conclusiones: El uso de atenolol oral como monoterapia, comparado con el uso de propranolol oral como monoterapia, podría resultar en poca o nula diferencia en cuanto a la probabilidad de remisión completa, la disminución del , la probabilidad de recaída posterior al tratamiento y el riesgo de presentar efectos adversos y efectos adversos severos, en el hemangioma infantil (certeza de la evidencia baja).

Further exploration of the collision-induced dissociation of select beta blockers: Acebutolol, atenolol, bisoprolol, carteolol, and labetalol.

Beta blockers are a class of drugs commonly used to treat heart-related diseases; they are also regulated under the World Anti-Doping Agency. Tandem mass spectrometry is often used in the pharmaceutical industry, clinical analysis laboratory, and antidoping laboratory for detection and characterization of drugs and their metabolites. A deeper chemical understanding of dissociation pathways may eventually lead to an improved ability to predict tandem mass spectra of compounds based strictly on their chemical structure (or vice versa), which is especially important for characterization of unknowns such as emerging designer drugs or novel metabolites. In addition to providing insights into dissociation pathways, the use of energy-resolved breakdown curves can produce improved selectivity and lend insights into optimal fragmentation conditions for liquid chromatography-tandem mass spectrometry LC-MS/MS workflows. Here, we perform energy-resolved collision cell and multistage ion trap collision-induced dissociation-mass spectrometry (CID-MS) experiments, along with complementary density functional theory calculations, on five beta blockers (acebutolol, atenolol, bisoprolol, carteolol, and labetalol), to better understand the details of the pathways giving rise to the observed MS/MS patterns. Results from this work are contextualized within previously reported literature on these compounds. New insights into the formation of the characteristic product ion m/z 116 and the pathway leading to characteristic loss of 77 u are highlighted. We also present comparisons of breakdown curves obtained via qToF, quadrupole ion trap, and in-source CID, allowing for differences between the data to be noted and providing a step toward allowing for improved selectivity of breakdown curves to be realized on simple instruments such as single quadrupoles or ion traps.

Effect of blood pressure-lowering agents on microvascular function in people with small vessel diseases (TREAT-SVDs): a multicentre, open-label, randomised, crossover trial.

BACKGROUND: Hypertension is the leading risk factor for cerebral small vessel disease. We aimed to determine whether antihypertensive drug classes differentially affect microvascular function in people with small vessel disease. METHODS: We did a multicentre, open-label, randomised crossover trial with blinded endpoint assessment at five specialist centres in Europe. We included participants aged 18 years or older with symptomatic sporadic small vessel disease or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and an indication for antihypertensive treatment. Participants were randomly assigned (1:1:1) to one of three sequences of antihypertensive treatment using a computer-generated multiblock randomisation, stratified by study site and patient group. A 2-week washout period was followed by three 4-week periods of oral monotherapy with amlodipine, losartan, or atenolol at approved doses. The primary endpoint was change in cerebrovascular reactivity (CVR) determined by blood oxygen level-dependent MRI response to hypercapnic challenge in normal-appearing white matter from the end of washout to the end of each treatment period. Efficacy analyses were done by intention-to-treat principles in all randomly assigned participants who had at least one valid assessment for the primary endpoint, and analyses were done separately for participants with sporadic small vessel disease and CADASIL. This trial is registered at ClinicalTrials.gov, NCT03082014, and EudraCT, 2016-002920-10, and is terminated. FINDINGS: Between Feb 22, 2018, and April 28, 2022, 75 participants with sporadic small vessel disease (mean age 64·9 years [SD 9·9]) and 26 with CADASIL (53·1 years [7·0]) were enrolled and randomly assigned to treatment. 79 participants (62 with sporadic small vessel disease and 17 with CADASIL) entered the primary efficacy analysis. Change in CVR did not differ between study drugs in participants with sporadic small vessel disease (mean change in CVR 1·8 × 10-4%/mm Hg [SE 20·1; 95% CI -37·6 to 41·2] for amlodipine; 16·7 × 10-4%/mm Hg [20·0; -22·3 to 55·8] for losartan; -7·1 × 10-4%/mm Hg [19·6; -45·5 to 31·1] for atenolol; poverall=0·39) but did differ in patients with CADASIL (15·7 × 10-4%/mm Hg [SE 27·5; 95% CI -38·3 to 69·7] for amlodipine; 19·4 × 10-4%/mm Hg [27·9; -35·3 to 74·2] for losartan; -23·9 × 10-4%/mm Hg [27·5; -77·7 to 30·0] for atenolol; poverall=0·019). In patients with CADASIL, pairwise comparisons showed that CVR improved with amlodipine compared with atenolol (-39·6 × 10-4%/mm Hg [95% CI -72·5 to -6·6; p=0·019) and with losartan compared with atenolol (-43·3 × 10-4%/mm Hg [-74·3 to -12·3]; p=0·0061). No deaths occurred. Two serious adverse events were recorded, one while taking amlodipine (diarrhoea with dehydration) and one while taking atenolol (fall with fracture), neither of which was related to study drug intake. INTERPRETATION: 4 weeks of treatment with amlodipine, losartan, or atenolol did not differ in their effects on cerebrovascular reactivity in people with sporadic small vessel disease but did result in differential treatment effects in patients with CADASIL. Whether antihypertensive drug classes differentially affect clinical outcomes in people with small vessel diseases requires further research. FUNDING: EU Horizon 2020 programme.

Single-atom Zr embedded Ti4O7 anode coupling with hierarchical CuFe2O4 particle electrodes toward efficient electrooxidation of actual pharmaceutical wastewater.

Electrocatalytic oxidation is commonly restricted by low degradation efficiency, slow mass transfer, and high energy consumption. Herein, a synergetic electrocatalysis system was developed for removal of various drugs, i.e., atenolol, florfenicol, and diclofenac sodium, as well as actual pharmaceutical wastewater, where the newly-designed single-atom Zr embedded Ti4O7 (Zr/Ti4O7) and hierarchical CuFe2O4 (CFO) microspheres were used as anode and microelectrodes, respectively. In the optimal reaction system, the degradation efficiencies of 40 mg L-1 atenolol, florfenicol, and diclofenac sodium could achieve up to 98.8%, 93.4%, and 85.5% in 120 min with 0.1 g L-1 CFO at current density of 25 mA cm-2. More importantly, in the flow-through reactor, the electrooxidation lasting for 150 min could reduce the COD of actual pharmaceutical wastewater from 432 to 88.6 mg L-1, with a lower energy consumption (25.67 kWh/m3). Meanwhile, the electrooxidation system maintained superior stability and environmental adaptability. DFT theory calculations revealed that the excellent performance of this electrooxidation system could be ascribed to the striking features of the reduced reaction energy barrier by single-atom Zr loading and abundant oxygen vacancies on the Zr/Ti4O7 surface. Moreover, the characterization and experimental results demonstrated that the CFO unique hierarchical structure and synergistic effect between electrodes were also the important factors that could improve the system performance. The findings shed light on the single-atom material design for boosting electrochemical oxidation performance.

Enantioselective uptake and translocation of atenolol in higher plants.

The presence of pharmaceuticals in surface water and wastewater has been an increasing area of research since they can represent a possible route for human exposure when these waters are used to irrigate crops. The concentration of these drugs in crops depends on their uptake and translocation within plants. A less recognized question is that over 50 % of pharmaceuticals are chiral compounds, but there is little knowledge about their enantioselectivity in plants. In this study, we evaluated the uptake, bioconcentration, and translocation of enantiomers of atenolol, a commonly used beta-blocker, in Arabidopsis thaliana cells and Lactuca sativa plants under hydroponic conditions. Atenolol was taken up by Arabidopsis thaliana cells during 120 h of exposure to solutions with 1 mg/L of R/S-(±)-atenolol. A moderate preference for R-(+)-atenolol over S-(-)-atenolol was observed, with the enantiomeric fraction (EF) reaching 0.532 ± 0.002 for the R enantiomer. Atenolol was also taken up and translocated by Lactuca sativa after hydroponic cultivation in nutrient solutions containing 1 or 10 µg/L R/S-(±)-atenolol. Moderate enantioselectivity was detected in the treatment with 10 µg/L, and the EF after 168 h was 0.42 ± 0.01, suggesting that S-(-)-atenolol was preferentially accumulated. Selectivity was also observed in the translocation factor (TF), calculated as the ratio of the concentration in the leaves over that in the roots. As many emerging contaminants are chiral, our findings highlight the importance to consider their fate and risks in terrestrial ecosystems at the enantiomer scale.

Development of a High-Field "Brick" Mass Spectrometer with Extended Mass Range and Capable of Characterizing Native Proteins.

One of the main challenges of analyzing intact proteins on an ion trap mass spectrometer is the mass range limitation, especially for miniature mass spectrometers. In this study, a high-field frequency scanning ion trap miniature mass spectrometer, namely the high-field "Brick" mass spectrometer, was developed to analyze intact proteins. A high-voltage broadband radio frequency (rf) amplifier was designed with a maximum output of 900 Vp-p over a frequency range of 130-700 kHz. Compared to the 600 Vp-p rf amplifier equipped in the conventional "Brick" mass spectrometer, the mass range of the instrument could be extended from 2000 to over 8000 Th. Sensitivity and mass resolution for native protein analyses were also evaluated and compared. Various proteins as well as their mixtures were analyzed on the high-field "Brick" mass spectrometer. The noncovalent interaction between protein-ligand complexes, lysozyme with triN-acetylchitotriose, was also analyzed. In addition, a hybrid ion scan mode was explored to further expand the mass range of the instrument at both low- and high-mass ends. In the hybrid ion scan mode, both rf frequency and amplitude were tuned, and a mass range from 100 to 12,000 Th was realized. As a result, both small drugs and proteins could be analyzed in a single mass scan. As proof-of-concept demonstrations, a mixture of atenolol and bovine serum albuminand oligomers of transferrin were analyzed.

Analyzing microbial communities and their biodegradation of multiple pharmaceuticals in membrane bioreactors.

Pharmaceuticals are of concern to our planet and health as they can accumulate in the environment. The impact of these biologically active compounds on ecosystems is hard to predict, and information on their biodegradation is necessary to establish sound risk assessment. Microbial communities are promising candidates for the biodegradation of pharmaceuticals such as ibuprofen, but little is known yet about their degradation capacity of multiple micropollutants at higher concentrations (100 mg/L). In this work, microbial communities were cultivated in lab-scale membrane bioreactors (MBRs) exposed to increasing concentrations of a mixture of six micropollutants (ibuprofen, diclofenac, enalapril, caffeine, atenolol, paracetamol). Key players of biodegradation were identified using a combinatorial approach of 16S rRNA sequencing and analytics. Microbial community structure changed with increasing pharmaceutical intake (from 1 to 100 mg/L) and reached a steady-state during incubation for 7 weeks on 100 mg/L. HPLC analysis revealed a fluctuating but significant degradation (30-100%) of five pollutants (caffeine, paracetamol, ibuprofen, atenolol, enalapril) by an established and stable microbial community mainly composed of Achromobacter, Cupriavidus, Pseudomonas and Leucobacter. By using the microbial community from MBR1 as inoculum for further batch culture experiments on single micropollutants (400 mg/L substrate, respectively), different active microbial consortia were obtained for each single micropollutant. Microbial genera potentially responsible for degradation of the respective micropollutant were identified, i.e. Pseudomonas sp. and Sphingobacterium sp. for ibuprofen, caffeine and paracetamol, Sphingomonas sp. for atenolol and Klebsiella sp. for enalapril. Our study demonstrates the feasibility of cultivating stable microbial communities capable of degrading simultaneously a mixture of highly concentrated pharmaceuticals in lab-scale MBRs and the identification of microbial genera potentially responsible for the degradation of specific pollutants. KEY POINTS: • Multiple pharmaceuticals were removed by stable microbial communities. • Microbial key players of five main pharmaceuticals were identified.

A synthesis on the sub-lethal toxicity of atenolol, a beta-blocker, in teleost fish.

Blood pressure medications like atenolol are detected in aquatic ecosystems. The objectives here were to (1) map the global presence of atenolol in surface water and sewage; (2) present current knowledge regarding removal efficiency and degradation of atenolol; (3) identify biological endpoints sensitive to exposure; (4) reveal molecular biomarkers that may be useful for exposure studies in fish; (5) determine whether toxicology studies are within environmental relevance. In fish, atenolol exposure affects endocrine and immune systems, metabolism, and epigenetics. Fewer than half of all studies measuring biological responses use environmentally-relevant concentrations. Heart rate appeared most sensitive to atenolol exposure relative to other endpoints. Data are lacking for behavioral responses to atenolol. Molecular biomarkers for atenolol may include those associated with acute kidney injury, cholestasis, and hypertriglyceridemia. Head kidney and liver may therefore be useful for detecting atenolol-induced effects. This review synthesizes knowledge regarding atenolol-induced toxicity in fish.

New spectrophotometric and smartphone-based colorimetric methods for determination of atenolol in pharmaceutical formulations.

Novel spectrophotometric and smartphone-based colorimetric methods were developed and validated for the estimation of atenolol (ATE) in pharmaceutical formulations. The measurement procedure is based on the de-diazotization reaction, in which ATE is able to inhibit the diazotized sulfanilic acid from reacting with 8-hydroxy quinoline (8-HQ) in a basic medium. As a result, the formation of red-orange color azo-dye is hindered, and the color intensity is decreased proportionally to concentration of ATE. In spectrophotometric method the azo-dye color fate was monitored at 495 nm. While in smartphone-based colorimetric (SBC) method the captured image in the design processed by RGB App and transferred to the absorbance. The reactant concentrations were optimized using a central composite design (CCD) and response surface method. The methods exhibit good linearity in the 8.0 to 60.0 µg mL-1 range with no significant effect of interferences. The spectrophotometric method yields a linear equation with a slope of 0.0187 (R2 = 0.9993), a limit of detection (LOD) of 1.28 µg mL-1, and a limit of quantification (LOQ) of 4.28 µg mL-1. On the other hand, the smartphone-based colorimetric (SBC) method demonstrates a linear equation with a slope of 0.0127 (R2 = 0.9965), an LOD of 2.13 µg mL-1, and an LOQ of 7.09 µg mL-1. Analyzing ATE in pharmaceutical tablets was utilized to validate the applicability of the developed methods, and the results were statistically compared with those obtained by the HPLC method using the t-test and F-test.

Sex Differences in Atrial Fibrillation and Associated Complications in Hypertensive Patients with Left Ventricular Hypertrophy: The LIFE Study.

BACKGROUND: There is no consensus on whether biological differences account for the higher risk of stroke seen in females compared to males with atrial fibrillation (AF). METHODS: Capitalizing on The Losartan Intervention for Endpoint study, a multicenter randomized clinical trial randomizing 9,193 patients and followed for at least four years, we aimed to identify sex differences in the risk of stroke in the presence of AF in patients with hypertension and left ventricular hypertrophy (LVH). RESULTS: 342 Patients had a history of AF, and 669 developed new-onset AF. History of AF and new-onset AF were more prevalent among males (5.0% vs. 2.9% and 3.0% vs. 0.9%) in patients aged 55-63 years, but the relative difference decreased with age. Females with new-onset AF tended to have a higher risk of stroke than males (HR 1.52 [95% CI 0.95-2.43]). However, females with a history of AF did not have a higher risk than males (HR 0.88 [95% CI 0.5-1.6]). In patients with new-onset AF, the relative higher stroke risk in females increased with age. Among patients with a history of AF, stroke risk was comparable and increased with age in both sexes. CONCLUSIONS: Among patients with hypertension and LVH, females with new-onset AF had a higher risk of stroke than males, especially in patients above 64 years. However, the risk did not differ between the sexes among patients with a history of AF.

Influence of Manure as a Complex Mixture on Soil Sorption of Pharmaceuticals-Studies with Selected Chemical Components of Manure.

Pharmaceutically active compounds (PhACs) enter soil with organic waste materials such as manure. Such complex substrates differently affect PhACs' soil sorption. For the first time, batch experiments were conducted using five selected chemicals as model constituents to elucidate the effects. Urea, phosphate (KH2PO4), acetic acid, phenol and nonadecanoic acid (C:19) altered the sorption strength and/or nonlinearity of sulfadiazine, caffeine, and atenolol in an arable Cambisol topsoil. The nonlinear Freundlich model best described sorption. Overall, the PhACs' Freundlich coefficients (sorption strength) increased in the sequence urea < phosphate < phenol < C:19 < acetic acid, while the Freundlich exponents largely decreased, indicating increasing sorption specificity. The effects on sulfadiazine and caffeine were rather similar, but in many cases different from atenolol. Phosphate mobilized sulfadiazine and caffeine and urea mobilized sulfadiazine, which was explained by sorption competition resulting from specific preference of similar sorption sites. Soil sorbed phenol strongly increased the sorption of all three PhACs; phenolic functional groups are preferred sorption sites of PhACs in soil. The large increase in sorption of all PhACs by acetic acid was attributed to a loosening of the soil organic matter and thus the creation of additional sorption sites. The effect of C:19 fatty acid, however, was inconsistent. These results help to better understand the sorption of PhACs in soil-manure mixtures.