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Molecules (Basel, Switzerland) Jun 2024Atenolol (ATE) and propranolol (PRO) inclusion complexes with β-cyclodextrin have been investigated in aqueous solution. The aqueous solution was examined and...
Atenolol (ATE) and propranolol (PRO) inclusion complexes with β-cyclodextrin have been investigated in aqueous solution. The aqueous solution was examined and characterized using UV-vis, fluorescence spectroscopy, and H NMR. The physical mixture was characterized using FTIR. The existence of inclusion complexes is confirmed by observing changes in spectroscopic properties. The ATE complex with β-CD exhibited an interaction as host and (β-CD) as a guest in a 1:1 ratio, with an inclusion constant K of 2.09 × 10 µM, as determined by the typical double-reciprocal graphs. Similarly, the PRO complex with β-CD exhibited an interaction as host and (β-CD) guest in 1:1 and 1:2 stoichiometry at the same time; the inclusion constants were K1 = 5.80 × 10 µM and K2 = 4.67 × 10 µM, as determined by typical double-reciprocal graphs. The variables influencing the formation of the inclusion complexes were investigated and optimized. Based on the enhancement in fluorescence intensity due to the formation of inclusion complexes, spectrofluorometric methods were developed and validated for determination of each drug's pharmaceutical formulation. The quantification of the fluorescence intensity for ATE and PRO was conducted at λ/λ 226/302 nm and λ/λ 231/338 nm, respectively. Under the optimal reaction circumstances, linear relationships with good correlation coefficients of 0.9918 and 0.99 were found in the concentration ranges of 0.3-1.7 μM, and 0.1-1.1 μM for ATE and PRO, respectively. The limits of detection (LODs) were found to be 0.13 and 0.01 μM for ATE and PRO, respectively. The suggested approach was effectively applied to the analysis of both drugs' pharmaceutical formulations.
Topics: Atenolol; beta-Cyclodextrins; Propranolol; Spectrometry, Fluorescence; Spectroscopy, Fourier Transform Infrared; Magnetic Resonance Spectroscopy
PubMed: 38930938
DOI: 10.3390/molecules29122875 -
International Journal of Molecular... Jun 2024Atenolol, one of the top five best-selling drugs in the world today used to treat angina and hypertension, and to reduce the risk of death after a heart attack, faces...
Atenolol, one of the top five best-selling drugs in the world today used to treat angina and hypertension, and to reduce the risk of death after a heart attack, faces challenges in current synthetic methods to address inefficiencies and environmental concerns. The traditional synthesis of this drug involves a process that generates a large amount of waste and other by-products that need disposal. This study presents a one-pot DES-based sustainable protocol for synthesizing atenolol. The use of the DES allowed the entire process to be conducted with no need for additional bases or catalysts, in short reaction times, under mild conditions, and avoiding chromatographic purification. The overall yield of atenolol was 95%. The scalability of the process to gram-scale production was successfully demonstrated, emphasizing its potential in industrial applications. Finally, the 'greenness' evaluation, performed using the First Pass CHEM21 Metrics Toolkit, highlighted the superiority in terms of the atom economy, the reaction mass efficiency, and the overall process mass intensity of the DES-based synthesis compared with the already existing methods.
Topics: Atenolol; Deep Eutectic Solvents; Green Chemistry Technology
PubMed: 38928384
DOI: 10.3390/ijms25126677 -
Veterinary Sciences Jun 2024The renin-angiotensin system (RAS) is increasingly being recognized to play a role in the tumor microenvironment, promoting tumor growth. Studies blocking a single part...
The renin-angiotensin system (RAS) is increasingly being recognized to play a role in the tumor microenvironment, promoting tumor growth. Studies blocking a single part of the RAS have shown mixed results, possibly due to the existence of different bypass pathways and redundancy within the RAS. As such, multimodal blockade of the RAS has been developed to exert more complete inhibition of the RAS. The aim of the present study was to assess the safety of multimodal RAS blockade in dogs. Five dogs (four with appendicular osteosarcoma, one with oral malignant melanoma) were treated with atenolol, benazepril, curcumin, meloxicam, and metformin. The dogs underwent clinical examination, blood pressure measurement, and hematology and serum biochemistry tests performed at 0, 1, 3, 6, 9, and 12 weeks, then every 3 months thereafter. End-of-life decisions were made by the owners. None of the dogs developed hypotension. One dog had intermittent vomiting during the 64 weeks it was on the trial. One dog had a one-off increase in serum SDMA(symmetrical dimethylarginine) concentration. Dogs were euthanized at weeks 3 (osteosarcoma), 10 (osteosarcoma), 17 (osteosarcoma), and 26 (oral malignant melanoma), and one dog was still alive at the end of the trial at 64 weeks (osteosarcoma). This is the first assessment of multimodal blockade of the RAS in dogs, and the results suggest it causes only mild adverse effects in some animals. The efficacy of the treatment was not assessed due to the small number of dogs. This pilot study allows for future larger studies assessing multimodal RAS blockade for the treatment of canine cancer.
PubMed: 38922022
DOI: 10.3390/vetsci11060275 -
Journal of Chromatography. B,... Jun 2024Cortex Morin Radicis (CMR) is the dried root bark of Morus alba. L. It has a variety of effects such as antibacterial, anti-tumour, treatment of cardiovascular diseases...
Screening for promising multi-target bioactive components from Cortex Mori Radicis for the treatment of chronic cor pulmonale based on immobilized beta-adrenergic receptor and beta-adrenergic receptor chromatography.
Cortex Morin Radicis (CMR) is the dried root bark of Morus alba. L. It has a variety of effects such as antibacterial, anti-tumour, treatment of cardiovascular diseases or upper respiratory tract disease and so on. The pursuit for drugs selected from Cortex Mori Radicis having improved therapeutic efficacy necessitates increasing research on new assays for screening bioactive compounds with multi-targets. In this work, we applied immobilized β-AR and β-AR as the stationary phase in chromatographic column to screen bioactive compounds from Cortex Morin Radicis. Specific ligands of the two receptors (e.g. esmolol, metoprolol, atenolol, salbutamol, methoxyphenamine, tulobuterol and clorprenaline) were utilized to characterize the specificity and bioactivity of the columns. We used high performance affinity chromatography coupled with ESI-MS to screen targeted compounds of Cortex Morin Radicis. By zonal elution, we identified morin as a bioactive compound simultaneously binding to β-AR and β-AR. The compound exhibited the association constants of 3.10 × 10 and 2.60 × 10 M on the β-AR and β-AR column. On these sites, the dissociation rate constants were calculated to be 0.131 and 0.097 s. Molecular docking indicated that the binding of morin to the two receptors occurred on Asp200, Asp121, and Val122 of β-AR, Asn312, Thr110, Asp113, Tyr316, Gly90, Phe193, Ile309, and Trp109 of β-AR. Likewise, mulberroside C was identified as the bioactive compound binding to β-AR. The association constants and dissociation rate constants were calculated to be 1.08 × 10 M and 0.900 s. Molecular docking also indicated that mulberroside C could bind to β-AR receptor on its agonist site. Taking together, we demonstrated that the chromatographic strategy to identify bioactive natural products based on the β-AR and β-AR immobilization, has potential for screening bioactive compounds with multi-targets from complex matrices including traditional Chinese medicines.
PubMed: 38917653
DOI: 10.1016/j.jchromb.2024.124175 -
Journal of Hazardous Materials Jun 2024Periodate (PI)-based advanced oxidation processes have gained increasing interest. This study for the first time elevates the light-activation capacity of PI by using...
Periodate (PI)-based advanced oxidation processes have gained increasing interest. This study for the first time elevates the light-activation capacity of PI by using far UVC at 222 nm (UV/PI) without extra chemical inputs. The effectiveness and the underlying mechanisms of UV/PI for the remediation of micropollutants were studied by selecting atenolol (ATL) as a representative. PI possessed a high molar absorption coefficient of 9480-6120 M cm at 222 nm in the pH range of 5.0-9.0, and it was rapidly decomposed by UV with first-order rate constants of 0.0055 to 0.002 s. ATL and the six other organic compounds were effectively degraded by the UV/PI process under different conditions with the fluence-based rate constants generally two to hundred times higher than by UVA photolysis. Hydroxyl radical and ozone were confirmed as the major contributors to ATL degradation, while direct photolysis also played a role at higher pH or lower PI dosages. Degradation pathways of ATL were proposed including hydroxylation, demethylation, and oxidation. The high energy efficiency of the UV/PI process was also confirmed. This study provides a cost-effective and convenient approach to enhance PI light-response activity for the treatment of micropollutants.
PubMed: 38905986
DOI: 10.1016/j.jhazmat.2024.134978 -
Clinical Kidney Journal May 2024Despite a lack of clinical trial data, β-blockers are widely prescribed to dialysis patients. Whether specific β-blocker agents are associated with improved long-term...
BACKGROUND
Despite a lack of clinical trial data, β-blockers are widely prescribed to dialysis patients. Whether specific β-blocker agents are associated with improved long-term outcomes compared with alternative β-blocker agents in the dialysis population remains uncertain.
METHODS
We analyzed data from an international cohort study of 10 125 patients on maintenance hemodialysis across 18 countries that were newly prescribed a β-blocker medication within the Dialysis Outcomes and Practice Patterns Study (DOPPS). The following β-blocker agents were compared: metoprolol, atenolol, bisoprolol and carvedilol. Multivariable Cox proportional hazards models were used to estimate the association between the newly prescribed β-blocker agent and all-cause mortality. Stratified analyses were performed on patients with and without a prior history of cardiovascular disease.
RESULTS
The mean (standard deviation) age in the cohort was 63 (15) years and 57% of participants were male. The most commonly prescribed β-blocker agent was metoprolol (49%), followed by carvedilol (29%), atenolol (11%) and bisoprolol (11%). Compared with metoprolol, atenolol {adjusted hazard ratio (HR) 0.77 [95% confidence interval (CI) 0.65-0.90]} was associated with a lower mortality risk. There was no difference in mortality risk with bisoprolol [adjusted HR 0.99 (95% CI 0.82-1.20)] or carvedilol [adjusted HR 0.95 (95% CI 0.82-1.09)] compared with metoprolol. These results were consistent upon stratification of patients by presence or absence of a prior history of cardiovascular disease.
CONCLUSIONS
Among patients on maintenance hemodialysis who were newly prescribed β-blocker medications, atenolol was associated with the lowest mortality risk compared with alternative agents.
PubMed: 38887596
DOI: 10.1093/ckj/sfae087 -
Journal of Chromatography. B,... Jun 2024Antiarrhythmic and antihypertensive drugs are frequently encountered in post mortem analysis, and the question may arise as to whether they were administered in...
Antiarrhythmic and antihypertensive drugs are frequently encountered in post mortem analysis, and the question may arise as to whether they were administered in therapeutic doses, and if they were taken in accidental, intentional, or suicidal overdose scenarios. Therefore, a novel analytical method was developed and validated for the quantification of 35 drugs with toxicological relevance, including antihypertensive and antiarrhythmic drugs (ajmaline, amlodipine, amiodarone, atenolol, bisoprolol, carvedilol, clonidine, desethylamiodarone, diltiazem, donepezil, doxazosin, dronedarone, esmolol, flecainide, lercanidipine, lidocaine, metoprolol, nebivolol, nimodipine, pindolol, prajmaline, propafenone, propranolol, sotalol, urapidil, and verapamil), as well as other medications commonly found in combination (sildenafil, tadalafil, atorvastatin, clopidogrel, dapoxetine, memantine, pentoxifylline, rivastigmine, and ivabradine). The method enables simultaneous identification and quantification in blood samples using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Validation exhibited excellent linearity across the concentration range for all analytes. Precision and accuracy were within acceptable limits, with bias and relative standard deviation (RSD) values consistently below 9 % and 10 %, respectively. Selectivity and specificity assessments confirmed the absence of any interference from contaminants or co-extracted drugs. The method demonstrated very high sensitivity, with limits of detection (LOD) as low as 0.01 ng/ml and limits of quantification (LOQ) as low as 0.04 ng/ml. Extraction recovery exceeded 57.5 % for all analytes except atenolol, and matrix effects were <17 % for all analytes except pindolol. Processed sample stability evaluations revealed consistent results with acceptable deviations for all analytes. In addition, the method was specifically tested for the use in post mortem analysis. The applicability of our method was demonstrated by the analysis of two authentic human autopsy blood samples.
PubMed: 38878710
DOI: 10.1016/j.jchromb.2024.124196 -
International Journal of Cardiology Sep 2024Beta-blockers are commonly used drugs during pregnancy, especially in women with heart disease, and are regarded as relatively safe although evidence is sparse....
BACKGROUND
Beta-blockers are commonly used drugs during pregnancy, especially in women with heart disease, and are regarded as relatively safe although evidence is sparse. Differences between beta-blockers are not well-studied.
METHODS
In the Registry of Pregnancy And Cardiac disease (ROPAC, n = 5739), a prospective global registry of pregnancies in women with structural heart disease, perinatal outcomes (small for gestational age (SGA), birth weight, neonatal congenital heart disease (nCHD) and perinatal mortality) were compared between women with and without beta-blocker exposure, and between different beta-blockers. Multivariable regression analysis was used for the effect of beta-blockers on birth weight, SGA and nCHD (after adjustment for maternal and perinatal confounders).
RESULTS
Beta-blockers were used in 875 (15.2%) ROPAC pregnancies, with metoprolol (n = 323, 37%) and bisoprolol (n = 261, 30%) being the most frequent. Women with beta-blocker exposure had more SGA infants (15.3% vs 9.3%, p < 0.001) and nCHD (4.7% vs 2.7%, p = 0.001). Perinatal mortality rates were not different (1.4% vs 1.9%, p = 0.272). The adjusted mean difference in birth weight was -177 g (-5.8%), the adjusted OR for SGA was 1.7 (95% CI 1.3-2.1) and for nCHD 2.3 (1.6-3.5). With metoprolol as reference, labetalol (0.2, 0.1-0.4) was the least likely to cause SGA, and atenolol (2.3, 1.1-4.9) the most.
CONCLUSIONS
In women with heart disease an association was found between maternal beta-blocker use and perinatal outcomes. Labetalol seems to be associated with the lowest risk of developing SGA, while atenolol should be avoided.
Topics: Humans; Female; Pregnancy; Adrenergic beta-Antagonists; Registries; Adult; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Prospective Studies; Infant, Newborn; Heart Diseases; Infant, Small for Gestational Age; Perinatal Mortality
PubMed: 38844094
DOI: 10.1016/j.ijcard.2024.132234 -
Biological & Pharmaceutical Bulletin 2024This study aimed to validate the In vitro Dissolution Absorption System 2 (IDAS2) containing a biological barrier of Caco-2 or Madin-Darby canine kidney (MDCK) cell...
This study aimed to validate the In vitro Dissolution Absorption System 2 (IDAS2) containing a biological barrier of Caco-2 or Madin-Darby canine kidney (MDCK) cell monolayer through dose sensitivity studies. Metoprolol and propranolol were selected as Biopharmaceutics Classification System (BCS) Class I model drugs, and atenolol as a Class III model drug. The IDAS2 is comprised of a dissolution vessel (500 mL) and two permeation chambers (2 × 8.0 mL) mounted with Caco-2 or MDCK cell monolayer. One or two immediate-release tablet(s) of the model drug were added to the dissolution vessel, and the time profiles of dissolution and permeation were observed. Greater than 85% of metoprolol and propranolol (tested at two dosing concentrations) were dissolved by 15 min, and all drugs were fully dissolved by 30 min. All three drugs were more permeable across Caco-2 cells than MDCK cells with a linear increase in permeation across both cells at both dose concentrations. Thus, the dose sensitivity of the IDAS2 was demonstrated using both cell barriers. These results indicate a successful qualification of IDAS2 for the development/optimization of oral formulations and that MDCK cells can be utilized as a surrogate for Caco-2 cells.
Topics: Dogs; Caco-2 Cells; Humans; Animals; Madin Darby Canine Kidney Cells; Propranolol; Metoprolol; Atenolol; Solubility; Dose-Response Relationship, Drug; Biopharmaceutics; Permeability; Intestinal Absorption
PubMed: 38839364
DOI: 10.1248/bpb.b24-00150 -
Microcirculation (New York, N.Y. : 1994) Jun 2024The sympathetic-parasympathetic (or axo-axonal) interaction mechanism mediated that neurogenic relaxation, which was dependent on norepinephrine (NE) releases from...
OBJECTIVE
The sympathetic-parasympathetic (or axo-axonal) interaction mechanism mediated that neurogenic relaxation, which was dependent on norepinephrine (NE) releases from sympathetic nerve terminal and acts on β-adrenoceptor of parasympathetic nerve terminal, has been reported. As NE is a weak β-adrenoceptor agonist, there is a possibility that synaptic NE is converted to epinephrine by phenylethanolamine-N-methyltransferase (PNMT) and then acts on the β-adrenoceptors to induce neurogenic vasodilation.
METHODS
Blood vessel myography technique was used to measure relaxation and contraction responses of isolated basilar arterial rings of rats.
RESULTS
Nicotine-induced relaxation was sensitive to propranolol, guanethidine (an adrenergic neuronal blocker), and N-nitro-l-arginine. Nicotine- and exogenous NE-induced vasorelaxation was partially inhibited by LY-78335 (a PNMT inhibitor), and transmural nerve stimulation depolarized the nitrergic nerve terminal directly and was not inhibited by LY-78335; it then induced the release of nitric oxide (NO). Epinephrine-induced vasorelaxation was not affected by LY-78335. However, these vasorelaxations were completely inhibited by atenolol (a β-adrenoceptor antagonist) combined with ICI-118,551 (a β-adrenoceptor antagonist).
CONCLUSIONS
These results suggest that NE may be methylated by PNMT to form epinephrine and cause the release of NO and vasodilation. These results provide further evidence supporting the physiological significance of the axo-axonal interaction mechanism in regulating brainstem vascular tone.
PubMed: 38837563
DOI: 10.1111/micc.12858