-
The Cochrane Database of Systematic... Nov 2014Partial agonists are a subclass of beta blockers used to treat hypertension in many countries. Partial agonist act by stimulating beta receptors when they are quiescent... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Partial agonists are a subclass of beta blockers used to treat hypertension in many countries. Partial agonist act by stimulating beta receptors when they are quiescent and blocking beta receptors when they are active. The blood pressure (BP) lowering effect of partial agonist beta blockers has not been quantified.
OBJECTIVES
To quantify the dose-related effects of various partial agonists beta blockers on systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate versus placebo in patients with primary hypertension.
SEARCH METHODS
We searched the Hypertension Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE In-Process, EMBASE and ClinicalTrials.gov for randomized controlled trials up to October 2014. The WHO International Clinical Trials Registry Platform (ICTRP) is searched for inclusion in the Group's Specialised Register.
SELECTION CRITERIA
Randomized double-blinded placebo-controlled parallel or cross-over trials. Studies must contain a partial agonist monotherapy arm with fixed dose. Patients enrolled into the studies must have primary hypertension at baseline (defined as SBP/DBP > 140/90 mmHg). Duration of studies must be between three to 12 weeks.
DATA COLLECTION AND ANALYSIS
Two authors (GW and HB) confirmed the inclusion of studies and extracted the data independently.
MAIN RESULTS
Thirteen randomized double-blinded placebo-controlled trials that examined the blood pressure lowering efficacy of six partial agonists in 605 hypertensive patients were included in this review. Five of the included studies were parallel studies and the other eight were cross-over studies. The overall risk of bias is high in this review due to the small sample size and high risk of detection bias. Pindolol, celiprolol and alprenolol lowered SBP and DBP compared to placebo. Acebutolol lowered SBP but there was no clear evidence that it lowered DBP. There was no clear evidence that pindolol and oxprenolol lowered SBP or DBP. Other than for celiprolol, sample sizes were generally small increasing the uncertainty in findings for individual agents versus placebo. In patients with moderate to severe hypertension, partial agonists (considered as a subclass) lowered peak BP by an average of 8 mmHg systolic (95% CI, -10 to -6, very low quality evidence), 4 mmHg diastolic (95%CI, -5 to -3, very low quality evidence) and reduced heart rate by five beats per minute (95%CI, -6 to -4, very low quality evidence). Higher dose partial agonists did not appear to provide additional BP lowering effects compared to lower dose. The maximum BP lowering effect of the overall subclass occurred at the starting dose. Partial agonists reduced pulse pressure by 4 mmHg (95% CI, -5 to -2, very low evidence). Only one study reported withdrawal due to adverse effects, the risk ratio (95% confidence interval) was 0.72 (0.07, 7.67).
AUTHORS' CONCLUSIONS
There was very low quality evidence that in patients with moderate to severe hypertension, partial agonists lowered peak BP by an average of 8/4 mmHg and reduced heart rate by five beats per minute. There was no evidence of a greater effect at doses higher than the initial doses. This estimate was probably exaggerated as it was subject to a high risk of bias. Based on the indirect comparison of the results in this review and two Cochrane reviews on angiotensin-converting-enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), which also used similar inclusion criteria as this review, the BP lowering effect appeared to be less than the effect in patients with mild to moderate elevated BP who were taking ACE inhibitors and ARBs based on an indirect comparison. Withdrawals due to adverse effects were only reported in one trial so it is impossible to assess the harm of these drugs.
Topics: Adrenergic beta-1 Receptor Antagonists; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Essential Hypertension; Heart Rate; Humans; Hypertension; Randomized Controlled Trials as Topic
PubMed: 25427719
DOI: 10.1002/14651858.CD007450.pub2 -
The Cochrane Database of Systematic... Sep 2020Beta-blockers are commonly used in the treatment of hypertension. We do not know whether the blood pressure (BP) lowering efficacy of beta-blockers varies across the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Beta-blockers are commonly used in the treatment of hypertension. We do not know whether the blood pressure (BP) lowering efficacy of beta-blockers varies across the day. This review focuses on the subclass of beta-blockers with partial agonist activity (BBPAA).
OBJECTIVES
To assess the degree of variation in hourly BP lowering efficacy of BBPAA over a 24-hour period in adults with essential hypertension.
SEARCH METHODS
The Cochrane Hypertension Information Specialist searched the following databases for relevant studies up to June 2020: the Cochrane Hypertension Specialised Register; CENTRAL; 2020, Issue 5; MEDLINE Ovid; Embase Ovid; the World Health Organization International Clinical Trials Registry Platform; and ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. The searches had no language restrictions.
SELECTION CRITERIA
We sought to include all randomised and non-randomised trials that assessed the hourly effect of BBPAA by ambulatory monitoring, with a minimum follow-up of three weeks.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected the included trials and extracted the data. We assessed the certainty of the evidence using the GRADE approach. Outcomes included in the review were end-point hourly systolic and diastolic blood pressure (SBP and DBP) and heart rate (HR), measured using a 24-hour ambulatory BP monitoring (ABPM) device.
MAIN RESULTS
Fourteen non-randomised baseline controlled trials of BBPAA met our inclusion criteria, but only seven studies, involving 121 participants, reported hourly ambulatory BP data that could be included in the meta-analysis. Beta-blockers studied included acebutalol, pindolol and bopindolol. We judged most studies at high or unclear risk of bias for selection bias, attrition bias, and reporting bias. We judged the overall certainty of the evidence to be very low for all outcomes. We analysed and presented data by each hour post-dose. Very low-certainty evidence showed that hourly mean reduction in BP and HR visually showed an attenuation over time. Over the 24-hour period, the magnitude of SBP lowering at each hour ranged from -3.68 mmHg to -17.74 mmHg (7 studies, 121 participants), DBP lowering at each hour ranged from -2.27 mmHg to -9.34 mmHg (7 studies, 121 participants), and HR lowering at each hour ranged from -0.29 beats/min to -10.29 beats/min (4 studies, 71 participants). When comparing between three 8-hourly time intervals that correspond to day, evening, and night time hours, BBPAA was less effective at lowering BP and HR at night, than during the day and evening. However, because we judged that these outcomes were supported by very low-certainty evidence, further research is likely to have an important impact on the estimate of effect and may change the conclusion.
AUTHORS' CONCLUSIONS
There is insufficient evidence to draw general conclusions about the degree of variation in hourly BP-lowering efficacy of BBPAA over a 24-hour period, in adults with essential hypertension. Very low-certainty evidence showed that BBPAA acebutalol, pindolol, and bopindolol lowered BP more during the day and evening than at night. However, the number of studies and participants included in this review was very small, further limiting the certainty of the evidence. We need further and larger trials, with accurate recording of time of drug intake, and with reporting of standard deviation of BP and HR at each hour.
Topics: Acebutolol; Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Adult; Antihypertensive Agents; Bias; Blood Pressure; Circadian Rhythm; Controlled Clinical Trials as Topic; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Pindolol; Time Factors
PubMed: 32888198
DOI: 10.1002/14651858.CD010054.pub2 -
Critical Care (London, England) Jun 2021β-adrenergic antagonists (BAAs) are used to treat cardiovascular disease such as ischemic heart disease, congestive heart failure, dysrhythmias, and hypertension....
BACKGROUND
β-adrenergic antagonists (BAAs) are used to treat cardiovascular disease such as ischemic heart disease, congestive heart failure, dysrhythmias, and hypertension. Poisoning from BAAs can lead to severe morbidity and mortality. We aimed to determine the utility of extracorporeal treatments (ECTRs) in BAAs poisoning.
METHODS
We conducted systematic reviews of the literature, screened studies, extracted data, and summarized findings following published EXTRIP methods.
RESULTS
A total of 76 studies (4 in vitro and 2 animal experiments, 1 pharmacokinetic simulation study, 37 pharmacokinetic studies on patients with end-stage kidney disease, and 32 case reports or case series) met inclusion criteria. Toxicokinetic or pharmacokinetic data were available on 334 patients (including 73 for atenolol, 54 for propranolol, and 17 for sotalol). For intermittent hemodialysis, atenolol, nadolol, practolol, and sotalol were assessed as dialyzable; acebutolol, bisoprolol, and metipranolol were assessed as moderately dialyzable; metoprolol and talinolol were considered slightly dialyzable; and betaxolol, carvedilol, labetalol, mepindolol, propranolol, and timolol were considered not dialyzable. Data were available for clinical analysis on 37 BAA poisoned patients (including 9 patients for atenolol, 9 for propranolol, and 9 for sotalol), and no reliable comparison between the ECTR cohort and historical controls treated with standard care alone could be performed. The EXTRIP workgroup recommends against using ECTR for patients severely poisoned with propranolol (strong recommendation, very low quality evidence). The workgroup offered no recommendation for ECTR in patients severely poisoned with atenolol or sotalol because of apparent balance of risks and benefits, except for impaired kidney function in which ECTR is suggested (weak recommendation, very low quality of evidence). Indications for ECTR in patients with impaired kidney function include refractory bradycardia and hypotension for atenolol or sotalol poisoning, and recurrent torsade de pointes for sotalol. Although other BAAs were considered dialyzable, clinical data were too limited to develop recommendations.
CONCLUSIONS
BAAs have different properties affecting their removal by ECTR. The EXTRIP workgroup assessed propranolol as non-dialyzable. Atenolol and sotalol were assessed as dialyzable in patients with kidney impairment, and the workgroup suggests ECTR in patients severely poisoned with these drugs when aforementioned indications are present.
Topics: Adrenergic beta-Antagonists; Consensus; Drug Overdose; Extracorporeal Membrane Oxygenation; Humans
PubMed: 34112223
DOI: 10.1186/s13054-021-03585-7 -
Kidney Medicine May 2022There is conflicting evidence regarding the type of β-blockers to use in dialysis patients. This systematic review seeks to determine whether highly dialyzable...
RATIONALE & OBJECTIVE
There is conflicting evidence regarding the type of β-blockers to use in dialysis patients. This systematic review seeks to determine whether highly dialyzable β-blockers are associated with higher rates of cardiovascular events and mortality in hemodialysis patients than poorly dialyzable β-blockers.
STUDY DESIGN
A systematic review of the existing literature was conducted. A meta-analysis was performed using data from the selected studies.
SETTING & STUDY POPULATIONS
Participants were from the United States, Canada, and Taiwan. The mean ages of participants ranged from 55.9-75.7 years.
SELECTION CRITERIA FOR STUDIES
We searched the Ovid MEDLINE database from 1990 to September 2020. Studies without adult hemodialysis participants and without comparisons of at least 2 β-blockers of different dialyzability were excluded.
DATA EXTRACTION
Baseline and adjusted outcome data were extracted from each study.
ANALYTICAL APPROACH
Random-effects models were used to calculate pooled risk ratios using fully adjusted models from individual studies.
RESULTS
Four cohort studies were included. Pooling fully adjusted models, highly dialyzable β-blockers did not influence mortality (HR, 0.94; 95% CI, 0.81-1.08; I = 0.84) compared with poorly dialyzable β-blockers but were associated with a reduction in cardiovascular events (HR, 0.88; 95% CI, 0.83-0.93). There was significant heterogeneity between studies (I = 0.35). Only 1 study reported on adverse events. Intradialytic hypotension was more common in those on carvedilol (a poorly dialyzable β-blocker) compared with those on metoprolol (a highly dialyzable β-blocker; adjusted incidence rate ratio, 1.10; 95% CI, 1.09-1.11).
LIMITATIONS
No randomized controlled trials were identified. Each study used different analytic methods and different definitions for outcomes. Classifications of β-blockers varied. Only 1 study reported on adverse events.
CONCLUSIONS
Pooled data suggest highly dialyzable β-blockers are associated with similar mortality events and fewer cardiovascular events compared with poorly dialyzable β-blockers.
PubMed: 35539430
DOI: 10.1016/j.xkme.2022.100460 -
Molecules (Basel, Switzerland) Oct 2019A wooden stick coated with a novel graphene-based nanocomposite (Graphene oxide/polyethylene glycol (GO/PEG)) is introduced and investigated for its efficacy in solid...
A wooden stick coated with a novel graphene-based nanocomposite (Graphene oxide/polyethylene glycol (GO/PEG)) is introduced and investigated for its efficacy in solid phase microextraction techniques. The GO/PEG-stick was prepared and subsequently applied for the extraction of β-blockers, acebutolol, and metoprolol in human oral fluid samples, which were subsequently detected by liquid chromatography tandem mass spectrometry (LC-MS/MS). Experimental parameters affecting the extraction protocol including sample pH, extraction time, desorption time, appropriate desorption solvent, and salt addition were optimized. Method validation for the detection from oral fluid samples was performed following FDA (Food and Drug Administration) guidelines on bioanalytical method validation. Calibration curves ranging from 5.0 to 2000 nmol L for acebutolol and 25.0 to 2000 nmol L for metoprolol were used. The values for the coefficient of determination (R) were found to be 0.998 and 0.996 ( = 3) for acebutolol and metoprolol, respectively. The recovery of analytes during extraction was 80.0% for acebutolol and 62.0% for metoprolol, respectively. The limit of detections (LODs) were 1.25, 8.00 nmol L for acebutolol and metoprolol and the lower limit of quantifications (LLOQ) were 5.00 nmol L for acebutolol and 25.0 nmol L for metoprolol. Validation experiments conducted with quality control (QC) samples demonstrated method accuracy between 80.0% to 97.0% for acebutolol and from 95.0% to 109.0% for metoprolol. The inter-day precision for QC samples ranged from 3.6% to 12.9% for acebutolol and 9.5% to 11.3% for metoprolol. Additionally, the GO/PEG-stick was demonstrated to be reusable, with the same stick observed to be viable for more than 10 extractions from oral fluid samples.
Topics: Acebutolol; Adrenergic beta-Antagonists; Body Fluids; Chromatography, Liquid; Graphite; Humans; Limit of Detection; Metoprolol; Mouth; Nanocomposites; Polyethylene Glycols; Solid Phase Microextraction; Tandem Mass Spectrometry
PubMed: 31614604
DOI: 10.3390/molecules24203664 -
Heliyon Oct 2023A straightforward approach for creating fast and novel potentiometric sensors that are modified with multi-walled nanotubes (MWCNTs) was described. The impact of the...
Fast and novel multiwalled carbon nanotubes decorated with metal oxide nanoparticles for potentiometric detection of a prohibited medication in sports acebutolol hydrochloride.
A straightforward approach for creating fast and novel potentiometric sensors that are modified with multi-walled nanotubes (MWCNTs) was described. The impact of the selective sensor's material was studied. The suggested sensors were successfully fabricated for instant and fast detection of the prohibited β-adrenoreceptor blocking agent acebutolol hydrochloride (AC) in commercial products. Acebutolol-phosphomolybdate (AC-PM) carbon paste sensor was formed by mixing AC and phosphomolybdic acid and graphite powder in the presence of -nitrophenyl octyl ether (-NPOE) as a plasticizing agent. The functionalized AC-PM-MWCNTs and AC-PM-MWCNTs-AlO nanocomposite sensors were prepared and all parameters affecting the sensors' potential responses have been investigated as well as the green synthesis of AlONPs has been characterized using various microscopic and spectroscopic techniques. AC-PM-MWCNTs and AC-PM-MWCNTs-AlO nanocomposite sensors demonstrated linearity of 1.0 × 10-1.0 × 10 and 1.0 × 10-1.0 × 10 mol L, respectively with regression equations -53.571x + 423.24 (r = 0.999) and -57.107x + 518.54 (r = 0.999). It also revealed excellent selectivity and sensitivity for the determination and quantification of AC. The developed potentiometric system was suitable for the determination of AC in bulk powder and commercial products.
PubMed: 37876475
DOI: 10.1016/j.heliyon.2023.e20997 -
Journal of the American Society For... Feb 2022Combining solid phase microextraction (SPME) and mass spectrometry (MS) analysis has become increasingly important to many bioanalytical, environmental, and forensic...
Combining solid phase microextraction (SPME) and mass spectrometry (MS) analysis has become increasingly important to many bioanalytical, environmental, and forensic applications due to its simplicity, rapid analysis, and capability of reducing matrix effects for complex samples. To further promote the adoption of SPME-MS based analysis and expand its application scope calls for efficient and convenient interfaces that couple the SPME sample handling with the efficient analyte ionization for MS. Here, we report a novel interface that integrates both the desorption and the ionization steps in one device based on the capillary vibrating sharp-edge spray ionization (cVSSI) method. We demonstrated that the cVSSI is capable of nebulizing liquid samples in a pulled-tip glass capillary with a battery powered function generator. The cVSSI device allows the insertion of a SPME probe into the spray capillary for desorption and then direct nebulization of the desorption solvent in situ. With the integrated interface, we have demonstrated rapid MS analysis of drug compounds from serum samples. Quantitative determination of various drug compounds including metoprolol, pindolol, acebutolol, oxprenolol, capecitabine, and irinotecan was achieved with good linearity ( = 0.97-0.99) and limit of detection ranging from 0.25 to 0.59 ng/mL without using a high voltage source. Only 3.5 μL of desorption solvent and 3 min desorption time were needed for the present method. Overall, we demonstrated a portable SPME-MS interface featuring high sensitivity, short analysis time, small footprint, and low cost, which makes it an attractive method for many applications requiring sample cleanup including drug compound monitoring, environmental sample analysis, and forensic sample analysis.
Topics: Carbamazepine; Equipment Design; Limit of Detection; Metoprolol; Pindolol; Sensitivity and Specificity; Serum Albumin, Bovine; Solid Phase Microextraction; Spectrometry, Mass, Electrospray Ionization
PubMed: 35040644
DOI: 10.1021/jasms.1c00305 -
Frontiers in Cell and Developmental... 2022Female reproductive cycle, also known as menstrual cycle or estrous cycle in primate or non-primate mammals, respectively, dominates the reproductive processes in...
Female reproductive cycle, also known as menstrual cycle or estrous cycle in primate or non-primate mammals, respectively, dominates the reproductive processes in non-pregnant state. However, in addition to reproductive tissues, reproductive cycle could also perform global regulation because the receptors of two major female hormones fluctuating throughout the cycle, estrogen and progesterone, are widely distributed. Therefore, a multi-tissue gene expression landscape is in continuous demand for better understanding the systemic changes during the reproductive cycle but remains largely undefined. Here we delineated a transcriptomic landscape covering 15 tissues of C57BL/6J female mice in two phases of estrous cycle, estrus and diestrus, by RNA-sequencing. Then, a number of genes, pathways, and transcription factors involved in the estrous cycle were revealed. We found the estrous cycle could widely regulate the neuro-functions, immuno-functions, blood coagulation and so on. And behind the transcriptomic alteration between estrus and diestrus, 13 transcription factors may play important roles. Next, bioinformatics modeling with 1,263 manually curated gene signatures of various physiological and pathophysiological states systematically characterized the beneficial/deleterious effects brought by estrus/diestrus on individual tissues. We revealed that the estrous cycle has a significant effect on cardiovascular system (aorta, heart, vein), in which the anti-hypertensive pattern in aorta induced by estrus is one of the most striking findings. Inspired by this point, we validated that two hypotensive drugs, felodipine and acebutolol, could exhibit significantly enhanced efficacy in estrus than diestrus by mouse and rat experiments. Together, this study provides a valuable data resource for investigating reproductive cycle from a transcriptomic perspective, and presents models and clues for investigating precision medicine associated with reproductive cycle.
PubMed: 36589755
DOI: 10.3389/fcell.2022.983712 -
Molecules (Basel, Switzerland) Nov 2020In this work, one of the most prevalent polypharmacology drug-drug interaction events that occurs between two widely used beta-blocker drugs-i.e., acebutolol and...
In this work, one of the most prevalent polypharmacology drug-drug interaction events that occurs between two widely used beta-blocker drugs-i.e., acebutolol and propranolol-with the most abundant blood plasma fibrinogen protein was evaluated. Towards that end, molecular docking and Density Functional Theory (DFT) calculations were used as complementary tools. A fibrinogen crystallographic validation for the three best ranked binding-sites shows 100% of conformationally favored residues with total absence of restricted flexibility. From those three sites, results on both the binding-site druggability and ligand transport analysis-based free energy trajectories pointed out the most preferred biophysical environment site for drug-drug interactions. Furthermore, the total affinity for the stabilization of the drug-drug complexes was mostly influenced by steric energy contributions, based mainly on multiple hydrophobic contacts with critical residues (THR22: P and SER50: Q) in such best-ranked site. Additionally, the DFT calculations revealed that the beta-blocker drug-drug complexes have a spontaneous thermodynamic stabilization following the same affinity order obtained in the docking simulations, without covalent-bond formation between both interacting beta-blockers in the best-ranked site. Lastly, experimental ultrasound density and velocity measurements were performed and allowed us to validate and corroborate the computational obtained results.
Topics: Adrenergic beta-Antagonists; Binding Sites; Density Functional Theory; Drug Interactions; Fibrinogen; Ligands; Molecular Conformation; Molecular Docking Simulation; Reproducibility of Results; Thermodynamics
PubMed: 33228181
DOI: 10.3390/molecules25225425 -
Chemistry (Weinheim An Der Bergstrasse,... Sep 2020Chemical exchange saturation transfer (CEST) MRI has recently emerged as a versatile molecular imaging approach in which diamagnetic compounds can be utilized to...
Chemical exchange saturation transfer (CEST) MRI has recently emerged as a versatile molecular imaging approach in which diamagnetic compounds can be utilized to generate an MRI signal. To expand the scope of CEST MRI applications, herein, we systematically investigated the CEST properties of N-aryl amides with different N-aromatic substitution, revealing their chemical shifts (4.6-5.8 ppm) and exchange rates (up to thousands s ) are favorable to be used as CEST agents as compared to alkyl amides. As the first proof-of-concept study, we used CEST MRI to detect the enzymatic metabolism of the drug acebutolol directly by its intrinsic CEST signal without any chemical labeling. Our study implies that N-aryl amides may enable the label-free CEST MRI detection of the metabolism of many N-aryl amide-containing drugs and a variety of enzymes that act on N-aryl amides, greatly expanding the scope of CEST MR molecular imaging.
Topics: Amides; Contrast Media; Magnetic Resonance Imaging; Molecular Imaging
PubMed: 32639618
DOI: 10.1002/chem.202002415