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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 -
The Analyst Aug 2022The flexible surface-enhanced Raman scattering (SERS) platform has ceaselessly propelled the development of point-of-care testing (POCT) in diverse fields. Herein, we...
The flexible surface-enhanced Raman scattering (SERS) platform has ceaselessly propelled the development of point-of-care testing (POCT) in diverse fields. Herein, we report a facile strategy for the SERS-chemometric analysis of four β-blockers (bisoprolol, metoprolol, acebutolol and esmolol) based on a super-sticky mussel-inspired hydrogel SERS tape. The surface morphology and mechanical properties of the hydrogel tape can be easily controlled by adjusting the compositional ratio. The optimized tape with excellent toughness and adhesiveness allows efficient collection of analytes through a simple "paste and peel off" approach, further by spraying with silver nanoparticles using a household sprayer to instantly assemble a flexible SERS substrate, the analytes can then detected by a portable Raman spectrometer. This POCT strategy enables the identification and discrimination of four similar β-blockers with high sensitivity and accuracy in combination with the statistical algorithms. The developed SERS tape is finally utilized for the recognition of β-blockers in simulated urine solution, which realizes a limit of detection of 1.0 ng mL, revealing a promising potential of this SERS-based POCT for the clinical detection of doping abuse.
Topics: Hydrogels; Metal Nanoparticles; Point-of-Care Testing; Silver; Spectrum Analysis, Raman
PubMed: 35839093
DOI: 10.1039/d2an00688j -
Biochemical Pharmacology Jan 2020Stereoselectivity is well described for receptor binding and enzyme catalysis, but so far has only been scarcely investigated in carrier-mediated membrane transport. We...
Stereoselectivity is well described for receptor binding and enzyme catalysis, but so far has only been scarcely investigated in carrier-mediated membrane transport. We thus studied transport kinetics of racemic (anti)adrenergic drugs by the organic cation transporters OCT1 (wild-type and allelic variants), OCT2, OCT3, MATE1, and MATE2-K with a focus on stereospecificity. OCT1 showed stereoselective uptake with up to 2-fold higher v over their corresponding counterpart enantiomers for (R,R)-fenoterol, (R,R)-formoterol, (S)-salbutamol, (S)-acebutolol, and (S)-atenolol. Orciprenaline and etilefrine were also transported stereoselectively. The K was 2.1-fold and 1.5-fold lower for the (S,S)-enantiomers of fenoterol and formoterol, while no significant difference in K was seen for the other aforementioned drugs. Common OCT1 variants showed similar enantiopreference to wild-type OCT1, with a few notable exceptions (e.g. a switch in enantiospecificity for fenoterol in OCT1*2 compared to the wild-type). Other cation transporters showed strong differences to OCT1 in stereoselectivity and transport activity: The closely related OCT2 displayed a 20-fold higher v for (S,S)-fenoterol compared to (R,R)-fenoterol and OCT2 and OCT3 showed 3.5-fold and 4.6-fold higher v for the pharmacologically active (R)-salbutamol over (S)-salbutamol. MATE1 and MATE2-K generally mediated transport with a higher capacity but lower affinity compared to OCT1, with moderate stereoselectivity. Our kinetic studies showed that significant stereoselectivity exists in solute carrier-mediated membrane transport of racemic beta-adrenergic drugs with surprising, and in some instances even opposing, preferences between closely related organic cation transporters. This may be relevant for drug therapy, given the strong involvement of these transporters in hepatic and renal drug elimination.
Topics: Acebutolol; Adrenergic Agonists; Adrenergic Antagonists; Atenolol; Biological Transport; Fenoterol; Formoterol Fumarate; HEK293 Cells; Humans; Kinetics; Organic Cation Transport Proteins; Organic Cation Transporter 1; Organic Cation Transporter 2; Stereoisomerism
PubMed: 31783011
DOI: 10.1016/j.bcp.2019.113731 -
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 -
Pain Practice : the Official Journal of... Sep 2023Acute pain is the most common type of pain. The aim of the present work was carried out to study the antinociceptive effect and pharmacological mechanisms of...
OBJECTIVE
Acute pain is the most common type of pain. The aim of the present work was carried out to study the antinociceptive effect and pharmacological mechanisms of thiocyanoacetamide (Thm) in rats exposed to thermal pain stimulus.
MATERIALS AND METHODS
The anti-nociceptive effect of the newly synthesized compound, Thm was studied in comparison to that of paracetamol (Para), dexamethasone (Dex), and morphine (Morph) at different doses using a hot plate test at a constant temperature of 48.0 ± 0.5°C. During this test, the latency time (LT) was measured when rats express pain behavior. Then, the pharmacological mechanisms were determined using receptor-antagonist drugs.
RESULTS
Firstly, the obtained result showed pain modulation of the pretreated rats with Thm at 10 mg/kg dose proved by the delay of latency time during the thermal test. This significant antinociceptive activity of the thiocyanoacetamide was more effective than that of paracetamol or dexamethasone and less than that of morphine. Second, the pretreatment with acebutolol or risperidone antagonist drugs of, respectively, adrenergic and serotonin receptors demonstrated the elimination of pain modulation with Thm 10 mg/kg dose proved by a short latency time of rat's response in hot plate test. In this case, the pharmacological mechanism of Thm was characterized by the involvement of adrenergic and serotoninergic systems.
CONCLUSIONS
It may be concluded that Thm constitutes a promising antinociceptive drug including beta-adrenergic and serotoninergic targets. The present study warrants further investigation to determine the side effects of this compound.
Topics: Rats; Animals; Acetaminophen; Morphine; Acute Pain; Analgesics; Adrenergic Agents; Dexamethasone; Dose-Response Relationship, Drug; Hot Temperature
PubMed: 37083025
DOI: 10.1111/papr.13234 -
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 -
Evaluation of Drug-Drug Interactions via Inhibition of Hydrolases by Orlistat, an Anti-Obesity Drug.Drug Metabolism and Disposition: the... Aug 2023Drug-drug interactions (DDI) have a significant impact on drug efficacy and safety. It has been reported that orlistat, an anti-obesity drug, inhibits the hydrolysis of...
Drug-drug interactions (DDI) have a significant impact on drug efficacy and safety. It has been reported that orlistat, an anti-obesity drug, inhibits the hydrolysis of -nitrophenol acetate, a common substrate of the major drug-metabolizing hydrolases, carboxylesterase (CES) 1, CES2, and arylacetamide deacetylase (AADAC), in vitro. The aim of this study was to examine whether orlistat affects the pharmacokinetics of drug(s) metabolized by hydrolases in vivo after evaluating its inhibitory potencies against CES1, CES2, and AADAC in vitro. Orlistat potently inhibited the hydrolysis of acebutolol, a specific substrate of CES2, in a non-competitive manner (inhibition constant, = 2.95 ± 0.16 nM), whereas it slightly inhibited the hydrolysis of temocapril and eslicarbazepine acetate, specific substrates of CES1 and AADAC, respectively (IC >100 nM). The in vivo DDI potential was elucidated using mice, in which orlistat showed strong inhibition against acebutolol hydrolase activities in the liver and intestinal microsomes, similar to humans. The area under the curve (AUC) of acebutolol was increased by 43%, whereas the AUC of acetolol, a hydrolyzed metabolite of acebutolol, was decreased by 47% by co-administration of orlistat. The ratio of the value to the maximum unbound plasma concentration of orlistat (<0.012) is lower than the risk criteria for DDI in the liver defined by the US Food and Drug Administration guideline (>0.02), whereas the ratio of the value to the estimated intestinal luminal concentration (3.3 × 10) is considerably higher than the risk criteria in the intestine (>10). Therefore, this suggests that orlistat causes DDI by inhibiting hydrolases in the intestine. SIGNIFICANCE STATEMENT: This study demonstrated that orlistat, an anti-obesity drug, causes drug-drug interactions in vivo by potently inhibiting carboxylesterase 2 in the intestine. This is the first evidence that inhibition of hydrolases causes drug-drug interactions.
Topics: Humans; Mice; Animals; Hydrolases; Orlistat; Carboxylic Ester Hydrolases; Anti-Obesity Agents; Acebutolol; Carboxylesterase; Pharmaceutical Preparations; Hydrolysis; Drug Interactions
PubMed: 37137721
DOI: 10.1124/dmd.123.001266 -
Die Pharmazie Sep 2022H/D exchange reactions can be observed by NMR spectroscopy of acebutolol (ACE). The results obtained showed deuterium incorporation at α-posi t ion of the carbonyl...
H/D exchange reactions can be observed by NMR spectroscopy of acebutolol (ACE). The results obtained showed deuterium incorporation at α-posi t ion of the carbonyl group of acebutolol, when using deuterium oxide or deuterated methanol as deuterium source and solvent. The spontaneous deuteration is proceeded by the following pathway CH₃→CH₂D→CHD→CD₃, through a keto-enol tautomerization reaction. Furthermore, LC-MS / QTOF analyses have confirmed the proposed H/D exchange. In order to reduce the time of total deuteration observed at the acetyl group alkaline catalysts were employed.
Topics: Acebutolol; Deuterium; Deuterium Oxide; Hydrogen; Methanol; Solvents
PubMed: 36199187
DOI: 10.1691/ph.2022.2419 -
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