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Journal of Chromatography. A Apr 2020Although micellar electrokinetic chromatography-mass spectrometry (MEKC-MS) using bare silica capillary filled with molecular micelles is an advantageous hyphenated...
Establishing repeatability and ruggedness of chiral separations in micellar electrokinetic chromatography mass spectrometry: Combined use of covalently bonded capillary column and molecular micelles.
Although micellar electrokinetic chromatography-mass spectrometry (MEKC-MS) using bare silica capillary filled with molecular micelles is an advantageous hyphenated technique for chiral analysis, it is still in the developmental stage. This is mainly because of the lower repeatability of retention time and peak area associated with the difficulty in controlling electroosmotic flow on bare silica capillaries. Besides the lower robustness and electrospray erosion of the fused-silica capillary tip, the lifetime is limited for 10-15 runs per capillary column. We have tested a new MEKC-MS method to eradicate this problem using a covalently bonded 2-acrylamido-2-methyl-1-propane-sulfonic acid (AMPS) column filled with free floating molecular micelles, polysodium N-undecenoxy carbonyl-L-leucinate (poly-L-SUCL). Simultaneous enantiomeric separations and MS/MS detection of three β-blockers [atenolol (ATEN), metoprolol (METO) and, pindolol (PINDO)] was achieved within 25 min with improved column lifetime of at least 45-50 runs. Excellent repeatability of retention time was observed for β-blockers, as evidenced by the relative standard deviation of less than 2% and 3% for intra-capillary and inter-capillary column, respectively. The linear calibration range of both β-blockers was simultaneously established using enantiomers of PINDO as an internal standard. The limit of detection and the lower limit of quantitation were 0.2 μg/mL and 0.5 μg/mL, respectively, for both ATEN and METO. Acceptable recovery of the enantiomeric content of the commercial METO tablet (98-99.5%) and ATEN tablet (89-92.5%) were obtained with adequate system suitability for the precision of peak area (≤10% RSD) under optimum conditions. The developed MEKC-MS approach was extended, which provided broader repeatibility of chiral separation to a panel of primary, secondary and tertiary amines as well as one anionic chiral compound.
Topics: Adrenergic beta-Antagonists; Chromatography, Micellar Electrokinetic Capillary; Leucine; Micelles; Polymers; Reproducibility of Results; Stereoisomerism; Tandem Mass Spectrometry
PubMed: 31928773
DOI: 10.1016/j.chroma.2019.460835 -
Frontiers in Behavioral Neuroscience 2019Long-term binge alcohol consumption alters the signaling of numerous neurotransmitters in the brain including noradrenaline (NE) and serotonin (5-HT). Alterations in the...
Long-term binge alcohol consumption alters the signaling of numerous neurotransmitters in the brain including noradrenaline (NE) and serotonin (5-HT). Alterations in the signaling of these neuronal pathways result in dysfunctional emotional states like anxiety and depression which are typically seen during alcohol withdrawal. Interestingly, studies have demonstrated that the development of alcohol-induced negative affective states is linked to disrupted neurogenesis in the dentate gyrus (DG) region of the hippocampus in alcohol-dependent animals. We have previously shown that modulation of NE and 5-HT activity by pharmacological targeting of β-adrenoreceptors (β-ARs) and 5-HT1A/1B receptors with pindolol reduces consumption in long-term alcohol-consuming mice. Since these receptors are also involved in emotional homeostasis and hippocampal neurogenesis, we investigated the effects of pindolol administration on emotional and neurogenic deficits in mice consuming long-term alcohol (18 weeks). We report that acute administration of pindolol (32 mg/kg) reduces anxiety-like behavior in mice at 24 h withdrawal in the marble-burying test (MBT) and the elevated plus-maze (EPM). We also show that chronic (2 weeks) pindolol treatment (32 mg/kg/day) attenuates alcohol-induced impairments in the density of immature neurons (DCX) but not newborn cells (BrdU) in the hippocampal DG. Pindolol treatment also restores the normal proportion of newborn proliferating cells (BrdU/Ki67/DCX), newborn proliferating immature neurons (BrdU/Ki67/DCX) and newborn non-proliferating immature neurons (BrdU/Ki67/DCX) following long-term alcohol intake. These results suggest that pindolol, through its unique pharmacology may rescue some but not all deficits of long-term alcohol abuse on the brain, adding further value to its properties as a strong pharmaceutical option for alcohol use disorders (AUDs).
PubMed: 31849624
DOI: 10.3389/fnbeh.2019.00264 -
Epilepsy & Behavior Reports 2019We report a case of a 52-year-old man with drug-resistant temporal lobe epilepsy, with post-ictal violent aggressive behaviors. Postictal violent outbursts would occur...
We report a case of a 52-year-old man with drug-resistant temporal lobe epilepsy, with post-ictal violent aggressive behaviors. Postictal violent outbursts would occur 3-4 times per year following clusters of seizures or generalized tonic-clonic convulsions. The violent outbursts were traumatizing for his family, and lead to multiple emergency department presentations as well as conflicts with police over the course of nine years. After initiation of pindolol the patient has had no episodes of violent behavior in two years despite experiencing the same frequency and severity of seizures as before pindolol. The abrupt cessation of postictal violent outbursts after introduction of pindolol in this case provides a novel management option for the treatment of postictal violence in patients with drug-resistant epilepsy and supports the importance of the beta adrenergic and potentially serotonergic systems in postictal violent behavior.
PubMed: 31799509
DOI: 10.1016/j.ebr.2019.100346 -
The Cochrane Database of Systematic... Sep 2019Randomized controlled trials (RCTs) have yielded conflicting results regarding the ability of beta-blockers to influence perioperative cardiovascular morbidity and...
BACKGROUND
Randomized controlled trials (RCTs) have yielded conflicting results regarding the ability of beta-blockers to influence perioperative cardiovascular morbidity and mortality. Thus routine prescription of these drugs in an unselected population remains a controversial issue. A previous version of this review assessing the effectiveness of perioperative beta-blockers in cardiac and non-cardiac surgery was last published in 2018. The previous review has now been split into two reviews according to type of surgery. This is an update, and assesses the evidence in non-cardiac surgery only.
OBJECTIVES
To assess the effectiveness of perioperatively administered beta-blockers for the prevention of surgery-related mortality and morbidity in adults undergoing non-cardiac surgery.
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase, CINAHL, Biosis Previews and Conference Proceedings Citation Index-Science on 28 June 2019. We searched clinical trials registers and grey literature, and conducted backward- and forward-citation searching of relevant articles.
SELECTION CRITERIA
We included RCTs and quasi-randomized studies comparing beta-blockers with a control (placebo or standard care) administered during the perioperative period to adults undergoing non-cardiac surgery. If studies included surgery with different types of anaesthesia, we included them if 70% participants, or at least 100 participants, received general anaesthesia. We excluded studies in which all participants in the standard care control group were given a pharmacological agent that was not given to participants in the intervention group, studies in which all participants in the control group were given a beta-blocker, and studies in which beta-blockers were given with an additional agent (e.g. magnesium). We excluded studies that did not measure or report review outcomes.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed studies for inclusion, extracted data, and assessed risks of bias. We assessed the certainty of evidence with GRADE.
MAIN RESULTS
We included 83 RCTs with 14,967 participants; we found no quasi-randomized studies. All participants were undergoing non-cardiac surgery, and types of surgery ranged from low to high risk. Types of beta-blockers were: propranolol, metoprolol, esmolol, landiolol, nadolol, atenolol, labetalol, oxprenolol, and pindolol. In nine studies, beta-blockers were titrated according to heart rate or blood pressure. Duration of administration varied between studies, as did the time at which drugs were administered; in most studies, it was intraoperatively, but in 18 studies it was before surgery, in six postoperatively, one multi-arm study included groups of different timings, and one study did not report timing of drug administration. Overall, we found that more than half of the studies did not sufficiently report methods used for randomization. All studies in which the control was standard care were at high risk of performance bias because of the open-label study design. Only two studies were prospectively registered with clinical trials registers, which limited the assessment of reporting bias. In six studies, participants in the control group were given beta-blockers as rescue therapy during the study period.The evidence for all-cause mortality at 30 days was uncertain; based on the risk of death in the control group of 25 per 1000, the effect with beta-blockers was between two fewer and 13 more per 1000 (risk ratio (RR) 1.17, 95% confidence interval (CI) 0.89 to 1.54; 16 studies, 11,446 participants; low-certainty evidence). Beta-blockers may reduce the incidence of myocardial infarction by 13 fewer incidences per 1000 (RR 0.72, 95% CI 0.60 to 0.87; 12 studies, 10,520 participants; low-certainty evidence). We found no evidence of a difference in cerebrovascular events (RR 1.65, 95% CI 0.97 to 2.81; 6 studies, 9460 participants; low-certainty evidence), or in ventricular arrhythmias (RR 0.72, 95% CI 0.35 to 1.47; 5 studies, 476 participants; very low-certainty evidence). Beta-blockers may reduce atrial fibrillation or flutter by 26 fewer incidences per 1000 (RR 0.41, 95% CI 0.21 to 0.79; 9 studies, 9080 participants; low-certainty evidence). However, beta-blockers may increase bradycardia by 55 more incidences per 1000 (RR 2.49, 95% CI 1.74 to 3.56; 49 studies, 12,239 participants; low-certainty evidence), and hypotension by 44 more per 1000 (RR 1.40, 95% CI 1.29 to 1.51; 49 studies, 12,304 participants; moderate-certainty evidence).We downgraded the certainty of the evidence owing to study limitations; some studies had high risks of bias, and the effects were sometimes altered when we excluded studies with a standard care control group (including only placebo-controlled trials showed an increase in early mortality and cerebrovascular events with beta-blockers). We also downgraded for inconsistency; one large, well-conducted, international study found a reduction in myocardial infarction, and an increase in cerebrovascular events and all-cause mortality, when beta-blockers were used, but other studies showed no evidence of a difference. We could not explain the reason for the inconsistency in the evidence for ventricular arrhythmias, and we also downgraded this outcome for imprecision because we found few studies with few participants.
AUTHORS' CONCLUSIONS
The evidence for early all-cause mortality with perioperative beta-blockers was uncertain. We found no evidence of a difference in cerebrovascular events or ventricular arrhythmias, and the certainty of the evidence for these outcomes was low and very low. We found low-certainty evidence that beta-blockers may reduce atrial fibrillation and myocardial infarctions. However, beta-blockers may increase bradycardia (low-certainty evidence) and probably increase hypotension (moderate-certainty evidence). Further evidence from large placebo-controlled trials is likely to increase the certainty of these findings, and we recommend the assessment of impact on quality of life. We found 18 studies awaiting classification; inclusion of these studies in future updates may also increase the certainty of the evidence.
Topics: Adrenergic beta-Antagonists; Anesthesia, General; Arrhythmias, Cardiac; Bradycardia; Cause of Death; Humans; Hypotension; Morbidity; Myocardial Infarction; Perioperative Care; Postoperative Complications; Quality of Life; Randomized Controlled Trials as Topic; Surgical Procedures, Operative
PubMed: 31556094
DOI: 10.1002/14651858.CD013438 -
BioMed Research International 2019Methanolic extract of Lindau leaves (MECN) has been reported to exert antinociceptive activity. The present study aimed to elucidate the possible antinociceptive...
Methanolic extract of Lindau leaves (MECN) has been reported to exert antinociceptive activity. The present study aimed to elucidate the possible antinociceptive mechanisms of a lipid-soluble fraction of MECN, which was obtained after sequential extraction in petroleum ether. The petroleum ether fraction of (PECN), administered orally to mice, was (i) subjected to capsaicin-, glutamate-, phorbol 12-myristate 13-acetate-, bradykinin-induced nociception model; (ii) prechallenged (intraperitoneal (i.p.)) with 0.15 mg/kg yohimbine, 1 mg/kg pindolol, 3 mg/kg caffeine, 0.2 mg/kg haloperidol, or 10 mg/kg atropine, which were the respective antagonist of -adrenergic, -adrenergic, adenosinergic, dopaminergic, or muscarinic receptors; and (iii) prechallenged (i.p.) with 10 mg/kg glibenclamide, 0.04 mg/kg apamin, 0.02 mg/kg charybdotoxin, or 4 mg/kg tetraethylammonium chloride, which were the respective inhibitor of ATP sensitive-, small conductance Ca-activated-, large conductance Ca-activated-, or nonselective voltage-activated-K channel. Results obtained demonstrated that PECN (100, 250, and 500 mg/kg) significantly (P<0.05) inhibited all models of nociception described earlier. The antinociceptive activity of 500 mg/kg PECN was significantly (P<0.05) attenuated when prechallenged with all antagonists or K channel blockers. However, only pretreatment with apamin and charybdotoxin caused full inhibition of PECN-induced antinociception. The rest of the K channel blockers and all antagonists caused only partial inhibition of PECN antinociception, respectively. Analyses on PECN's phytoconstituents revealed the presence of antinociceptive-bearing bioactive compounds of volatile (i.e., derivatives of -tocopherol, -tocopherol, and lupeol) and nonvolatile (i.e., cinnamic acid) nature. In conclusion, PECN exerts a non-opioid-mediated antinociceptive activity involving mainly activation of adenosinergic and cholinergic receptors or small- and large-conductance Ca-activated-K channels.
Topics: Acanthaceae; Alkanes; Analgesics; Analgesics, Non-Narcotic; Animals; Bradykinin; Capsaicin; Glutamic Acid; Humans; Methanol; Mice; Nociceptive Pain; Plant Extracts; Plant Leaves; Potassium Channels; Tetradecanoylphorbol Acetate
PubMed: 31467905
DOI: 10.1155/2019/6593125 -
Pharmaceutics Aug 2019Retinal pigment epithelium (RPE) acts as an outer blood-retinal barrier that limits the access of circulating xenobiotics to the eye. In addition, the RPE limits...
Retinal pigment epithelium (RPE) acts as an outer blood-retinal barrier that limits the access of circulating xenobiotics to the eye. In addition, the RPE limits posterior elimination of intravitreally injected drugs to circulation. Thus, permeation in the RPE has a significant effect on ocular pharmacokinetics. The RPE is also a potentially important drug target in age-related macular degeneration. Therefore, the cell models of the RPE are important tools in ocular drug development, but poor availability and problems in reproducibility limit the use of primary RPE cell cultures. Furthermore, the best and widely used human cell line ARPE19 requires specialized culture conditions and a long time for cellular differentiation. In this paper, we describe a cell population arisen from the ARPE19 culture, with fast differentiation and improved barrier properties. This cell line, LEPI, forms clear microvilli and rapidly displays RPE-like cobblestone morphology after subculture in simple culture conditions. The LEPI cells show RPE-specific functions and expression of RPE65, ezrin, and BEST1 proteins. On filter, the LEPI cells develop tighter barrier than the ex vivo bovine RPE-choroid: permeability coefficients of beta-blockers (atenolol, nadolol, timolol, pindolol, metoprolol, betaxolol) ranged from 0.4 × 10 cm/sec to 2.3 × 10 cm/sec depending on the drug lipophilicity. This rapidly differentiating cell line will be an asset in ocular studies since it is easily maintained, it grows and differentiates quickly and does not require specialized culture conditions for differentiation. Thus, this cell line is suitable for both small scale assays and high throughput screening in drug discovery and development.
PubMed: 31412689
DOI: 10.3390/pharmaceutics11080412 -
Pharmacology Research & Perspectives Aug 2019The aim of this study was to evaluate the pharmacokinetic variability of beta-adrenergic blocking agents used in cardiology by reviewing single-dose and steady-state... (Review)
Review
The aim of this study was to evaluate the pharmacokinetic variability of beta-adrenergic blocking agents used in cardiology by reviewing single-dose and steady-state pharmacokinetic studies from the literature. PubMed was searched for pharmacokinetic studies of beta-adrenergic blocking agents, both single-dose and steady-state studies. The studies included reported maximum plasma concentration (C) and/or area under the concentration curve (AUC). The coefficient of variation (CV%) was calculated for all studies, and a CV% <40% was considered low or moderate variability, and a CV% >40% was considered high variability. The C and AUC were reported a total of 672 times in 192 papers. Based on AUC, metoprolol, propranolol, carvedilol, and nebivolol showed high pharmacokinetic variability (highest first), whereas bisoprolol, atenolol, sotalol, labetalol, nadolol, and pindolol showed low to moderate variability (lowest first). We have shown a high interindividual pharmacokinetic variability that varies markedly in different beta-adrenergic blocking agents; the extreme being steady state ratios as high as 30 in metoprolol. A more personalized approach to the medical treatment of patients may be obtained by combining known pharmacokinetic information about variability, pharmaco-genetics and -dynamics, and patient characteristics, to avoid adverse events or lack of treatment effect.
Topics: Adrenergic beta-Antagonists; Area Under Curve; Biological Availability; Carvedilol; Healthy Volunteers; Humans; Male; Metoprolol; Propranolol
PubMed: 31338197
DOI: 10.1002/prp2.496 -
Translational Psychiatry Apr 2019Developing positron emission tomography (PET) radioligands for the detection of endogenous serotonin release will enable the investigation of serotonergic deficits in... (Randomized Controlled Trial)
Randomized Controlled Trial
Developing positron emission tomography (PET) radioligands for the detection of endogenous serotonin release will enable the investigation of serotonergic deficits in many neuropsychiatric disorders. The present study investigates how acute challenges that aim to increase or decrease cerebral serotonin levels affect binding of the serotonin 2A receptor (5-HTR) agonist radioligand [C]Cimbi-36. In a randomized, double-blind, placebo-controlled, three-arm design, 23 healthy volunteers were PET scanned twice with [C]Cimbi-36: at baseline and following double-blind assignment to one of three interventions (1) infusion of the selective serotonin reuptake inhibitor (SSRI) citalopram preceded by oral dosing of the 5-HTR antagonist pindolol, (n = 8) (2) acute tryptophan depletion (ATD) (n = 7) and (3) placebo (n = 8). Two-sample t-tests revealed no significant group differences in percent change of neocortical [C]Cimbi-36 binding from baseline to intervention between placebo and citalopram/pindolol (p = 0.4) or between placebo and ATD (p = 0.5). Notably, there was a significantly larger within-group variation in 5-HTR binding after intervention with citalopram/pindolol, as compared with placebo (p = 0.007). These findings suggest that neither ATD nor a combination of citalopram and pindolol elicit acute unidirectional changes in serotonin levels sufficient to be detected with [C]Cimbi-36 PET in neocortex. We suggest that the large interindividual variation in 5-HTR binding after citalopram/pindolol reflects that after an acute SSRI intervention, individuals respond substantially different in terms of their brain serotonin levels. Our observation has a potential impact for the understanding of patient responses to SSRI.
Topics: Benzylamines; Brain; Carbon Radioisotopes; Citalopram; Double-Blind Method; Female; Healthy Volunteers; Humans; Male; Phenethylamines; Pindolol; Positron-Emission Tomography; Serotonergic Neurons; Serotonin; Selective Serotonin Reuptake Inhibitors; Synaptic Transmission; Young Adult
PubMed: 30975977
DOI: 10.1038/s41398-019-0468-8 -
Psychiatry Investigation Jan 2019Treatment for panic disorder (PD) have evolved, although there is still a strong unmet need for more effective and tolerable options. The present study summarizes and...
OBJECTIVE
Treatment for panic disorder (PD) have evolved, although there is still a strong unmet need for more effective and tolerable options. The present study summarizes and discusses recent evidence regarding the pharmacological and neuromodulatory treatment of PD.
METHODS
MEDLINE, Cochrane Library, PsycINFO and Thomson Reuters's Web of Science were searched for clinical trials published between 2010 and 2018. We included all prospective experimental studies including randomized controlled trials (RCT) and other clinical trials with more than 10 patients.
RESULTS
Only 11 articles met the inclusion criteria, including 4 RCT, 3 open clinical trials and 5 comparative clinical trials. RCT demonstrated efficacy of transcranial magnetic stimulation (TMS) in only one of two trials. Neither pindolol nor d-fenfluramine were effective in blocking flumazenil-induced panic attacks. Augmentation with quetiapine was not superior to placebo. Open trials indicated that escitalopram, vortioxetine and TMS may be effective. Comparative trials did not demonstrate superiority from any drug, but confirmed tranylcypromine, paroxetine, clonazepam and alprazolam as effective options.
CONCLUSION
The current study confirmed the efficacy of tranylcypromine, paroxetine, clonazepam, alprazolam and escitalopram. Vortioxetine and TMS, with duration of 4 or more weeks, also seems to be effective. Quetiapine, pindolol and d-fenfluramine were not considered effective compounds.
PubMed: 30696238
DOI: 10.30773/pi.2018.12.21.1 -
American Family Physician Jan 2019Migraines impose significant health and financial burdens. Approximately 38% of patients with episodic migraines would benefit from preventive therapy, but less than 13%...
Migraines impose significant health and financial burdens. Approximately 38% of patients with episodic migraines would benefit from preventive therapy, but less than 13% take prophylactic medications. Preventive medication therapy reduces migraine frequency, severity, and headache-related distress. Preventive therapy may also improve quality of life and prevent the progression to chronic migraines. Some indications for preventive therapy include four or more headaches a month, eight or more headache days a month, debilitating headaches, and medication-overuse headaches. Identifying and managing environmental, dietary, and behavioral triggers are useful strategies for preventing migraines. First-line medications established as effective based on clinical evidence include divalproex, topiramate, metoprolol, propranolol, and timolol. Medications such as amitriptyline, venlafaxine, atenolol, and nadolol are probably effective but should be second-line therapy. There is limited evidence for nebivolol, bisoprolol, pindolol, carbamazepine, gabapentin, fluoxetine, nicardipine, verapamil, nimodipine, nifedipine, lisinopril, and candesartan. Acebutolol, oxcarbazepine, lamotrigine, and telmisartan are ineffective. Newer agents target calcitonin gene-related peptide pain transmission in the migraine pain pathway and have recently received approval from the U.S. Food and Drug Administration; however, more studies of long-term effectiveness and adverse effects are needed. The complementary treatments petasites, feverfew, magnesium, and riboflavin are probably effective. Nonpharmacologic therapies such as relaxation training, thermal biofeedback combined with relaxation training, electromyographic feedback, and cognitive behavior therapy also have good evidence to support their use in migraine prevention.
Topics: Combined Modality Therapy; Humans; Migraine Disorders; Secondary Prevention
PubMed: 30600979
DOI: No ID Found