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The Journal of Clinical Psychiatry Nov 2014Organic anion transporting polypeptides (OATPs) are a group of membrane transport proteins that facilitate the influx of endogenous and exogenous substances across... (Review)
Review
Organic anion transporting polypeptides (OATPs) are a group of membrane transport proteins that facilitate the influx of endogenous and exogenous substances across biological membranes. OATPs are found in enterocytes and hepatocytes and in brain, kidney, and other tissues. In enterocytes, OATPs facilitate the gastrointestinal absorption of certain orally administered drugs. Fruit juices such as grapefruit juice, orange juice, and apple juice contain substances that are OATP inhibitors. These fruit juices diminish the gastrointestinal absorption of certain antiallergen, antibiotic, antihypertensive, and β-blocker drugs. While there is no evidence, so far, that OATP inhibition affects the absorption of psychotropic medications, there is no room for complacency because the field is still nascent and because the necessary studies have not been conducted. Patients should therefore err on the side of caution, taking their medications at least 4 hours distant from fruit juice intake. Doing so is especially desirable with grapefruit juice, orange juice, and apple juice; with commercial fruit juices in which OATP-inhibiting substances are likely to be present in higher concentrations; with calcium-fortified fruit juices; and with medications such as atenolol and fexofenadine, the absorption of which is substantially diminished by concurrent fruit juice intake.
Topics: Beverages; Food-Drug Interactions; Fruit; Humans; Organic Anion Transporters; Psychotropic Drugs
PubMed: 25470100
DOI: 10.4088/JCP.14f09572 -
The Journal of Clinical Investigation Feb 2022Propranolol and atenolol, current therapies for problematic infantile hemangioma (IH), are composed of R(+) and S(-) enantiomers: the R(+) enantiomer is largely devoid...
Propranolol and atenolol, current therapies for problematic infantile hemangioma (IH), are composed of R(+) and S(-) enantiomers: the R(+) enantiomer is largely devoid of beta blocker activity. We investigated the effect of R(+) enantiomers of propranolol and atenolol on the formation of IH-like blood vessels from hemangioma stem cells (HemSCs) in a murine xenograft model. Both R(+) enantiomers inhibited HemSC vessel formation in vivo. In vitro, similar to R(+) propranolol, both atenolol and its R(+) enantiomer inhibited HemSC to endothelial cell differentiation. As our previous work implicated the transcription factor sex-determining region Y (SRY) box transcription factor 18 (SOX18) in propranolol-mediated inhibition of HemSC to endothelial differentiation, we tested in parallel a known SOX18 small-molecule inhibitor (Sm4) and show that this compound inhibited HemSC vessel formation in vivo with efficacy similar to that seen with the R(+) enantiomers. We next examined how R(+) propranolol alters SOX18 transcriptional activity. Using a suite of biochemical, biophysical, and quantitative molecular imaging assays, we show that R(+) propranolol directly interfered with SOX18 target gene trans-activation, disrupted SOX18-chromatin binding dynamics, and reduced SOX18 dimer formation. We propose that the R(+) enantiomers of widely used beta blockers could be repurposed to increase the efficiency of current IH treatment and lower adverse associated side effects.
Topics: Animals; Atenolol; Hemangioma; Humans; Mice; Neoplastic Stem Cells; Neovascularization, Pathologic; Propranolol; Xenograft Model Antitumor Assays
PubMed: 34874911
DOI: 10.1172/JCI151109 -
Fluids and Barriers of the CNS Oct 2017Atenolol, a hydrophilic beta blocker, has been used as a model drug for studying passive permeability of biological membranes such as the blood-brain barrier (BBB) and...
BACKGROUND
Atenolol, a hydrophilic beta blocker, has been used as a model drug for studying passive permeability of biological membranes such as the blood-brain barrier (BBB) and the intestinal epithelium. However, the extent of S-atenolol (the active enantiomer) distribution in brain has never been evaluated, at equilibrium, to confirm that no transporters are involved in its transport at the BBB.
METHODS
To assess whether S-atenolol, in fact, depicts the characteristics of a low passive permeable drug at the BBB, a microdialysis study was performed in rats to monitor the unbound concentrations of S-atenolol in brain extracellular fluid (ECF) and plasma during and after intravenous infusion. A pharmacokinetic model was developed, based on the microdialysis data, to estimate the permeability clearance of S-atenolol into and out of brain. In addition, the nonspecific binding of S-atenolol in brain homogenate was evaluated using equilibrium dialysis.
RESULTS
The steady-state ratio of unbound S-atenolol concentrations in brain ECF to that in plasma (i.e., K) was 3.5% ± 0.4%, a value much less than unity. The unbound volume of distribution in brain (V) of S-atenolol was also calculated as 0.69 ± 0.10 mL/g brain, indicating that S-atenolol is evenly distributed within brain parenchyma. Lastly, equilibrium dialysis showed limited nonspecific binding of S-atenolol in brain homogenate with an unbound fraction (f) of 0.88 ± 0.07.
CONCLUSIONS
It is concluded, based on K being much smaller than unity, that S-atenolol is actively effluxed at the BBB, indicating the need to re-consider S-atenolol as a model drug for passive permeability studies of BBB transport or intestinal absorption.
Topics: Animals; Atenolol; Blood-Brain Barrier; Capillary Permeability; Male; Rats; Rats, Sprague-Dawley
PubMed: 29089037
DOI: 10.1186/s12987-017-0078-x -
Cureus Oct 2021Supraventricular tachycardia (SVT) is a tachyarrhythmia characterized by a heart rate above 120 beats per minute (BPM). Patients with SVT exhibit the following symptoms:... (Review)
Review
Supraventricular tachycardia (SVT) is a tachyarrhythmia characterized by a heart rate above 120 beats per minute (BPM). Patients with SVT exhibit the following symptoms: palpitations, shortness of breath, chest pain, hemodynamic instability, or possibly asymptomatic. The increase in cardiac output and the increase in resting heart rate during pregnancy predispose pregnant women to SVT. The management of SVT in pregnancy, although remarkably similar, varies slightly based on the trimester of pregnancy. Atenolol and verapamil are effective methods of treating SVT, which can be used during the second and third trimesters. Both medications are contraindicated in the first trimester. At the same time, intravenous adenosine can be used in all three trimesters, including labor. Electrical cardioversion is an effective treatment method for hemodynamically unstable or drug-refractory patients, which has proven to be safe in all three trimesters, including labor but can result in pre-term labor in the third trimester. Non-fluoroscopic ablation proved to be the only treatment method that definitively resolved SVT without recurrence.
PubMed: 34659918
DOI: 10.7759/cureus.18479 -
Scientific Reports Jan 2016Metformin can induce breast cancer (BC) cell apoptosis and reduce BC local and metastatic growth in preclinical models. Since Metformin is frequently used along with...
Metformin can induce breast cancer (BC) cell apoptosis and reduce BC local and metastatic growth in preclinical models. Since Metformin is frequently used along with Aspirin or beta-blockers, we investigated the effect of Metformin, Aspirin and the beta-blocker Atenolol in several BC models. In vitro, Aspirin synergized with Metformin in inducing apoptosis of triple negative and endocrine-sensitive BC cells, and in activating AMPK in BC and in white adipose tissue (WAT) progenitors known to cooperate to BC progression. Both Aspirin and Atenolol added to the inhibitory effect of Metformin against complex I of the respiratory chain. In both immune-deficient and immune-competent preclinical models, Atenolol increased Metformin activity against angiogenesis, local and metastatic growth of HER2+ and triple negative BC. Aspirin increased the activity of Metformin only in immune-competent HER2+ BC models. Both Aspirin and Atenolol, when added to Metformin, significantly reduced the endothelial cell component of tumor vessels, whereas pericytes were reduced by the addition of Atenolol but not by the addition of Aspirin. Our data indicate that the addition of Aspirin or of Atenolol to Metformin might be beneficial for BC control, and that this activity is likely due to effects on both BC and microenvironment cells.
Topics: AMP-Activated Protein Kinases; Adipose Tissue, White; Animals; Antineoplastic Agents; Apoptosis; Aspirin; Atenolol; Biomarkers, Tumor; Breast Neoplasms; Cell Line, Tumor; Disease Models, Animal; Drug Synergism; Electron Transport Complex I; Female; Humans; Metformin; NAD; Neoplasm Metastasis; Stem Cells; Triple Negative Breast Neoplasms; Tumor Burden; Tumor Microenvironment; Xenograft Model Antitumor Assays
PubMed: 26728433
DOI: 10.1038/srep18673 -
Pharmaceutics Oct 2021The development of oral dissolving film (ODF) of atenolol is an attempt to enhance convenience and compliance for geriatric patients suffering from hypertension. Film...
The development of oral dissolving film (ODF) of atenolol is an attempt to enhance convenience and compliance for geriatric patients suffering from hypertension. Film former is the most essential component in ODF that determines the physical characteristic and drug release. In this study, three different types of film former including HPMC E5 4% (/), 5% (/), CMC-Na 3% (/), 4% (/), and Na-alginate 2.5% (/), 3% (/) were optimized in Formula 1 (F1) to Formula 6 (F6), respectively. A solvent casting method was employed to develop ODF of atenolol. The films formed by HPMC E5 produced a smooth and flexible surface, whereas CMC-Na and Na-alginate produced gritty textured films. Satisfactory results were obtained from several physical parameters such as film thickness, folding endurance, swelling index, and disintegration time. The homogeneity, drug content, and dissolution properties of ODF with HPMC exhibited better characteristics than the other formulas. Formula 1 exhibited the highest drug release compared to the other ODFs. The molecular docking results showed that there was a hydrogen bonding between atenolol and film formers which was also supported by the FTIR spectrum. The findings of this study suggest that HPMC E5 is the most favorable film former for ODF of atenolol.
PubMed: 34684021
DOI: 10.3390/pharmaceutics13101727 -
European Journal of Pharmaceutics and... Sep 2021Quantitative understanding of pharmacokinetics of topically applied ocular drugs requires more research to further understanding and to eventually allow predictive in...
Quantitative understanding of pharmacokinetics of topically applied ocular drugs requires more research to further understanding and to eventually allow predictive in silico models to be developed. To this end, a topical cocktail of betaxolol, timolol and atenolol was instilled on albino rabbit eyes. Tear fluid, corneal epithelium, corneal stroma with endothelium, bulbar conjunctiva, anterior sclera, iris-ciliary body, lens and vitreous samples were collected and analysed using LC-MS/MS. Iris-ciliary body was also analysed after intracameral cocktail injection. Non-compartmental analysis was utilized to estimate the pharmacokinetics parameters. The most lipophilic drug, betaxolol, presented the highest exposure in all tissues except for tear fluid after topical administration, followed by timolol and atenolol. For all drugs, iris-ciliary body concentrations were higher than that of the aqueous humor. After topical instillation the most hydrophilic drug, atenolol, had 3.7 times higher AUC than AUC, whereas the difference was 1.4 and 1.6 times for timolol and betaxolol, respectively. This suggests that the non-corneal route (conjunctival-scleral) was dominating the absorption of atenolol, while the corneal route was more important for timolol and betaxolol. The presented data increase understanding of ocular pharmacokinetics of a cocktail of drugs and provide data that can be used for quantitative modeling and simulation.
Topics: Administration, Ophthalmic; Animals; Aqueous Humor; Atenolol; Betaxolol; Biological Availability; Drug Combinations; Ophthalmic Solutions; Outcome Assessment, Health Care; Rabbits; Solubility; Tears; Timolol; Tissue Distribution
PubMed: 34139290
DOI: 10.1016/j.ejpb.2021.06.003 -
Journal of Atherosclerosis and... Jun 2021The mechanism underlying the stiffness of the aorta and iliofemoral artery that is required to maintain blood pressure (BP) is unclear. A new stiffness index of the...
AIM
The mechanism underlying the stiffness of the aorta and iliofemoral artery that is required to maintain blood pressure (BP) is unclear. A new stiffness index of the aorta (aBeta) and iliac-femoral arteries (ifBeta) was defined by applying the cardio-ankle vascular index (CAVI). We compared changes in stiffness of the two arteries in response to reduced BP, due to the non-selective α adrenergic blocker phentolamine and the β adrenergic blocker atenolol, in rabbits.
METHODS
Pressure waves at the origin (oA) and distal ends of the aorta (dA) and the distal end of the left femoral artery (fA) were recorded simultaneously using three pressure sensors in 25 anesthetized rabbits. Phentolamine (50 µg/kg/min) and atenolol (10 mg/kg/min) were infused for 2 min. The pulse wave velocity (PWV) in each artery was determined; aBeta, ifBeta, and whole Beta (aifBeta) were calculated by the following formula; Beta=2ρ/PP×ln(SBP/DBP)×PWV (ρ: blood density; SBP, SBP, and PP: systolic, diastolic, and pulse pressures, respectively).
RESULTS
SBP and DBP at oA, dA, and fA decreased by the administration of phentolamine and atenolol, with and without decreased total peripheral vascular resistance. After phentramine infusion, cardiac output (CO), aBeta, and aifBeta increased, while ifBeta decreased. After infusion of atenolol, CO decreased, while aBeta, ifBeta, and aifBeta remained unchanged.
CONCLUSION
The contradictory reactions of aBeta and ifBeta to phentolamine suggest that the stiffness of the aorta and ilio-femoral artery is regulated separately during decreased BP induced by phentolamine, but not by atenolol.
Topics: Animals; Antihypertensive Agents; Aorta; Atenolol; Blood Flow Velocity; Blood Pressure Determination; Cardiac Output; Disease Models, Animal; Femoral Artery; Hypertension; Phentolamine; Pulse Wave Analysis; Rabbits; Vascular Stiffness
PubMed: 32921698
DOI: 10.5551/jat.57364 -
Pharmaceutics Nov 2022Intrinsically, enteric capsule shells offer several advantages compared to coating of dosage forms with enteric polymers. We undertook a systematic investigation to...
Intrinsically, enteric capsule shells offer several advantages compared to coating of dosage forms with enteric polymers. We undertook a systematic investigation to elucidate capsule-fill parameters that may result in premature gastric drug release from Vcaps Enteric capsules (Lonza CHI, Morristown, NJ, USA). Four model drugs with different ionization and solubility profiles were investigated: acetaminophen, ketoprofen, trimethoprim and atenolol. Different fill loads, diluents and drug-to-diluent ratios were explored. Enteric capsules were filled with drug or drug and diluent powder mix and underwent USP II dissolution testing using mini-vessels and paddles. Capsules were tested in pH 2 (0.01 M HCl) or pH 4.5 (3.2 × 10 M HCl) 200 mL acid media to simulate normal, fasted or hypochlorhydric gastric pH, respectively. Acetaminophen, trimethoprim and atenolol displayed premature gastric drug release from enteric capsules. The extent of premature release was dependent on drug solubility, ionization profile and capsule-fill level. At 100 mg drug-fill level, acetaminophen, trimethoprim and atenolol gave rise to 10.6, 12.2 and 83.1% drug release, respectively, in normal, fasted, gastric fluids. Diffusion layer pH of trimethoprim and atenolol in pH 2 media was determined to be pH 6.3 and 10.3, respectively. Upon increasing capsule-fill load using microcrystalline cellulose as a diluent, a significant reduction in premature gastric release was observed. However, including mannitol as a diluent was only effective at decreasing premature drug release at a low drug-to-diluent ratio. Systematic in vitro screening of enteric capsule fills needs to be conducted to ensure that drug product performance is not compromised.
PubMed: 36432696
DOI: 10.3390/pharmaceutics14112505 -
The Journal of Veterinary Medical... May 2020This study aimed to assess the effects of atenolol on left ventricular (LV) and left atrial (LA) function in healthy cats and investigate the relationship between...
This study aimed to assess the effects of atenolol on left ventricular (LV) and left atrial (LA) function in healthy cats and investigate the relationship between atenolol administration and LA enlargement (LAE) in cats with hypertrophic cardiomyopathy (HCM). In study 1, nine experimental cats were used to assess the effects of atenolol in healthy subjects. Cats were administered one of three medication protocols for 7 days: atenolol 6.25 mg/cat twice daily, 12.5 mg/cat twice daily, or placebo (biofermin) 1 tab/cat twice daily. In study 2, cats with HCM were retrospectively recruited and divided into four groups according to atenolol administration [(control group (Cont) or atenolol administration group (Ate)] and the presence or absence of LAE as follows: Cont LAE (-) group (n=42), Cont LAE (+) group (n=20), Ate LAE (-) group (n=17), and Ate LAE (+) group (n=12). LV and LA functions were compared in both studies. LV and LA functions were decreased by atenolol administration in study 1. In study 2, the peak myocardial velocity during early diastole (E') was significantly decreased in the Cont LAE (+), Ate LAE (-), and Ate LAE (+) groups compared to that in the Cont LAE (-) group, but there were no significant differences between LAE (+) groups. Multivariate logistic analysis revealed that atenolol administration was not associated with LAE. Diastolic dysfunction may be associated with LAE; however, atenolol administration did not affect LAE in cats with HCM.
Topics: Adrenergic beta-1 Receptor Antagonists; Animals; Atenolol; Atrial Function, Left; Atrial Remodeling; Cardiomyopathy, Hypertrophic; Cat Diseases; Cats; Echocardiography; Female; Male; Retrospective Studies; Ventricular Function, Left
PubMed: 32188801
DOI: 10.1292/jvms.19-0670