Effects on cerebral blood flow after single doses of the ß2 agonist, clenbuterol, in healthy volunteers and patients with mild cognitive impairment or Parkinson's disease.

AIMS: Cerebral hypometabolism occurs years prior to a diagnosis of neurodegenerative diseases and coincides with reduced cerebral perfusion and declining noradrenergic transmission from the locus coeruleus. In pre-clinical models, ß-adrenoceptor (ß-AR) agonists increase cerebrocortical glucose metabolism, and may have therapeutic potential for neurodegenerative diseases. This study investigated the safety and effects on regional cerebral blood flow (rCBF) of the oral, brain-penetrant ß2-AR agonist, clenbuterol, in healthy volunteers (HV) and patients with mild cognitive impairment (MCI) or Parkinson's disease (PD). METHODS: This study evaluated the safety and effects on cerebral activity of the oral, brain-penetrant, ß2-AR agonist clenbuterol (20-160 µg) in healthy volunteers and patients with MCI or PD. Regional CBF, which is tightly coupled to glucose metabolism, was measured by arterial spin labelling MRI in 32 subjects (25 HV and 8 MCI or PD) across five cohorts. In some cohorts, low doses of nadolol (1-5 mg), a ß-AR antagonist with minimal brain penetration, were administered with clenbuterol to control peripheral ß2-AR responses. RESULTS: Significant, dose-dependent increases in rCBF were seen in multiple brain regions, including hippocampus, amygdala and thalamus, following the administration of clenbuterol to HVs (mean changes from baseline in hippocampal rCBF of -1.7%, 7.3%, 22.9%, 28.4% 3 h after 20, 40, 80 and 160 µg clenbuterol, respectively). In patients with MCI or PD, increases in rCBF following 80 µg clenbuterol were observed both without and with 5 mg nadolol (in hippocampus, 18.6%/13.7% without/with nadolol). Clenbuterol was safe and well-tolerated in all subjects; known side effects of ß2-agonists, including increased heart rate and tremor, were mild in intensity and were blocked by low-dose nadolol. CONCLUSIONS: The effects of clenbuterol on rCBF were evident both in the absence and presence of low-dose nadolol, suggesting central nervous system (CNS) involvement. Concomitant inhibition of the peripheral effects of clenbuterol by nadolol confirms that meaningful ß2-AR antagonism in the periphery was achieved without interrupting the central effects of clenbuterol on rCBF.

An International Multicenter Cohort Study on ß-Blockers for the Treatment of Symptomatic Children With Catecholaminergic Polymorphic Ventricular Tachycardia.

BACKGROUND: Symptomatic children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. ß-Blockers decrease this risk, but studies comparing individual ß-blockers in sizeable cohorts are lacking. We aimed to assess the association between risk for arrhythmic events and type of ß-blocker in a large cohort of symptomatic children with CPVT. METHODS: From 2 international registries of patients with CPVT, RYR2 variant-carrying symptomatic children (defined as syncope or sudden cardiac arrest before ß-blocker initiation and age at start of ß-blocker therapy <18 years), treated with a ß-blocker were included. Cox regression analyses with time-dependent covariates for ß-blockers and potential confounders were used to assess the hazard ratio (HR). The primary outcome was the first occurrence of sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter-defibrillator shock, or syncope. The secondary outcome was the first occurrence of any of the primary outcomes except syncope. RESULTS: We included 329 patients (median age at diagnosis, 12 [interquartile range, 7-15] years, 35% females). Ninety-nine (30.1%) patients experienced the primary outcome and 74 (22.5%) experienced the secondary outcome during a median follow-up of 6.7 (interquartile range, 2.8-12.5) years. Two-hundred sixteen patients (66.0%) used a nonselective ß-blocker (predominantly nadolol [n=140] or propranolol [n=70]) and 111 (33.7%) used a ß1-selective ß-blocker (predominantly atenolol [n=51], metoprolol [n=33], or bisoprolol [n=19]) as initial ß-blocker. Baseline characteristics did not differ. The HRs for both the primary and secondary outcomes were higher for ß1-selective compared with nonselective ß-blockers (HR, 2.04 [95% CI, 1.31-3.17]; and HR, 1.99 [95% CI, 1.20-3.30], respectively). When assessed separately, the HR for the primary outcome was higher for atenolol (HR, 2.68 [95% CI, 1.44-4.99]), bisoprolol (HR, 3.24 [95% CI, 1.47-7.18]), and metoprolol (HR, 2.18 [95% CI, 1.08-4.40]) compared with nadolol, but did not differ from propranolol. The HR of the secondary outcome was only higher in atenolol compared with nadolol (HR, 2.68 [95% CI, 1.30-5.55]). CONCLUSIONS: ß1-selective ß-blockers were associated with a significantly higher risk for arrhythmic events in symptomatic children with CPVT compared with nonselective ß-blockers, specifically nadolol. Nadolol, or propranolol if nadolol is unavailable, should be the preferred ß-blocker for treating symptomatic children with CPVT.

Photocatalytic Activity of the V2O5 Catalyst toward Selected Pharmaceuticals and Their Mixture: Influence of the Molecular Structure on the Efficiency of the Process.

Due to the inability of conventional wastewater treatment procedures to remove organic pharmaceutical pollutants, active pharmaceutical components remain in wastewater and even reach tap water. In terms of pharmaceutical pollutants, the scientific community focuses on ß-blockers due to their extensive (over)usage and moderately high solubility. In this study, the photocatalytic activity of V2O5 was investigated through the degradation of nadolol (NAD), pindolol (PIN), metoprolol (MET), and their mixture under ultraviolet (UV) irradiation in water. For the preparation of V2O5, facile hydrothermal synthesis was used. The structural, morphological, and surface properties and purity of synthesized V2O5 powder were investigated by scanning electron microscopy (SEM), X-ray, and Raman spectroscopy. SEM micrographs showed hexagonal-shaped platelets with well-defined morphology of materials with diameters in the range of 10−65 µm and thickness of around a few microns. X-ray diffraction identified only one crystalline phase in the sample. The Raman scattering measurements taken on the catalyst confirmed the result of XRPD. Degradation kinetics were monitored by ultra-fast liquid chromatography with diode array detection. The results showed that in individual solutions, photocatalytic degradation of MET and NAD was relatively insignificant (<10%). However, in the PIN case, the degradation was significant (64%). In the mixture, the photodegradation efficiency of MET and NAD slightly increased (15% and 13%). Conversely, it reduced the PIN to the still satisfactory value of 40%. Computational analysis based on molecular and periodic density functional theory calculations was used to complement our experimental findings. Calculations of the average local ionization energy indicate that the PIN is the most reactive of all three considered molecules in terms of removing an electron from it.

Clinical pharmacokinetics of nadolol: A systematic review.

WHAT IS KNOWN AND OBJECTIVE: Nadolol is a non-selective beta-adrenergic antagonist that is used for the treatment of hypertension and angina. The primary route for its administration is oral. It is given once daily as it has a longer half-life (t½). The purpose of conducting this systematic review is to provide a comprehensive view of all the available pharmacokinetic (PK) data on nadolol in humans. This review aimed to systematically collate and analyze publish data on the clinical PK of nadolol in humans and this can be beneficial for the clinicians in dosage adjustments. METHODS: Two electronic databases PubMed and Google Scholar were used for conducting a systematic literature search. All the relevant articles containing PK data of nadolol in humans were retrieved. A total of 1275 articles were searched from both databases and after applying eligibility criteria finally, 22 articles were included for conducting the systematic review. RESULTS AND DISCUSSION: The area under the plasma concentration curve (AUC) and maximum plasma concentration (Cmax ) of nadolol increased in a dose-dependent manner. The t½ of nadolol was increased to double (18.2-68.6 h) in the patients with chronic kidney disease while the serum t½ became shorter (3.2-4.3 h) when administered to the children. The bioavailability of nadolol was greatly reduced by the coadministration of green tea. Nadolol can be effectively removed by hemodialysis. It undergoes enterohepatic circulation thus activated charcoal decreased its bioavailability. WHAT IS NEW AND CONCLUSION: Since, there is no previous report of a systematic review on the PK of nadolol, the current review encompasses all the relevant published articles on nadolol in humans. The analysis and understanding of PK parameters (AUC, Cmax , and t½) of nadolol may be helpful in the development and evaluation of PK models.

The cytotoxic and apoptotic effects of beta-blockers with different selectivity on cancerous and healthy lung cell lines.

ß-blockers having specific affinities to ß-adrenergic receptors are routinely used to treat cardiovascular problems. Additionally, it has been demonstrated that these drugs can be effective in treating apoptosis-related diseases. The current study was conducted to investigate the cytotoxic and apoptotic effects of ß-1 selective esmolol, ß-2 selective ICI-118,551, and non-selective nadolol blockers on the cancerous and healthy lung cells. MTT test was used to evaluate cytotoxicity. Apoptotic actions were examined by using Annexin V-FITC/PI assay, JC-1 staining, ROS test, and the determination of the caspase-4 and -9, Bcl-2, Bax, Bax/Bcl-2, and JNK levels. Although the MRC-5 showed greater resistance than A549 cells, the ß-blockers at 150-250 µM exhibited different levels of cytotoxic effect on both lung cell lines. Esmolol was found to be the most ineffective blocker and the increases in Bcl-2 protein levels were appeared to be effective in resistance to this drug. The increases in reactive oxygen species (ROS) together with the increase in caspase-4 and Bax protein levels have been shown to play a role in ICI-118,551 induced lung cell death. Nadolol was the most effective blocker increasing the total apoptotic cell population in both lung cells, which was based on both mitochondrial and endoplasmic reticulum stress. When the selectivities of the ß-blockers are considered, it seems that ß-2 specific antagonism predominantly mediated the death of lung cells, and the overwhelming factors causing apoptosis mainly varied depending on the selectivity of the blockers.

Effects of single green tea ingestion on pharmacokinetics of nadolol in healthy volunteers.

AIMS: The aim of this study was to investigate the effects of a single green tea (GT), administered concomitantly or 1 hour before nadolol intake on nadolol pharmacokinetics. METHODS: In a randomized 3-phase crossover study, 11 healthy volunteers received an oral administration of nadolol with, or 1 hour after preingestion of brewed GT, or with water in a volume of 150 mL. RESULTS: Geometric mean ratio with 90% confidence interval for nadolol AUC0-48 was 0.371 (0.303-0.439) with concomitant GT. In addition, ingestion of GT 1 hour before nadolol administration resulted in a significant reduction of nadolol AUC0-48 with geometric mean ratio of 0.536 (0.406-0.665). There were no differences in time to maximal plasma concentration and renal clearance of nadolol among groups. CONCLUSION: These results suggest that single concomitant ingestion of GT substantially decreases plasma concentrations of nadolol. Moreover, the reduction in nadolol bioavailability could persist for at least 1 hour after drinking a cup of GT.

Use of beta-blockers for rosacea-associated facial erythema and flushing: A systematic review and update on proposed mode of action.

BACKGROUND: Flushing and erythema are frequent skin symptoms in rosacea. Because their adequate treatment remains a clinical challenge, new treatment options are explored, such as oral ß-blockers. OBJECTIVES: To evaluate the efficacy of oral ß-blockers for rosacea-associated facial flushing and erythema. METHODS: PubMed, Embase, Web of Science, and Cochrane Library were systematically searched, including studies providing original data on the efficacy of oral ß-blockers in rosacea patients with facial flushing and/or persistent erythema. Risk of bias was assessed using the Cochrane Risk of Bias tool, Newcastle-Ottawa scale, and Quality in Prognosis Studies tool. RESULTS: Nine studies evaluating the use of carvedilol, propranolol, nadolol, and ß-blockers in general were included. Articles studying carvedilol and propranolol showed a large reduction of erythema and flushing during treatment with a rapid onset of symptom control. Bradycardia and hypotension were the most commonly described adverse events. LIMITATIONS: Most studies had a retrospective design with a small sample size, and outcome measurement was often subjective. CONCLUSIONS: Oral ß-blockers could be an effective treatment option for patients with rosacea with facial erythema and flushing that does not respond to conventional therapy. Larger prospective trials with objective outcome assessment are needed to validate the promising results of these studies.

Use of Nonselective ß-Blockers in Patients With End-Stage Liver Disease and Select Complications.

Objective: To review the literature and recommendations for nonselective ß-blockers (NSBBs) in the setting of variceal bleeding prophylaxis and decompensated liver disease. Data Sources: Literature search of MEDLINE was performed (1988 to October 2019) using the following search terms: cirrhosis, advanced cirrhosis, ß-blocker, decompensation, prophylaxis. Abstracts, peer-reviewed publications, clinical practice guidelines, and product monographs were reviewed. Study Selection and Data Extraction: Relevant English language studies and those conducted in humans were considered for analysis and inclusion. Data Synthesis: Evidence that suggests that NSBBs are harmful in advanced cirrhosis is overshadowed by confounding variables and small patient populations. The majority of the available evidence suggests neutral or beneficial effects on mortality with continuation of NSBBs despite liver disease progression. Based on the available literature, guidelines, and expert consensuses, NSBBs can be considered within this patient population and may have a positive impact on the majority of these patients. Relevance to Patient Care and Clinical Practice: This review summarizes current place in therapy for NSBBs in the setting of cirrhosis and variceal bleeding prophylaxis. It also includes a discussion of the literature for use of NSBBs within the setting of different acute decompensations in which the data and recommendations for use are less clear. Conclusions: Recent evidence shows neutral or positive results for NSBB use in particular decompensation subgroups, which suggests that NSBBs can be used cautiously with close monitoring in patients with advanced cirrhosis. Questions still remain regarding optimal agent and dose and whether agents can be safely restarted after an acute decompensation episode.

Improving the performance of nadolol stereoisomers' preparative separation using Chiralpak IA by SMB chromatography.

The pseudobinary preparative separation of nadolol stereoisomers is performed by simulated moving bed chromatography (SMB). Using the Chiralpak IA adsorbent, a new 25:75:0.1 (v/v/v) methanol-acetonitrile-diethylamine solvent composition was selected to perform the experimental SMB separation and compare it with the previous results obtained using pure methanol. Using a 2 g L-1 total feed concentration of an equimolar mixture of the four stereoisomers of nadolol, the more retained component was fully recovered (100% purity and 100% recovery), with a system productivity of 0.77 g L-1  hour-1 and a solvent consumption of 9.62 L g-1 . Comparing these results with the ones previously reported using 100:0.1 methanol-diethylamine solvent composition, this work shows that the 25:75:0.1 methanol-acetonitrile-diethylamine is a better alternative for the preparative separation of nadolol stereoisomers by SMB chromatography. These results are confirmed by simulation of the SMB operation for higher feed concentrations, by comparing the performances of the two solvent compositions using the data obtained experimentally through the measurement of the adsorption equilibrium isotherms and the kinetic data obtained for both solvents. The new experimental and simulation results stress out that the performance of the preparative separation can be improved by a careful selection of the solvent composition.

ß2-Adrenergic receptor signaling mediates the preferential mobilization of differentiated subsets of CD8+ T-cells, NK-cells and non-classical monocytes in response to acute exercise in humans.

Acute exercise preferentially mobilizes cytotoxic T-cells, NK-cells and non-classical monocytes to the bloodstream under the influence of hemodynamic forces and/or ß2-adrenergic receptor (ß2-AR) signaling. However, the relative contribution of these mechanisms to the redeployment of the most exercise-responsive cell types is largely unknown. We determined the lymphocyte and monocyte subtypes mobilized to blood during exercise via ß2-AR signaling whilst controlling for ß1-AR mediated reductions in hemodynamic forces. In a randomized, double blind, complete cross-over design, 14 healthy cyclists exercised for 30-minutes at +10% of blood lactate threshold after ingesting: (1) a placebo, (2) a ß1-preferential antagonist (10 mg bisoprolol), or (2) a non-preferential ß1 + ß2-antagonist (80 mg nadolol) across three trials separated by >7-days. Bisoprolol was administered to reduce hemodynamic forces (heart rate and blood pressure) during exercise to levels comparable with nadolol but without blocking ß2-ARs. The mobilization of total NK-cells, terminally differentiated (CD57+) NK-cells, central memory, effector memory and CD45RA+ effector memory CD8+ T-cells; non-classical monocytes; and γδ T-cells were significantly blunted or abrogated under nadolol compared to both bisoprolol and placebo, indicating that the exercise-induced mobilization of these cell types to the blood is largely influenced by ß2-AR signaling. Nadolol failed to inhibit the mobilization of classical monocytes, CD4+ T-cells (and their subsets) or naïve CD8+ T-cells, indicating that these cell types are mobilized with exercise independently of the ß2-AR. We conclude that the preferential mobilization of NK-cells, non-classical monocytes and differentiated subsets of CD8+ T-cells with exercise is largely dependent on catecholamine signaling through the ß2-AR. These findings provide mechanistic insights by which distinct lymphocyte and monocyte subtypes are preferentially mobilized to protect the host from anticipated injury or infection in response to an acute stress response.

Vigorous exercise mobilizes CD34+ hematopoietic stem cells to peripheral blood via the ß2-adrenergic receptor.

Acute dynamic exercise mobilizes CD34+ hematopoietic stem cells (HSCs) to the bloodstream, potentially serving as an economical adjuvant to boost the collection of HSCs from stem cell transplant donors. The mechanisms responsible for HSC mobilization with exercise are unknown but are likely due to hemodynamic perturbations, endogenous granulocyte-colony stimulating factor (G-CSF), and/or ß2-adrenergic receptor (ß2-AR) signaling. We characterized the temporal response of HSC mobilization and plasma G-CSF following exercise, and determined the impact of in vivo ß-AR blockade on the exercise-induced mobilization of HSCs. Healthy runners (n = 15) completed, in balanced order, two single bouts of steady state treadmill running exercise at moderate (lasting 90-min) or vigorous (lasting 30-min) intensity. A separate cohort of healthy cyclists (n = 12) completed three 30-min cycling ergometer trials at vigorous intensity after ingesting: (i) 10 mg bisoprolol (ß1-AR antagonist); (ii) 80 mg nadolol (ß1 + ß2-AR antagonist); or (iii) placebo, in balanced order with a double-blind design. Blood samples collected before, during (runners only), immediately after, and at several points during exercise recovery were used to determine circulating G-CSF levels (runners only) and enumerate CD34+ HSCs by flow cytometry (runners and cyclists). Steady state vigorous but not moderate intensity exercise mobilized HSCs, increasing the total blood CD34+ count by ∼4.15 ±â€¯1.62 Δcells/µl (+202 ±â€¯92%) compared to resting conditions. Plasma G-CSF increased in response to moderate but not vigorous exercise. Relative to placebo, nadolol and bisoprolol lowered exercising heart rate and blood pressure to comparable levels. The number of CD34+ HSCs increased with exercise after the placebo and bisoprolol trials, but not the nadolol trial, suggesting ß2-AR signaling mediated the mobilization of CD34+ cells [Placebo: 2.10 ±â€¯1.16 (207 ±â€¯69.2%), Bisoprolol 1.66 ±â€¯0.79 (+163 ±â€¯29%), Nadolol: 0.68 ±â€¯0.54 (+143 ±â€¯36%) Δcells/µL]. We conclude that the mobilization of CD34+ HSCs with exercise is not dependent on circulating G-CSF and is likely due to the combined actions of ß2-AR signaling and hemodynamic shear stress.

Role of (-)-epigallocatechin gallate in the pharmacokinetic interaction between nadolol and green tea in healthy volunteers.

PURPOSE: The aim of the present study is to investigate a possible role of a single dose of (-)-epigallocatechin gallate (EGCG), the major catechin in green tea, for the pharmacokinetic interaction between green tea and nadolol in humans. METHODS: In a randomized three-phase crossover study, 13 healthy volunteers received single doses of 30 mg nadolol orally with water (control), or an aqueous solution of EGCG-concentrated green tea extract (GTE) at low or high dose. Plasma concentrations and urinary excretion of nadolol were determined up to 48 h. In addition, blood pressure and pulse rate were monitored. In vitro transport kinetic experiments were performed using human embryonic kidney 293 cells stably expressing organic anion transporting polypeptide (OATP)1A2 to evaluate the inhibitory effect of EGCG on OATP1A2-mediated substrate transport. RESULTS: Single coadministration of low and high dose GTE significantly reduced the plasma concentrations of nadolol. The geometric mean ratios with 90% CI for area under the plasma concentration-time curves from 0 to infinity of nadolol were 0.72 (0.56-0.87) for the low and 0.60 (0.51-0.69) for the high dose. There were no significant differences in Tmax, elimination half-life, and renal clearance between GTE and water phases. No significant changes were observed for blood pressure and pulse rate between phases. EGCG competitively inhibited OATP1A2-mediated uptake of sulphobromophthalein and nadolol with Ki values of 21.6 and 19.4 µM, respectively. CONCLUSIONS: EGCG is suggested to be a key contributor to the interaction of green tea with nadolol. Moreover, even a single coadministration of green tea may significantly affect nadolol pharmacokinetics.

The Nonmetabolized ß-Blocker Nadolol Is a Substrate of OCT1, OCT2, MATE1, MATE2-K, and P-Glycoprotein, but Not of OATP1B1 and OATP1B3.

Nadolol is a nonmetabolized ß-adrenoceptor antagonist and is a substrate of OATP1A2, but not of OATP2B1. However, other drug transporters involved in translocation of nadolol have not been characterized in detail. We therefore investigated nadolol as a potential substrate of the hepatic uptake transporters OATP1B1, OATP1B3, and OCT1 and of the renal transporters OCT2, MATE1, and MATE2-K expressed in HEK cells. Moreover, the importance of P-glycoprotein (P-gp) for nadolol transport was studied using double transfected MDCK-OCT1-P-gp cells. Nadolol was not transported by OATP1B1 and OATP1B3. In contrast, a significantly higher nadolol accumulation (at 1 and 10 µM) was found in OCT1, OCT2, MATE1, and MATE2-K cells compared to control cells (P < 0.01). Km values for OCT2-, MATE1-, and MATE2-K-mediated nadolol uptake were 122, 531, and 372 µM, respectively. Cimetidine (100 µM, P < 0.01) and trimethoprim (100 µM, P < 0.001) significantly inhibited OCT1-, OCT2-, MATE1-, and MATE2-K-mediated nadolol transport. The P-gp inhibitor zosuquidar significantly reduced basal to apical nadolol transport in monolayers of MDCK-OCT1-P-gp cells. In summary, nadolol is a substrate of the cation transporters OCT1, OCT2, MATE1, MATE2-K, and of P-gp. These data will aid future in vivo studies on potential transporter-mediated drug-drug or drug-food interactions with involvement of nadolol.

Separation of Nadolol Stereoisomers Using Chiralpak IA Chiral Stationary Phase.

Chiralpak IA adsorbent is used for both analytical and preparative chromatographic separation of nadolol stereoisomers. The results include a complete screening of the mobile phase composition for both the baseline resolution of all four nadolol stereoisomers (analytical separation) and the simulated moving bed (SMB) pseudo-binary separation of the most retained stereoisomer. The experimental results show that analytical baseline resolution of nadolol stereoisomers can be achieved using alcohol/hydrocarbon and alcohol/acetonitrile solvent mixtures. The 10%ethanol/90%acetonitrile mixture is presented as the one that presents baseline resolution with lower retention. For the preparative pseudo-binary separation, pure ethanol, pure methanol, alcohol/acetonitrile, and alcohol/tetrahydrofuran mixtures proved to allow good separation results. The 100%methanol/0.1%diethylamine solvent composition was selected to perform the experimental SMB separation. Using a 10 g/L total feed concentration, the more retained stereoisomer was recovered at the extract outlet stream with 99.5% purity, obtaining a system productivity of 1.98 gL(-1)  h(-1) and requiring a solvent consumption of 3.13 L/g of product. Comparing these results with the ones recently presented by Ribeiro et al. (2013), this work shows that the Chiralpak IA chiral adsorbent is an interesting alternative to Chiralpak AD for the separation of nadolol stereoisomers at both analytical and preparative scales. Chirality 28:399-408, 2016. © 2016 Wiley Periodicals, Inc.

Nadolol Attenuates Brain Cell Ferroptosis in Ischemic Stroke Rats by Targeting the HOIL-1/IRP2 Pathway.

INTRODUCTION: Heme-oxidized iron regulatory protein 2 (IRP2) ubiquitin ligase-1 (HOIL-1) is believed to contribute to the ubiquitination of IRP2, which facilitates the transcription of transferrin receptor 1 (TfR1) while preventing the transcription of ferroportin-1 (FPN-1). Bioinformatics analysis predicts that nadolol (a ß-blocker) interacts with the HOIL-1. METHOD: The present study is intended to explore whether nadolol suppresses ferroptosis in the brains of rats suffering from ischemic stroke via targeting the HOIL-1/IRP2 pathway. A rat model of ischemic stroke was established by blocking the middle cerebral artery for 2 h plus 24 h reperfusion, and nadolol (2.5 or 5 mg/kg) was given at 1h after reperfusion. HT22 cells were subjected to 12 h of hypoxia, followed by 24 h of reoxygenation for simulating ischemic stroke, and nadolol (0.1 or 0.25 µM) was administered to the culture medium before reoxygenation. RESULTS: The stroke rats showed evident brain injury (increases in neurological deficit score and infarct volume) and ferroptosis, along with up-regulation of IRP2 and TfR1 while downregulation of HOIL-1 and FPN-1; these phenomena were reversed in the presence of nadolol. In the cultured HT22 cells, hypoxia/reoxygenation-induced LDH release, ferroptosis, and changes in the levels of relevant proteins (IRP2, TfR1, HOIL-1, and FPN-1) were also reversed by nadolol. CONCLUSION: In terms of these findings, it is concluded that nadolol can protect the ischemic rats' brains against ferroptosis by targeting the HOIL-1/IRP2 pathway, thereby preventing intracellular iron overload. Thus, nadolol may be a novel indication for treating patients with ischemic stroke.

A Comprehensive Physiologically Based Pharmacokinetic Model of Nadolol in Adults with Renal Disease and Pediatrics with Supraventricular Tachycardia.

Nadolol is a long-acting non-selective ß-adrenergic antagonist that helps treat angina and hypertension. The current study aimed to develop and validate the physiologically based pharmacokinetic model (PBPK) of nadolol in healthy adults, renal-compromised, and pediatric populations. A comprehensive PBPK model was established by utilizing a PK-Sim simulator. After establishing and validating the model in healthy adults, pathophysiological changes i.e., blood flow, hematocrit, and GFR that occur in renal failure were incorporated in the developed model, and the drug exposure was assessed through Box plots. The pediatric model was also developed and evaluated by considering the renal maturation process. The validation of the models was carried out by visual predictive checks, calculating predicted to observed (Rpre/obs) and the average fold error (AFE) of PK parameters i.e., the area under the concentration-time curve (AUC0-t), the maximum concentration in plasma (Cmax), and CL (clearance). The presented PBPK model successfully simulates the nadolol PK in healthy adults, renal-impaired, and pediatric populations, as the Rpre/obs values of all PK parameters fall within the acceptable range. The established PBPK model can be useful in nadolol dose optimization in patients with renal failure and children with supraventricular tachycardia.

Carvedilol Versus Other Nonselective Beta Blockers for Variceal Bleeding Prophylaxis and Death: A Network Meta-analysis.

Background and Aims: We aimed to perform a network meta-analysis (NWM) to examine comparative effectiveness of non-selective beta blockers (NSBBs) on prophylaxis of gastroesophageal variceal bleeding (GVB) and mortality benefit. Methods: MEDLINE (OVID) and EMBASE databases were searched for eligible randomized clinical trials (RCTs) from inception to July 3, 2021. Outcomes of interest included primary/secondary prophylaxis of GVB, failure to achieve hepatic venous pressure gradient (HVPG) decremental response, liver-related and all-cause mortality. A Bayesian NWM was performed to derive relative risk (RR) with 95% credible intervals (CrIs). The ranking probability of each NSBB was assessed by surface under cumulative ranking curve (SUCRA). Results: Thirty-three RCTs including 3,188 cirrhosis patients with gastroesophageal varices were included. Compared with placebo, nadolol ranked first for reducing variceal bleeding [RR:0.25, (95% CrI:0.11-0.51); SUCRA:0.898], followed by carvedilol [RR:0.33, (95% CrI: 0.11-0.88); SUCRA:0.692] and propranolol [RR:0.52, (95% CrI:0.37-0.75); SUCRA:0.405]. Carvedilol was more effective than propranolol in achieving HVPG decremental response [RR:0.43, (95% CrI: 0.26-0.69)]. Carvedilol ranked first for reducing all-cause mortality [RR: 0.32, (95% CrI:0.17-0.57); SUCRA:0.963), followed by nadolol [RR:0.48, (95% CI:0.29-0.77); SUCRA:0.688], and propranolol [RR:0.77, (95% CI:0.58-1.02); SUCRA: 0.337]. Similar findings were observed for liver-related mortality. Carvedilol ranked the safest. The RR of adverse events was 4.38, (95% CrI:0.33-161.4); SUCRA:0.530, followed by propranolol [RR: 7.54, (95% CrI:1.90-47.89); SUCRA:0.360], and nadolol [RR: 18.24, (95% CrI:91.51-390.90); SUCRA:0.158]. Conclusions: Carvedilol is the preferred NSBB with better survival benefit and lower occurrence of adverse events among patients with gastroesophageal varices.

Urinary Excretion of Nadolol as a Possible In Vivo Probe for Drug Interactions Involving P-Glycoprotein.

Nadolol is a hydrophilic and nonselective ß-adrenoceptor blocker with a bioavailability of 30%, relatively longer half-life, negligible metabolism, and predominant renal excretion. Previous studies have reported that nadolol is a substrate of P-glycoprotein, and the coadministration with itraconazole, a typical P-glycoprotein inhibitor, results in elevated plasma concentrations and cumulative urinary excretion of nadolol. In this study, we assessed whether measurements of urinary-excreted nadolol can be an alternative method of plasma pharmacokinetics for P-glycoprotein-mediated drug interactions in humans. We reanalyzed the pooled data set of plasma concentration and urinary excretion of nadolol from our previous clinical studies in a total of 32 healthy Japanese adults. The area under the plasma concentration-time curve from 0 to infinity (AUC0-∞ ) of nadolol in individual subjects was significantly correlated with the maximum plasma concentration (r = 0.80, P < .01) and the cumulative amount excreted into urine (Ae ) at 4 (r = 0.51, P = .01), 8 (r = 0.63, P < .01), 24 (r = 0.75, P < .01), and 48 (r = 0.77, P < .01) hours. Significant correlations were also observed between the AUC and Ae during the same respective periods. In the drug interactions of nadolol with itraconazole, rifampicin, a well-known P-glycoprotein inducer, or grapefruit juice, there were significant correlations between the differences in AUC0-48 and those in Ae, 0-48 from the controls in individual subjects. These results suggest that the measurements of urinary excretion of nadolol can be employed as a sensitive and reliable alternative to plasma pharmacokinetics for the evaluation of P-glycoprotein-mediated drug interactions.

Oral epigallocatechin gallate reduces intestinal nadolol absorption via modulation of Oatp1a5 and Oct1 transcriptional levels in spontaneously hypertensive rats.

BACKGROUND: Concurrent use of epigallocatechin-3-gallate (EGCG) and medication may lead to botanical-drug interactions, subsequently therapeutic failure or drug toxicity. It has been reported that EGCG reduces plasma nadolol bioavailability in normotensive models. Nevertheless, evidence on the effects of EGCG on hypertensive model, and the possible underlying mechanism have not been elucidated. OBJECTIVES: This study aims (i) to investigate the effects of EGCG on nadolol pharmacokinetics (maximum plasma concentration, time to achieve maximum concentration, area under the time-plasma concentration curve, plasma half-life and total clearance) and subsequently its impact on blood pressure control; and (ii) to identify transcriptional regulatory roles of EGCG on the nadolol intestinal and hepatic drug-transporters in SHR. METHODS: Male SHR were pre-treated with a daily dose of EGCG (10 mg/kg body weight, i.g.) for 13 days. On day-14, a single dose of nadolol (10 mg/kg body weight) was given to the rats 30 min after the last dose of EGCG administration. Systolic blood pressure (SBP) was measured at 6-h and 22-h post-nadolol administration. Plasma and urinary nadolol concentrations were quantified using high-performance liquid chromatography, and pharmacokinetic parameters were analyzed by using non-compartmental analysis. Hepatic and ileal Oatp1a5, P-gp, and Oct1 mRNA expressions were determined by real-time PCR. RESULTS: SBP of SHR pre-treated with EGCG and received nadolol was significantly higher than those which were not pre-treated with EGCG but received nadolol. Pre-treatment of EGCG resulted in a marked reduction of plasma nadolol maximum concentration (Cmax) and area under the time-plasma concentration curve (AUC) by 53% and 51% compared to its control. The 14-day treatment with oral EGCG led to a significant downregulation of mRNA levels of ileal Oatp1a5, P-gp, and Oct1 genes by 4.03-, 8.01- and 4.03-fold; and hepatic P-gp, and Oct1 genes by 2.61- and 2.66-fold. CONCLUSION: These data concluded that exposure to EGCG could lead to reduced nadolol bioavailability and therefore, uncontrolled raised blood pressure and higher risks of cardiovascular events. Our data suggest that the reduced nadolol bioavailability is associated with the downregulation of ileal Oatp1a5 and Oct1 mRNA levels that subsequently lead to poor absorption of nadolol to the systemic circulation.

Dose response to nadolol in congenital long QT syndrome.

BACKGROUND: Beta-blocker therapy is the cornerstone of treatment for patients with long QT syndrome (LQTS). Few details on the dose to be used are available. As the response is variable between patients, we systematically evaluated the effect of treatment by performing an exercise test. OBJECTIVE: The purpose of this study was to explore dose response to nadolol on exercise test in LQTS patients in order to propose a more personalized therapeutic approach. METHODS: LQTS patients followed at the Reference Centre for Hereditary Arrhythmic Diseases of Nantes with at least 1 exercise test under nadolol were included retrospectively between 1993 and 2017. All patients underwent gradual cycle exercise tests. Doses adjusted to weight and response to treatment were recorded and evaluated by the percentage of age-predicted maximum heart rate reached on exercise test. RESULTS: Ninety-five patients were included in the study, and 337 stress tests under nadolol were analyzed. No correlation existed between dose and percentage of age-predicted maximum heart rate on exercise tests. Twenty-one patients were overresponders, mostly LQTS1, and 20 were underresponders, mainly LQTS2 (P = .0229). Forty-two patients had at least 3 stress tests under nadolol. We found a negative correlation between dose change and percentage of age-predicted maximum heart rate change (P <.0001). We then proposed a table to adapt dose according to exercise test response. CONCLUSION: Our study demonstrated a major variability of dose response to nadolol in patients with LQTS, thus underlining the need for a tailored dosage for each patient. Intraindividual analysis showed a relatively constant dose-response relationship, allowing guided dose adaptation after the first exercise test.