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.

Noninferiority and Safety of Nadolol vs Propranolol in Infants With Infantile Hemangioma: A Randomized Clinical Trial.

Importance: Propranolol for infantile hemangiomas (IH) has been shown to be effective and relatively safe. However, other less lipophilic ß-blockers, such as nadolol, may be preferable in individuals who experience propranolol unresponsiveness or adverse events. Objective: To document the noninferiority and safety of oral nadolol compared with oral propranolol in infants with IH. Design, Setting, and Participants: This double-blind noninferiority prospective study with a noninferiority margin of 10% compared propranolol with nadolol in infants aged 1 to 6 months with problematic IH. The study was conducted in 2 academic pediatric dermatology centers in Canada between 2016 and 2020. Infants aged 1 to 6 months with a hemangioma greater than 1.5 cm on the face or 3 cm or greater on another body part causing or with potential to cause functional impairment or cosmetic disfigurement. Interventions: Oral propranolol and nadolol in escalating doses up to 2 mg/kg/d. Main Outcomes and Measure: Between-group differences comparing changes in the bulk (size and extent) and color of the IH at week 24 with baseline using a 100-mm visual analog scale. Results: The study included 71 patients. Of these, 36 were treated with propranolol. The mean (SD) age in this group was 3.1 (1.4) months, and 31 individuals (86%) were female. Thirty-five infants were treated with nadolol. The mean (SD) age in this group was 3.2 (1.6) months, and 26 individuals (74%) were female. The difference in IH between groups by t test was 8.8 (95% CI, 2.7-14.9) for size and 17.1 (95% CI, 7.2-30.0) for color in favor of the nadolol group, demonstrating that nadolol was noninferior to propranolol. Similar differences were noted at 52 weeks: 6.0 (95% CI, 1.9-10.1) and 10.1 (95% CI, 2.9-17.4) for size and color improvement, respectively. For each doubling of time unit (week), the coefficient of involution was 2.4 (95% CI, 0.5-4.4) higher with nadolol compared with propranolol. Safety data were similar between the 2 interventions. Conclusions and Relevance: Oral nadolol was noninferior to oral propranolol, indicating it may be an efficacious and safe alternative in cases of propranolol unresponsiveness or adverse events, or when faster involution is required. Trial Registration: ClinicalTrials.gov Identifier: NCT02505971.

Propranolol versus nadolol for treatment of pediatric subglottic hemangioma.

PURPOSE: The beta-blocker propranolol is the standard medical therapy for subglottic hemangioma (SGH), but side effects and incomplete response rates require close monitoring. Nadolol has been identified as a potential alternative but its use has not been examined for SGH. METHODS: Single institution retrospective cohort study of pediatric SGH treated with propranolol or nadolol. RESULTS: Thirteen children (1 male, 12 female) with SGH were included: 6 were treated with propranolol (2.0-3.5 mg/kg/d) and 7 with nadolol (2.0-4.0 mg/kg/d). The most common presenting symptom was stridor (85%) and mean (SD) symptom duration prior to diagnosis was 4.6 (3.8) weeks. Cutaneous vascular lesions were present in 54%. There were 7 right-sided, 5 left-sided and 1 bilateral SGH. The mean (SD) percentage of airway obstruction was 60.6% (27.4). The response rate was 100% (6/6) for propranolol and 85.7% (6/7) for nadolol (p = 0.36). Mean (SD) time to symptomatic improvement was 2.6 (2.2) days with no difference across groups (p = 0.71). There was no hypotension, hypoglycemia, weight loss, or sleep disturbances in either group. One patient in the propranolol group experienced vomiting. Two patients in the nadolol group required dosage reduction due to asymptomatic bradycardia. The mean (SD) duration of admission was 14.4 (12.6) days and duration of treatment was 13.8 (11.2) days with no difference across groups (p = 0.23; p = 0.31, respectively). All patients had treatment initiated as inpatients and completed as outpatients. CONCLUSION: Children with SGH treated with propranolol or nadolol had similar response rates and side effect profiles.

Severe hypoglycemia in children treated with nadolol: A case report and FDA adverse event reporting system (FAERS) database analysis.

OBJECTIVE: We describe a case of severe hypoglycemia in a 14-month-old child as a suspected adverse drug reaction (ADR) to nadolol, and we performed an analysis of the FDA Adverse Event Reporting System (FAERS) database. Although previous reports have identified the risk of severe hypoglycemia in children during treatment with ß-blockers, little is known about hypoglycemia as an ADR in infants treated with nadolol. Moreover, the pharmacodynamic and pharmacokinetic profiles of nadolol in children aged less than 1 year old are still not fully known. MATERIALS AND METHODS: We extracted all ADR reports involving nadolol from the FAERS database; in order to reduce the risk of bias, we only considered cases that exclusively reported nadolol as the suspect drug. We then selected cases of hypoglycemia in the pediatric population and conducted a manual deduplication. RESULTS: Upon FAERS database analysis, a total of 2,674 suspected ADR reports to nadolol were found. Of these, 1,950 (73%) were solely attributed to nadolol, and 63 of them were hypoglycemic events. A total of 47 reports included the relevant pediatric age (74.6%). After deduplication, we identified 25 cases (mean age: 3.65 years old); all of these reports were categorized as serious, and hospitalization was required in 15 cases. CONCLUSION: Hypoglycemia is a reported life-threatening ADR associated with nadolol, especially in infants, in whom this drug should be used with caution.

Death Associated With Nadolol for Infantile Hemangioma: A Case for Improving Safety.

Nadolol is a ß-adrenergic antagonist that has been shown to be efficacious in the treatment of infantile hemangioma. It has been suggested that this drug may have fewer side effects compared with the gold standard therapy, propranolol, because it does not exhibit membrane-stabilizing effects and has little ability to cross the blood-brain barrier. However, the pharmacokinetics and safety of nadolol in infants are not well understood, potentially making this therapy dangerous. ß-adrenergic antagonist toxicity causes bradycardia, hypotension, hypoglycemia, and even death. We report a case of a 10-week-old girl who was started on nadolol for infantile hemangioma, died 7 weeks later, and was found to have an elevated postmortem cardiac blood nadolol level of 0.94 mg/L. The infant had no bowel movements for 10 days before her death, which we hypothesize contributed to nadolol toxicity. Pharmacokinetics studies show a large fraction of oral nadolol either remains in the feces unchanged or is excreted into feces via the biliary system, allowing continued absorption over time in infants who stool infrequently. Propranolol may be a safer therapy overall. Not only does it have a shorter half-life, but propranolol is hepatically metabolized and renally eliminated, allowing for less drug accumulation in healthy infants with variable stooling patterns. We suggest that if nadolol is selected for therapy, pediatricians should instruct parents to monitor their infants' bowel movements closely and encourage early intervention in the event of decreased stooling. This intervention may greatly improve the safety of nadolol in this vulnerable patient population.

Carvedilol versus traditional, non-selective beta-blockers for adults with cirrhosis and gastroesophageal varices.

BACKGROUND: Non-selective beta-blockers are recommended for the prevention of bleeding in people with cirrhosis, portal hypertension and gastroesophageal varices. Carvedilol is a non-selective beta-blocker with additional intrinsic alpha1-blocking effects, which may be superior to traditional, non-selective beta-blockers in reducing portal pressure and, therefore, in reducing the risk of upper gastrointestinal bleeding. OBJECTIVES: To assess the beneficial and harmful effects of carvedilol compared with traditional, non-selective beta-blockers for adults with cirrhosis and gastroesophageal varices. SEARCH METHODS: We combined searches in the Cochrane Hepato-Biliary's Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, and Science Citation Index with manual searches. The last search update was 08 May 2018. SELECTION CRITERIA: We included randomised clinical trials comparing carvedilol versus traditional, non-selective beta-blockers, irrespective of publication status, blinding, or language. We included trials evaluating both primary and secondary prevention of upper gastrointestinal bleeding in adults with cirrhosis and verified gastroesophageal varices. DATA COLLECTION AND ANALYSIS: Three review authors (AZ, RJ and LH), independently extracted data. The primary outcome measures were mortality, upper gastrointestinal bleeding and serious adverse events. We undertook meta-analyses and presented results using risk ratios (RR) or mean differences (MD), both with 95% confidence intervals (CIs), and I2 values as a marker of heterogeneity. We assessed bias control using the Cochrane Hepato-Biliary domains and the quality of the evidence with GRADE. MAIN RESULTS: Eleven trials fulfilled our inclusion criteria. One trial did not report clinical outcomes. We included the remaining 10 randomised clinical trials, involving 810 participants with cirrhosis and oesophageal varices, in our analyses. The intervention comparisons were carvedilol versus propranolol (nine trials), or nadolol (one trial). Six trials were of short duration (mean 6 (range 1 to 12) weeks), while four were of longer duration (13.5 (6 to 30) months). Three trials evaluated primary prevention; three evaluated secondary prevention; while four evaluated both primary and secondary prevention. We classified all trials as at 'high risk of bias'. We gathered mortality data from seven trials involving 507 participants; no events occurred in four of these. Sixteen of 254 participants receiving carvedilol and 19 of 253 participants receiving propranolol or nadolol died (RR 0.86, 95% CI 0.48 to 1.53; I2 = 0%, low-quality evidence). There appeared to be no differences between carvedilol versus traditional, non-selective beta-blockers and the risks of upper gastrointestinal bleeding (RR 0.77, 95% CI 0.43 to 1.37; 810 participants; 10 trials; I2 = 45%, very low-quality evidence) and serious adverse events (RR 0.97, 95% CI 0.67 to 1.42; 810 participants; 10 trials; I2 = 14%, low-quality evidence). Significantly more deaths, episodes of upper gastrointestinal bleeding and serious adverse events occurred in the long-term trials but there was not enough information to determine whether there were differences between carvedilol and traditional, non-selective beta-blockers, by trial duration. There was also insufficient information to detect differences in the effects of these interventions in trials evaluating primary or secondary prevention. There appeared to be no differences in the risk of non-serious adverse events between carvedilol versus its comparators (RR 0.55, 95% CI 0.23 to 1.29; 596 participants; 6 trials; I2 = 88%; very low-quality evidence). Use of carvedilol was associated with a greater reduction in hepatic venous pressure gradient than traditional, non-selective beta-blockers both in absolute (MD -1.75 mmHg, 95% CI -2.60 to -0.89; 368 participants; 6 trials; I2 = 0%; low-quality evidence) and percentage terms (MD -8.02%, 95% CI -11.49% to -4.55%; 368 participants; 6 trials; I2 = 0%; low-quality evidence). However, we did not observe a concomitant reduction in the number of participants who failed to achieve a sufficient haemodynamic response (RR 0.76, 95% CI 0.57 to 1.02; 368 participants; 6 trials; I2 = 42%; very low-quality evidence) or in clinical outcomes. AUTHORS' CONCLUSIONS: We found no clear beneficial or harmful effects of carvedilol versus traditional, non-selective beta-blockers on mortality, upper gastrointestinal bleeding, serious or non-serious adverse events despite the fact that carvedilol was more effective at reducing the hepatic venous pressure gradient. However, the evidence was of low or very low quality, and hence the findings are uncertain. Additional evidence is required from adequately powered, long-term, double-blind, randomised clinical trials, which evaluate both clinical and haemodynamic outcomes.

Nadolol for Treatment of Supraventricular Tachycardia in Infants and Young Children.

Supraventricular tachycardia (SVT) is a common infant arrhythmia, for which beta-blockers are frequently chosen as therapy. Propranolol is a common choice though it is dosed every 6-8 h. We reviewed the clinical results of treating infant SVT with an extemporaneous preparation of nadolol. Retrospective cohort study of patients under 2 years old receiving nadolol for SVT at a single center. Patients were ascertained by patient and pharmacy databases. Twenty-eight infants received nadolol, of whom 25 had regular narrow complex tachycardia, 2 atrial flutter, and 1 focal atrial tachycardia. Patient age at initiation was a median 54 days (range 10-720). The final dose was 1 mg/kg/day in 22/28 patients (range 0.5-2). Once-daily dosing was used in 20 patients (71.4%); dosing was BID in 7, TID in 1. Among regular narrow complex tachycardia patients, 18/25 received nadolol monotherapy and 7 required additional agents; flecainide in 6, digoxin in 1. The median age of tachyarrhythmia onset was 18 days (range 1-180) with a median age of nadolol initiation of 30 days (range 11-390). Of the 20 regular narrow complex tachycardia patients initiated on nadolol monotherapy, 85% had no recurrences as of 1-year follow-up. Side effects were suspected in 3 of 28 (10.7%), including wheezing (n = 1, 3.5%), irritability and diarrhea (n = 1, 3.5%), and bradycardia (n = 1, 3.5%). Oral nadolol suspension was a successful treatment for SVT in 85% of patients with minimal adverse effects. Single daily dosing was used in the majority of patients.

Nadolol reduces insulin sensitivity in liver cirrhosis: a randomized double-blind crossover trial.

BACKGROUND: Liver cirrhosis is frequently complicated by portal hypertension leading to increased mortality from variceal bleeding and hepatic decompensation. Noncardioselective ß-blockers not only reduce portal hypertension and prevent variceal bleeding in cirrhosis but also impair glucose tolerance and insulin sensitivity in other settings. This study aimed to determine whether nonselective ß-blockade with nadolol impairs glucose metabolism in liver cirrhosis. METHODS: A randomized, double-blind, placebo-controlled crossover trial of nadolol in cirrhotic patients examined insulin sensitivity, disposition index, and glucose tolerance. Stable cirrhotic patients of mixed etiology underwent an intravenous glucose tolerance test and hyperinsulinemic-euglycemic clamp for the measurement of insulin secretion and insulin sensitivity (n = 16) and a 75-g oral glucose tolerance test (n = 17). These measurements were conducted twice (after 3 months of treatment with nadolol or placebo and, after a 1-month washout period, after 3 months on the alternative treatment). Total body fat and plasma catecholamines were measured at the end of each 3-month treatment. RESULTS: Compared with placebo, nadolol treatment reduced insulin sensitivity (79.7 ± 10.1 vs 99.6 ± 10.3 µL/kg fat-free mass·min-1 ·(mU/L)-1 , P = .005). Insulin secretion was unchanged (P = .24), yielding a lower disposition index with nadolol (6083 ± 2007 vs 8692 ± 2036, P = .050). There was no change in total body fat or plasma catecholamines. A 2-hour plasma glucose concentration from the oral glucose tolerance test was higher on nadolol than placebo (10.8 ± 0.9 vs 9.9 ± 0.9 mmol/L, P = .035). CONCLUSIONS: Nadolol significantly worsened insulin sensitivity, glycemia, and disposition index in patients with liver cirrhosis. These findings may have significant clinical implications because cirrhosis is already associated with an increased prevalence of diabetes.

Nadolol decreases the incidence and severity of ventricular arrhythmias during exercise stress testing compared with ß1-selective ß-blockers in patients with catecholaminergic polymorphic ventricular tachycardia.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inheritable cardiac disease predisposing to malignant ventricular arrhythmias. OBJECTIVE: We aimed to explore the incidence and severity of ventricular arrhythmias in patients with CPVT before the initiation of ß-blocker treatment, when treated with ß1-selective ß-blockers, and when treated with nadolol. METHODS: In this study, 34 patients with CPVT were included (mean age 34 ± 19 years; 15 (44%) women; 30 (88%) ryanodine receptor 2 variant positive). We performed 3 bicycle exercise stress tests in each patient: (1) before the initiation of ß-blocker treatment, (2) after >6 weeks of treatment with ß1-selective ß-blockers and (3) after >6 weeks of treatment with nadolol. We recorded resting and maximum heart rates and the most severe ventricular arrhythmia occurring. Severity of arrhythmias was scored as 1 point for no arrhythmias or only single ventricular extrasystoles, 2 points for >10 ventricular extrasystoles per minute or bigeminy, 3 points for couplets, and 4 points for nonsustained ventricular tachycardia or sustained ventricular tachycardia. RESULTS: Resting heart rate was similar during treatment with nadolol and ß1-selective ß-blockers (54 ± 10 beats/min vs 56 ± 14 beats/min; P = .50), while maximum heart rate was lower during treatment with nadolol compared with ß1-selective ß-blockers (122 ± 21 beats/min vs 139 ± 24 beats/min; P = .001). Arrhythmias during exercise stress testing were less severe during treatment with nadolol compared with during treatment with ß1-selective ß-blockers (arrhythmic score 1.6 ± 0.9 vs 2.5 ± 0.8; P < .001) and before the initiation of ß-blocker treatment (arrhythmic score 1.6 ± 0.9 vs 2.7 ± 0.9; P = .001); however, no differences were observed during treatment with ß1-selective ß-blockers compared with before the initiation of ß-blocker treatment (arrhythmic score 2.5 ± 0.8 vs 2.7 ± 0.9; P = .46). CONCLUSION: The incidence and severity of ventricular arrhythmias decreased during treatment with nadolol compared with during treatment with ß1-selective ß-blockers. ß1-Selective ß-blockers did not change the occurrence or severity of arrhythmias compared with no medication.

Oral Nadolol for the Treatment of Infantile Hemangiomas: A Single-Institution Retrospective Cohort Study.

BACKGROUND: Beta-blockers have become the treatment of choice for problematic infantile hemangiomas (IHs). Nadolol, a nonselective beta-blocker with potential dosing advantages and a better safety profile than that of other beta-blockers, has been studied as an alternative therapeutic option. Our objective was to characterize the efficacy and safety of oral nadolol in the treatment of proliferating IHs. METHODS: A retrospective cohort study was conducted at the Hospital for Sick Children between February 2010 and April 2012 in patients treated with nadolol for proliferating IHs causing functional impairment or cosmetic disfigurement. The primary outcome was the percentage involution measured independently by two assessors who scored changes in the extent of IHs by comparing serial photographs using a 100-mm visual analogue scale (VAS), on which 5 mm represented 10% change. RESULTS: Forty-four patients treated with nadolol for IHs with adequate photographic documentation were identified. The median age at presentation was 4.5 months (interquartile range 1.5-7.9 mos). There was a mean improvement of 91.8 ± 11.1%. At least 50% improvement was noted in 42 (95%) patients and 75% improvement in 39 (89%) patients. The mean time to 50% and 75% improvement was 2.9 and 3.7 months, respectively. Analysis of variance showed that younger age at the time of treatment start was associated with a higher mean VAS score (% involution) (p < 0.05). Treatment duration (mean 9.5 ± 5.6 months) had no significant effect on VAS score. Test of interobserver correlation showed good agreement (intraclass correlation coefficient = 0.86, p = 0.001). CONCLUSIONS: Oral nadolol is efficacious in patients with problematic IHs. Further large-scale prospective comparative studies are warranted to compare nadolol with other beta-blockers.

Frequency and severity of hypoglycemia in children with beta-blocker-treated long QT syndrome.

BACKGROUND: Hypoglycemia is a potential side effect of beta-blockers; however, no cases have been reported in children with long QT syndrome (LQTS). OBJECTIVE: The purpose of this study was to determine the frequency and severity of hypoglycemia among children with beta-blocker-treated LQTS. METHODS: A retrospective study was performed to identify children with LQTS evaluated from 2000 to 2014 who developed symptomatic hypoglycemia while being treated with a beta-blocker. RESULTS: Nine children (3%; 7 boys; average corrected QT interval 486 ± 35 ms) developed 13 episodes (0.005 events per 100 treatment years) of beta-blocker-associated hypoglycemia (mean initial glucose 21 ± 7 mg/dL), including 3 of 157 patients with LQTS type 1 (LQT1; 1.9%) and 6 of 105 with LQTS type 2 (LQT2; 5.7%). The mean age at hypoglycemic event was 3.5 ± 2 years (range 7 months to 9 years), involving nadolol in 6 cases (mean dose 1.4 ± 0.2 mg/kg/d) and propranolol in 3 (mean dose 2.7±1 mg/kg/d). Hypoglycemic events were more frequent in patients with LQT2 than in those with LQT1 (10 vs. 3 events; P = .02). Hypoglycemia-triggered seizures were observed in 6 patients, fasting ketoacidosis in 5, and 7 patients required hospitalization (mean of 3 ± 2 days). Decreased caloric intake before the event was identified in all patients and a concomitant viral infection in 3. CONCLUSION: This is the largest single-center case series of beta-blocker-induced hypoglycemia. Clinicians should be cognizant of hypoglycemia symptoms in younger children during periods of poor appetite and during viral illness, and parents of these children should be educated about the signs and symptoms of hypoglycemia. A potential LQT2-hypoglycemia genotype-phenotype relationship warrants further investigation.

Randomized, controlled trial of carvedilol versus nadolol plus isosorbide mononitrate for the prevention of variceal rebleeding.

BACKGROUND AND AIM: Carvedilol has been shown to be more effective than propranolol in decreasing portal pressure. Sufficient data from controlled trials remains limited. This trial compared the relative safety and efficacy between carvedilol and nadolol plus isosorbide mononitrate in preventing variceal rebleeding. METHODS: After successful control of acute esophageal variceal bleeding, eligible patients were randomized to the carvedilol group, 61 patients, using carvedilol 6.25-12.5 mg daily or the N + I group, 60 patients, using nadolol 40-80 mg plus isorsorbide-5-mononitrate 20 mg daily. The end points were rebleeding from varices, adverse events or death. RESULTS: After a median follow up of 30 months, recurrent upper gastrointestinal bleeding developed in 37 patients (61%) in the carvedilol group and 37 patients (62%) in the N + I group (P = 0.90). Recurrent bleeding from esophageal varices occurred in 31 patients (51%) in the carvedilol group and in 26 patients (43%) in the N + I group (P = 0.46). Recurrent bleeding from gastric varices occurred in two patients (3%) in the carvedilol group and in eight patients (13%) in the N + I group (P = 0.05). Severe adverse events occurred in one patient in the carvedilol group and 17 patients in the N + I group (P < 0.0001). Fifteen patients of the carvedilol group and 17 patients in the N + I group died (P = 0.83). Two patients in the carvedilol group and three patients in the N + I group died of variceal bleeding. CONCLUSIONS: Carvedilol was as effective as nadolol plus isorsorbide-5 -mononitrate mononitrate in the prevention of gastroesophageal variceal rebleeding with fewer severe adverse events and similar survival.

Nadolol plus isosorbide mononitrate alone or associated with band ligation in the prevention of recurrent bleeding: a multicentre randomised controlled trial.

BACKGROUND AND AIMS: Previous clinical trials suggest that adding non-selective beta-blockers improves the efficacy of endoscopic band ligation (EBL) in the prevention of recurrent bleeding, but no study has evaluated whether EBL improves the efficacy of beta-blockers + isosorbide-5-mononitrate. The present study was aimed at evaluating this issue in a multicentre randomised controlled trial (RCT) and to correlate changes in hepatic venous pressure gradient (HVPG) during treatment with clinical outcomes METHODS: 158 patients with cirrhosis, admitted because of variceal bleeding, were randomised to receive nadolol+isosorbide-5-mononitrate alone (Drug: n = 78) or combined with EBL (Drug+EBL; n = 80). HVPG measurements were performed at randomisation and after 4-6 weeks on medical therapy. RESULTS: Median follow-up was 15 months. One-year probability of recurrent bleeding was similar in both groups (33% vs 26%: p = 0.3). There were no significant differences in survival or need of rescue shunts. Overall adverse events or those requiring hospital admission were significantly more frequent in the Drug+EBL group. Recurrent bleeding was significantly more frequent in HVPG non-responders than in responders (HVPG reduction >or=20% or

Clinical trial: a randomized controlled study on prevention of variceal rebleeding comparing nadolol + ligation vs. hepatic venous pressure gradient-guided pharmacological therapy.

BACKGROUND: Hepatic venous pressure gradient (HVPG) monitoring of therapy to prevent variceal rebleeding provides strong prognostic information. Treatment of nonresponders to beta-blockers +/- nitrates has not been clarified. AIM: To assess the value of HVPG-guided therapy using nadolol + prazosin in nonresponders to nadolol + isosorbide-5-mononitrate (ISMN) compared with a control group treated with nadolol + ligation. METHODS: Cirrhotic patients with variceal bleeding were randomized to HVPG-guided therapy (n = 30) or nadolol + ligation (n = 29). A Baseline haemodynamic study was performed and repeated within 1 month. In the guided-therapy group, nonresponders to nadolol + ISMN received nadolol and carefully titrated prazosin and had a third haemodynamic study. RESULTS: Nadolol + prazosin decreased HVPG in nonresponders to nadolol + ISMN (P < 0.001). Finally, 74% of patients were responders in the guided-therapy group vs. 32% in the nadolol + ligation group (P < 0.01). The probability of rebleeding was lower in responders than in nonresponders in the guided therapy group (P < 0.01), but not in the nadolol + ligation group (P = 0.41). In all, 57% of nonresponders rebled in the guided-therapy group and 20% in the nadolol + ligation group (P = 0.05). The incidence of complications was similar. CONCLUSIONS: In patients treated to prevent variceal rebleeding, the association of nadolol and prazosin effectively rescued nonresponders to nadolol and ISMN, improving the haemodynamic response observed in controls receiving nadolol and endoscopic variceal ligation. Our results also suggest that ligation may rescue nonresponders.

Heartbeat dynamics in adrenergic blocker treated conscious beagle dogs.

INTRODUCTION: Adrenergic blockade as a treatment for chronic heart failure (CHF) has proved effective, but its pharmacological mechanism on CHF remains unclear. In the past two decades, studies on heart rate variability (HRV) have reported that CHF patients generally have a reduced temporal complexity in heart rate variability. On the other hand, adrenergic blockers have been shown to restore such complexity. Fractal analysis is a novel and efficient tool to explore the adrenergic blockade effect on HRV. This paper applies the detrended fluctuation analysis (DFA) and multifractal DFA (MF-DFA) methods in an attempt to understand the effect of adrenergic blockade on cardiac dynamics in conscious beagle dogs. METHODS: DFA and MF-DFA analysis are conducted on RR interval data generated from telemetry instrumented dogs receiving a combination of 15 mg/kg nadolol and 5 mg/kg phenoxybenzamine orally administered at the 22nd and 34th hour in a parallel design (n=12). All dogs had approximately 48 h of beat-to-beat heart rate measurements recorded in the left ventricle. Complexity measures for heartbeat series are compared between the blocker and vehicle group. We also compute traditional statistics for HRV and spectral parameters and examine their correlation with fractal analysis. RESULTS: When compared to the vehicle group, the adrenergic blocker group had: 1) longer RR intervals (p=0.02) and lower beat-to-beat variability (p=0.04); 2) decreased low frequency (LF) and high frequency (HF) power (p=0.03), and higher LF-to-HF ratio; 3) larger middle-range scaling exponents (p<0.01); 4) broader multifractal spectra (p=0.03) with higher dominant singularity indices (p=0.02). DISCUSSION: Our results show that 1) adrenergic blockade alters the sympathovagal balance; 2) adrenergic blockers enhance the complexity of the cardiac dynamics; 3) the adrenergic blockade effect on cardiac dynamics is primarily the attenuation of small fluctuations in RR intervals. Fractal analysis also has the potential to be applied to early QT diagnosis.

The safety and effects of the beta-blocker, nadolol, in mild asthma: an open-label pilot study.

Beta-blockers are currently contraindicated in asthma because their acute administration may be associated with worsening bronchospasm. However, their effects and safety with their chronic administration are not well evaluated. The rationale for this pilot study was based on the paradigm shift that was observed with the use of beta-blockers in congestive heart failure, which once contraindicated because of their acute detrimental effects, have now been shown to reduce mortality with their chronic use. We hypothesized that certain beta-blockers may also be safe and useful in chronic asthma therapy. In this prospective, open-label, pilot study, we evaluated the safety and effects of escalating doses of the beta-blocker, nadolol, administered over 9 weeks to 10 subjects with mild asthma. Dose escalation was performed on a weekly basis based on pre-determined safety, lung function, asthma control and hemodynamic parameters. The primary objective was to evaluate safety and secondary objectives were to evaluate effects on airway hyperresponsiveness, and indices of respiratory function. The escalating administration of nadolol was well tolerated. In 8 out of the 10 subjects, 9 weeks of nadolol treatment produced a significant, dose-dependent increase in PC20 that reached 2.1 doubling doses at 40 mg (P<0.0042). However, there was also a dose-independent 5% reduction in mean FEV1 over the study period (P<0.01). We conclude that in most patients with mild asthma, the dose-escalating administration of the beta-blocker, nadolol, is well tolerated and may have beneficial effects on airway hyperresponsiveness. Our findings warrant further testing in future larger trials.

Testing the combination beta-blocker plus topiramate in refractory migraine.

OBJECTIVE: To test treatment combining a beta-blocker plus topiramate in migraine patients previously resistant to the two medications in monotherapy. PATIENTS AND METHODS: Those patients who had not responded to a beta-blocker and topiramate received combined treatment. RESULTS: Fifty-eight patients (47 women, age 25-76 years) received the combined treatment. Thirty-three (57%) met criteria for chronic migraine/medication overuse headache, 18 (31%) for migraine without aura and seven (12%) with aura. Ten (17%) discontinued due to adverse events. Among the 48 patients who tolerated the combination, 36 (75%, 62% of the total series) showed response (>50% reduction in frequency), while 12 (25%) did not. The number of days with headache/month decreased from 15.1 to 6.5 (-57%). Sixteen (44% of responders) showed an excellent (>75%) response. Eighteen patients (38%) experienced a total of 26 adverse events (mild-moderate). CONCLUSIONS: The combination of beta-blocker plus topiramate showed a benefit in around 60% of patients who had not previously responded to monotherapy. Adverse events led to discontinuation in one out of six patients. From these open results, it seems reasonable to recommend this combination, complementary in terms of mechanism of action, as a potential strategy in patients with refractory migraine.