SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Explore the source record for details and available documents.
The association beta-blockers plus nitrates has been reported to impair renal function and renal sodium handling, leading to increased risk of development of ascites, or worsening of a preexisting ascites, or increase in the requirements of diuretic agents. In 81 patients with cirrhosis and esophageal varices, participating in a multicenter controlled clinical trial of prophylaxis of variceal bleeding comparing nadolol (NAD) plus isosorbide-5-mononitrate (I5M) with NAD alone, renal function, presence of ascites, and diuretic requirements were assessed at inclusion and after 6 months of follow-up. No significant variation in s-urea or s-creatinine was observed in either group, Three patients in the nadolol group and two in the NAD plus I5M developed ascites at 6 months (P = .70), and a need to increase diuretic regimen was observed in four and three patients, respectively (P = .76). Decrease in heart rate and in mean arterial pressure was similar in the two groups. There was a significant correlation between increases in s-creatinine and decrease in mean arterial pressure in the whole series (P = .015). Only in patients treated with the association was there a significant larger proportion of patients ascitic who became anascitic, than of patients anascitic who became ascitic (P = .03). In patients treated with the association, there was a significantly larger decrease in hepatic venous pressure gradient (P = .05). It is concluded that patients treated with the association NAD plus I5M are not at increased risk of developing renal dysfunction or worsening of ascites compared with patients treated with NAD alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
We examined the clinical efficacy and safety of intravenous nadolol acutely, as well as chronic nadolol alone or combined with a type IA antiarrhythmic drug in 19 patients with sustained ventricular tachycardia and heart disease, mean age 62 +/- 15 years, and mean left ventricular ejection fraction 39 +/- 8%. Patients underwent electrophysiological studies in the drug-free state (control), after intravenous nadolol (dose = 0.05 mg/kg), and oral nadolol (dose = 80 mg/day) for 5 days alone or in combination with a type IA antiarrhythmic drug. Electrocardiographic and electrophysiological effects as well as ventricular tachycardia induction at electrophysiological study were analyzed. Long-term therapy with oral nadolol alone or in combination with a type IA antiarrhythmic drug was evaluated in responders. Intravenous nadolol prolonged RR and QRS intervals but had no effect on PR and QTc intervals. Oral nadolol alone tended to prolong RR intervals (P = 0.08). Oral nadolol with type IA antiarrhythmic drug prolonged RR and QTc intervals (P less than 0.001). The mean right ventricular effective refractory period tended to prolong after intravenous nadolol alone (from 251 +/- 29 to 263 +/- 25 msec, P = 0.08). Oral nadolol and type IA antiarrhythmic drugs did not prolong right ventricular effective refractory period (P = 0.3). Eighteen patients had inducible sustained ventricular tachycardia at control electrophysiological study. After intravenous nadolol, ventricular tachycardia was no longer inducible in seven patients. Ventricular tachycardia did not recur and remained noninducible in two of six patients who tolerated oral nadolol alone. Mean right ventricular effective refractory period prolonged from baseline values (from 249 +/- 30 to 271 +/- 30 msec, P less than 0.02) in patients who became noninducible on intravenous nadolol. In patients who remained inducible, mean right ventricular effective refractory period remained unchanged (from 253 +/- 29 to 258 +/- 22 msec, P greater than 0.2). In nonresponders to intravenous or oral nadolol, oral nadolol, and type IA antiarrhythmic drug suppressed ventricular tachycardia induction in two of ten patients. During follow-up, three patients continued on oral nadolol alone (one patient) or oral nadolol and type IA antiarrhythmic drug (two patients). Adverse effects resulting in nadolol discontinuation occurred in five patients. Therefore, we concluded that intravenous nadolol is effective in acute suppression of inducible ventricular tachycardia in selected patients. Oral nadolol alone or in combination with type IA antiarrhythmic drug is infrequently effective and poorly tolerated by this patient population. In addition, electrophysiological studies on intravenous nadolol do not predict the outcome of oral nadolol therapy.
This study was carried out to assess whether nadolol undergoes enterohepatic circulation. Eight healthy subjects received 80 mg nadolol orally on three occasions at least 2 wk apart. The first experiment was a control. The second consisted of nadolol followed in 3 hr by 3 gm activated charcoal given over a 9-hr period. In the third, the subjects received 0.5 gm erythromycin base and 0.5 gm neomycin four times a day orally for 2 days before nadolol. After the activated charcoal, the nadolol AUC fell from 2455 +/- 155 to 1355 +/- 123 ng . hr/ml (mean +/- SE), as did the percentage nadolol recovered in urine (15.4 +/- 1.4 to 10.2 +/- 0.7%) and the nadolol t1/2 (17.3 +/- 1.7 to 11.8 +/- 1.6 hr). These data suggest that nonrenal elimination increased. After the antibiotics, nadolol AUC was constant, percentage of nadolol recovered in urine fell to 12.7 +/- 1.7%, nadolol t1/2 fell to 11.6 +/- 1.3 hr, and mean peak nadolol concentration rose from 146 +/- 15 to 397 +/- 52 ng/ml. These results suggest that there is an enterohepatic circulation for nadolol, that activated charcoal may decrease nadolol bioavailability, and that antibiotics may increase the nadolol effect.
Diacetyl nadolol, a prodrug of nadolol and a beta-blocker, has corneal permeability approximately 20 times higher than that of its parent compound due to its higher lipophilicity. Hydrolysis studies were conducted for diacetyl nadolol at various elevated temperatures and pH values to provide stability information for its ophthalmic preparations. The apparent rate constants for diacetyl nadolol hydrolysis to acetyl nadolols and nadolol were determined. Within the neutral pH range (6.8 to 8.2), the hydrolysis of diacetyl nadolol may be proposed as specific base catalysis. Various constants for diacetyl nadolol hydrolysis to acetyl nadolols and acetyl nadolols to nadolol were respectively listed as following: activation energy, 9.78 and 11.39 kcal/mol; entropy at 25 degrees C, -9.78 and -5.86 cal/mol.deg; second-order rate constant at 75 degrees C, 3.47 X 10(4) and 2.22 X 10(4) M-1h-1. According to these kinetic constants, a diacetyl nadolol aqueous solution with pH 6.5 may be prepared as an antiglaucoma agent. The shelf-life was estimated to be only 43 d at room temperature (25 degrees C). However, when the storage temperature is lowered to 5 degrees C, the shelf-life can be extended to greater than 2 years.
The electrocardiographic and electrophysiologic effects, clinical efficacy and safety of intravenous and oral nadolol therapy were examined in 34 patients with recurrent supraventricular tachyarrhythmias (SVT) undergoing electrophysiologic evaluation. Programmed electrical stimulation was performed in the control (drug-free) state, after infusion of intravenous nadolol (mean dose 0.09 +/- 0.03 mg/kg) and after chronic oral nadolol therapy in patients who responded to intravenous nadolol (mean dose 83 +/- 12 mg for 5 days). Intravenous nadolol administration prolonged mean sinus cycle length (p = 0.009), mean PR interval (p = 0.001) and mean AH interval (p = 0.001), with no significant electrophysiologic effects in the atrium, ventricle or accessory bypass tracts. Oral nadolol had similar electrocardiographic and electrophysiologic effects, but of lesser magnitude. Intravenous nadolol resulted in complete suppression of induced SVT in 78% of patients with sinus and atrioventricular nodal reentrant tachycardia and 11% of patients with atrioventricular (AV) reentrant tachycardia (p less than 0.001). Partial responses were frequent in intraatrial or AV reentrant tachycardia (37%). Oral nadolol suppressed induction of SVT in patients who responded to intravenous nadolol. Adverse reactions to intravenous and oral nadolol were infrequent--6% and 8%, respectively--and usually did not require drug withdrawal. Intravenous nadolol is highly effective in sinus and AV nodal reentrant tachycardia, and a successful electrophysiologic response to it predicts efficacy of long-term oral nadolol therapy. It has limited efficacy alone in AV reentrant tachycardia and should be considered in combination with other antiarrhythmic therapy in this type of SVT.
Nadolol, a nonspecific beta-blocker, is a racemate composed of equal amounts of four stereoisomers, namely, SQ-12148, SQ-12149, SQ-12150, and SQ-12151. In an open-label, randomized, four-period crossover study, the pharmacokinetics of nadolol and its stereoisomers and the bioequivalence of two formulations of nadolol were assessed in 20 healthy male subjects following a single dose (80 mg) and multiple doses (80 mg; once daily for 7 days). A standard granulated tablet and direct compressed tablet formulations, each containing 80 mg of nadolol, with different in vitro dissolution profiles that met current USP requirements were used. The four treatments were single and multiple doses of granulated tablet, and single and multiple doses of compressed tablet. There was a 7 day washout period between successive treatments. All doses of nadolol were administered after an overnight fast. Serial blood samples were collected up to 72 h following the single dose and during multiple dose treatments, following day 6 and 7 doses. Validated high-performance liquid chromatographic assays were applied to measure nadolol and its stereoisomers in the study samples. Plasma concentration data were subjected to noncompartmental pharmacokinetic analysis. Both C(max) and AUC values were significantly greater for SQ-12150 when compared to other nadolol stereoisomers obtained after a single dose or at steady state. However, T(max) and T1/2 values were similar among the four isomers. The observed steady state AUC tau values for nadolol (2278-2331 ng h/ML) or its stereoisomers (550-874 ng h/ML) were significantly greater than those predicted from the single dose AUCinf values (nadolol, 1840-1845 ng h/ML; isomers, 450-713 ng h/ML). The intrasubject variability, computed from multiple dose data, was generally greater for the stereoisomers (17-40%) than for nadolol (10-32%). The two formulations were bioequivalent for nadolol (C(max) = 0.98 [84%, 117%]; AUCinf = 1.03 [93%, 116%]) and SQ-12150 (C(max) = 1.12 [89%, 122%]; AUCinf = 0.98 [82%, 119%]) after a single dose, and only for nadolol (C(max) = 1.07 [84%, 118%]; AUCinf = 1.02 [91%, 113%]) at steady state.
BACKGROUND: The risk of having a first cirrhosis-associated variceal bleed is lowered by about 50% by beta-blockers. Use of beta-blockers is currently recommended for patients with cirrhosis and oesophageal varices that are at risk of bleeding. We aimed to test the effectiveness of isosorbide mononitrate as an adjunct to the beta-blocker nadolol in the prophylaxis of first variceal bleeding in these patients. METHODS: We did a randomised multicentre study to compare the non-selective beta-blocker, nadolol, with nadolol plus isosorbide mononitrate in 146 relatively well (Child-Pugh score < or = 11) patients who had oesophageal varices at risk of bleeding. Patients on nadolol alone received a single oral 40 mg daily dose. Every second day the dose was titrated to achieve 20-25% decrease in resting heart rate (maximum dose 160 mg daily). Patients receiving both drugs received nadolol as above then isosorbide mononitrate was added starting with 10 mg orally twice daily, which was increased to 20 mg unless hypotension or severe headache occurred. The main endpoint was the occurrence of variceal bleeding of any severity. Patients were followed up for up to 40 months. FINDINGS: During the study period 11 of 74 patients from the nadolol alone group and four of 72 from the nadolol plus isosorbide mononitrate group had variceal bleeding (log-rank test p = 0.03). Cumulative risk of variceal bleeding was 18% in the nadolol group and 7.5% in the combined treatment group (95% CI for difference 1-25%). Two patients in each group had a non-variceal bleed related to portal hypertension. 14 patients from the nadolol only group and eight from the combined treatment group died during the study period (log-rank test p = 0.09). Four and eight patients, respectively, had to discontinue one of the drugs because of side-effects. INTERPRETATION: Nadolol plus isosorbide mononitrate is significantly more effective than nadolol alone in the primary prophylaxis of variceal bleeding in relatively well patients with cirrhosis, and has few side-effects.
On topical application to rabbit eyes, the diacetate ester of nadolol was more easily absorbed into ocular tissue than nadolol and was enzymatically hydrolyzed to nadolol within the eye. In a 24-hour clinical study, the ocular hypotensive activities of 0.5% diacetyl nadolol, 2% diacetyl nadolol, 2% nadolol, and 0.5% timolol maleate in subjects with open-angle glaucoma or ocular hypertension were compared. Both concentrations of diacetyl nadolol significantly reduced intraocular pressure during the first six hours. Two percent diacetyl nadolol was as effective as 0.5% timolol maleate during the first eight hours. During the remainder of the testing period, timolol showed greater IOP control. Two percent diacetyl nadolol and 2% nadolol showed similar ocular hypotensive effects both in magnitude and duration in this short-term study.
The efficacy and tolerability of amlodipine 2.5-10 mg once daily was compared with nadolol 40-160 mg once daily in a long-term double-blind parallel-group study in patients with stable exertional angina pectoris. A total of 80 patients were randomized to receive amlodipine or nadolol for 26 weeks after a 2-week single-blind placebo run-in period. The effects of amlodipine and nadolol on total exercise time were minimal and not significantly different. However, amlodipine produced a slightly but not significantly greater increase in time to onset of angina than nadolol (+21% amlodipine; +8% nadolol). No significant differences were noted between amlodipine and nadolol on ST-segment depression, angina attack rate, or nitroglycerin consumption. A slightly greater improvement was attained after amlodipine on patient and investigator assessments of treatments. A statistically significant difference (p < 0.0001) was found between treatments on the effects on myocardial oxygen requirements (as assessed by the rate pressure product). Nadolol produced a reduction of 29% compared with a slight reduction of 4% with amlodipine. Fewer side effects were reported with amlodipine (43%) than with nadolol (83%) (p < 0.0001), resulting in discontinuation of therapy in three amlodipine and four nadolol patients. Long-term treatment with amlodipine and nadolol produced comparable effects in patients with angina pectoris, with fewer side effects being reported after treatment with amlodipine.
OBJECTIVES: The aim of this study was to determine whether therapy with a beta-adrenergic or calcium channel blocking agent can improve the functional capacity and quality of life of patients with mild or moderately symptomatic hypertrophic cardiomyopathy. BACKGROUND: Both beta-blockers and calcium channel blockers may alleviate symptoms in hypertrophic cardiomyopathy, but previous studies have been performed in hospitalized patients or have been open studies without control subjects. METHODS: A randomized, double-blind crossover trial of nadolol, verapamil and placebo, administered for periods of 4 weeks each, was performed in 18 patients with mild or moderately symptomatic hypertrophic cardiomyopathy (10 men, 8 women; mean age +/- SD 39 +/- 17 years). A detailed symptom assessment, bicycle exercise testing, echocardiography and Holter monitoring were performed in each period. RESULTS: Two patients withdrew from the study owing to symptomatic sinus bradycardia during nadolol therapy. Neither drug improved maximal oxygen consumption (placebo 26 +/- 8, verapamil 23 +/- 6, nadolol 21 +/- 7 ml/kg per min; p = 0.1). Peak exercise work load was reduced by > or = 10 W in 13 patients (81%) during nadolol therapy and in 4 patients (25%) during verapamil therapy (p = 0.005, nadolol vs. verapamil). Despite the effects on exercise capacity, 13 patients (81%) preferred drug treatment (8 verapamil, 5 nadolol) over placebo (p = 0.001). Verapamil improved reported performance at work compared with nadolol (p = 0.01) and tended to improve other measures of health-related behavior and symptoms compared with nadolol and placebo. CONCLUSIONS: In patients with mild or moderately symptomatic hypertrophic cardiomyopathy, exercise capacity was not improved by nadolol or verapamil, and individuals were more often impaired by nadolol than with verapamil. Nevertheless, many patients derived symptomatic benefit from drug therapy, especially with verapamil.
The efficacy and safety of oral nadolol in supraventricular tachycardia were evaluated prospectively in 27 children (median age 5.5 years). Fifteen patients had an unsuccessful trial of digoxin therapy. Intravenous nadolol was given to seven patients during electrophysiologic study; five of these had an excellent response and two had a partial response (25% decrease in tachycardia rate). Six of these patients had a similar response to oral nadolol. Twelve patients received both propranolol and nadolol. Among six patients, intravenous propranolol was successful in four and unsuccessful in two; all six had a similar response to oral nadolol. With oral propranolol, tachycardia was well controlled in four patients and persistent in two; five of five patients had a similar response to oral nadolol. Twenty-six patients were treated with oral nadolol; the arrhythmia was well controlled in 23, 2 had recurrent tachycardia and 1 patient had tachycardia at a 25% slower rate. The effective dose of nadolol ranged between 0.5 and 2.5 mg/kg body weight once daily (median dose 1 mg/kg per day). During follow-up (3 to 36 months), compliance and tolerance were excellent; excluding 2 patients with reactive airway disease who developed wheezing, only 3 (12%) of 24 had side effects necessitating a change in drug therapy. Once a day nadolol is a safe and effective agent in the management of supraventricular tachycardia in children. Its long-term efficacy can be predicted by the short-term response to intravenous nadolol or propranolol during programmed electrophysiologic study.
The association beta-blockers plus isosorbide-5-mononitrate (I5M) has been proposed for the treatment of portal hypertension in patients with insufficient response to beta-blockers alone, according to hemodynamic criteria. The mechanism of action in these patients is not clearly defined. Fifteen patients with cirrhosis and esophageal varices were evaluated by hepatic venous pressure gradient (HVPG) measurement and duplex-Doppler ultrasonography before and after 1 month of treatment with nadolol. Nine patients who did not exhibit a decrease in HVPG to 12 mm Hg or a percent decrease greater than 20% were classified as poor responders, and were studied again with the same methodology after 3 months of chronic administration of nadolol + I5M 20 mg twice per day. In poor responders, mean HVPG decrease after nadolol was 8.9% +/- 2.8%, and after the combination, it was 25.7% +/- 1.7% (P = .004). All patients except one became good responders to the association. Portal blood flow (PBF) decreased significantly after nadolol (P = .004), and remained unchanged after the addition of nitrates. Resistance to portal blood flow (RPBF) increased after nadolol (P = .02) and returned to baseline values during combined treatment (P = .03). In good responders, an adequate decrease in HVPG was associated with a decrease in PBF (P = .06) but no change in RPBF. A wide spectrum of combined changes in PBF and in RPBF after nadolol was observed in poor responders, ranging from no change in either parameter to a marked decrease in PBF counterbalanced by a marked increase in RPBF. The addition of I5M was followed in most cases by larger effects on resistance than on flow. Doppler parameters were not significantly correlated with the HVPG response to nadolol alone or associated with I5M. It is concluded that good hemodynamic responders to nadolol differ from poor responders in the lack of increase in RPBF after the drug. The addition of nitrates to nadolol is effective in decreasing portal pressure in most poor responders to nadolol alone. A decrease in outflow resistance is the main mechanism involved.
We used standard microelectrode techniques to determine developmental differences in the direct membrane and beta-blocking effects of nadolol on the electrophysiologic properties of adult and neonatal canine Purkinje fibers (PF). To study direct membrane effects, we superfused PF with nadolol 1 X 10(-8)-1 X 10(-4) M while stimulating them at a BCL of 800 ms. Nadolol less than 1 X 10(-5) M had no effect on the transmembrane potential in either age group. Nadolol, greater than or equal to 1 X 10(-5) M, increased action potential duration at 100% repolarization (APD100) in adult fibers and nadolol, 1 X 10(-4) M, decreased Vmax and APD at 50% repolarization (APD50) in neonatal fibers (p less than 0.05). The beta-blocking effects of nadolol were studied by examining the chronotropic response in automatic PF to cumulative doses of l-isoproterenol.HCl 3 X 10(-10)-3 X 10(-6) M, alone and then in the continued presence of nadolol 5 X 10(-8)-5 X 10(-6) M. Nadolol caused a concentration-dependent shift to the right of the concentration-response curve in both age groups. pA2 determinations in adult (7.88) and neonatal (7.57) PF indicated that there was no developmental difference in the affinity of nadolol for the beta-receptor (p greater than 0.05). Our results indicate that nadolol shows developmental changes in its direct membrane effects but not its beta-blocking effects. The latter characteristic differs from that of the more highly lipid-soluble beta-blocker, propranolol. This suggests that different beta-blocking molecules have differing abilities to block the beta-receptor at different ages that are influenced importantly by their lipid solubility.
Nadolol, a new nonselective beta 1 and beta 2 adrenergic blocking agent, has a plasma half-life of 17 to 23 hours. We studied 37 volunteers with stable angina pectoris who had five or more episodes of pain per week and who also had a 1 mm or greater ST segment depression 80 msec past the J point during a Bruce protocol treadmill test. An eight-week placebo controlled run-in period preceded double-blind randomization to nadolol administered once per day (17 patients) or identical appearing placebo for four weeks (20 patients), after which an exercise test was done. Diaries for pain episodes and nitroglycerin consumption were kept. Exercise tests were performed 24 hours after the last nadolol or placebo dose. Episodes of pain per week were reduced 59.8 percent after nadolol and 28.2 percent after placebo (P less than .01). Nitroglycerin consumption after nadolol was reduced 66.8 percent while after placebo it was reduced 36.2 percent (P less than .05). Resting and peak heart rates and peak rate-pressure products showed typical reductions due to beta-blockade 24 hours after nadolol compared with stability of these during placebo, all P less than .001. Exercise time after nadolol increased 42.2 percent, which was more than the 14.5 percent increase after placebo (P less than .05). Exercise work after nadolol increased 64.7 percent, greater than the 22 percent increase after placebo (P less than .05). Mean ST segment depression at end of exercise was little changed before and after treatment in both groups, reflecting consistency of effort. Improvement in symptoms and work capacity associated with nadolol significantly exceeded the placebo group responses. Unlike other available agents of this class, a single daily dose of nadolol produced therapeutically effective 24-hour beta-blockade in patients with disabling angina pectoris.