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Effects of propranolol inhalation on the diurnal increase in FEV1 and on propranolol airways responsiveness in atopic subjects with asthma.

BACKGROUND: Propranolol inhalation provocation tests are used to measure indirect airways responsiveness in the investigation of asthma. In this study the effects of repeated propranolol inhalation provocation tests within the same day on normal diurnal variation in the forced expiratory volume in one second (FEV1) and subsequent propranolol airways responsiveness were investigated. METHODS: Fifteen atopic asthmatic subjects were challenged with doubling concentrations of propranolol at 08.00 and 16.00 hours on the same study day and at 16.00 hours on a control day to exclude changes related to normal diurnal variation. RESULTS: Mean (SD) baseline FEV1 at 16.00 hours on the study day was 3.38 (0.23) 1, significantly lower than the value at 16.00 hours on the control day of 3.70 (0.24) 1 (p = 0.001). No differences were found between the geometric mean provocative concentration of propranolol causing a 20% fall in FEV1 (PC20) measured on the study day (08.00 hours, 9.3 mg/ml; 16.00 hours, 11.3 mg/ml) and on the control day (16.00 hours 9.3 mg/ml). CONCLUSIONS: The results suggest that propranolol provocation at 08.00 hours has a long lasting effect on FEV1, thereby counteracting the normal diurnal increase in diameter of the airways. This makes propranolol challenge tests less suitable for studying indirect airways responsiveness in the course of one day. Because the FEV1 does not return to control values, it is not possible to determine whether tachyphylaxis to repeated propranolol challenge with a time interval of up to eight hours occurs.

Adolescent↗

Measurement of propranolol, 4-hydroxypropranolol and propranolol glycol in human plasma.

An HPLC method for the quantitative determination of propranolol, 4-hydroxypropranolol, and propranolol glycol in human plasma is described. The limits of sensitivity for the method were: 1 ng/ml propranolol; 5 ng/ml 4-hydroxypropranolol; and 1 ng/ml propranolol glycol. Data obtained from 6 healthy volunteers given a single 160 mg oral dose of propranolol revealed mean (+/- SEM) peak plasma levels of 31 +/- 10 ng/ml for 4-hydroxypropranolol and 9 +/- 2 ng/ml for propranolol glycol. These plasma levels were less than the peak concentrations recorded for propranolol (123 +/- 34 ng/ml. The rates of plasma decay of these two metabolites were greater than that observed for propranolol.

Chromatography, High Pressure Liquid↗

Propranolol compared with propranolol plus isosorbide dinitrate in portal-hypertensive patients: long-term hemodynamic and renal effects.

The long-term hemodynamic and renal effects of propranolol were compared with those of propranolol plus isosorbide dinitrate in 44 portal-hypertensive alcoholic cirrhotic patients. Eight control patients, 8 patients receiving propranolol and 14 patients receiving propranolol plus isosorbide dinitrate were hemodynamically evaluated. Renal function was studied in a fourth group of 14 patients receiving propranolol plus isosorbide dinitrate. Portal pressure decreased more (p < 0.05) with combined therapy (-21.6%, from 19.5 +/- 4.8 to 15.4 +/- 4.3 mm Hg) than with propranolol alone (-12.5%, from 19.9 +/- 1.2 to 17.4 +/- 1.8 mm Hg). Serum urea and creatinine levels, plasma sodium concentration, urine volume and urinary sodium excretion showed nonsignificant changes in all groups studied. Combined therapy induced a significant (p < 0.05) decrease in plasma renin activity (from 4.42 +/- 4.7 to 1.59 +/- 1.9 ng/ml/hr) and nonsignificant reductions in plasma aldosterone concentration and creatinine clearance. None of the eight patients with ascites or history of ascites not receiving isosorbide dinitrate showed evidence of impairment in renal sodium metabolism during the study period. In contrast, 8 of the 14 patients (57%) with ascites or history of ascites receiving isosorbide dinitrate showed impairment in renal sodium metabolism (p < 0.01), as reflected by the development or worsening of ascites and the need of higher diuretic requirements. Long-term combined administration of propranolol plus isosorbide dinitrate is superior to propranolol alone in the pharmacological treatment of portal hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Pressure↗

Plasma propranolol levels in beagle dogs after administration of propranolol hemisuccinate ester.

The hemisuccinate ester of propranolol was administered to beagle dogs to test its applicability as a potential prodrug of propranolol. Following oral administration of propranolol hemisuccinate, plasma propranolol levels were eight times higher than after an equivalent dose of propranolol hydrochloride. The hemisuccinate was absorbed rapidly, with peak plasma levels observed at 0.5--1 hr. Following intravenous dosing, the disappearance half-life of the prodrug from the plasma was 0.5 hr while the propranolol half-life was 1.7 hr. This study demonstrated the potential usefulness of the prodrug approach when a highly metabolized drug such as propranolol is protected from first-pass elimination.

Animals↗

[The EEG of patients with acute manic psychoses before, during and after treatment with high doses of d-propranolol and dl-propranolol (author's transl)].

Six manic patients, drug-free for at least 10 days, were treated with high doses (up to 3,000 mg/day, corresponding serum levels up to 1,600 ng/ml) of d-propranolol or dl-propranolol in a double-blind, placebo-controlled study. The EEG's of these patients were studied over a maximum period of 21 days. All 82 EEG's were normal, they showed neither epileptic patterns nor any other signs for hypersynchronisation, as a possible side-effect of propranolol, nor other abnormalities, due to the manic condition. Analysis by fast-fourier-transformation produced no difference between the effect of d-propranolol or dl-propranolol on EEG compared intra- and inter-hemispherically by power-spectra, cross-spectra, phase-differences and coherences. At high serum levels (more than 1,000 ng/ml) there was a corresponding increase of power and a drop in frequency of the alpha-activity, maximally--1.1 c/s, which probably depended on the serum level. This result is in agreement with the hypothesis of a direct antimanic effect of the drug and comparable to the clinical effect of lithium, which produces similar changes in EEG. A comparison of the propranolol-induced EEG changes with EEG changes usually induced by sedative drugs, contradicts the hypothesis that the antimatic properties of propranolol are caused by unspecific sedation.

Adult↗

Comparison of concomitant nicardipine hydrochloride and propranolol with propranolol alone in patients with essential hypertension.

A twelve-week parallel study was conducted to compare the efficacy and safety of nicardipine plus propranolol with that of propranolol alone in 67 patients with mild to moderate essential hypertension. Efficacy data was analysed for 50 patients. The regimens used were 90 mg X day-1 of nicardipine and 120 mg X day-1 of propranolol. Both treatments significantly reduced supine and standing systolic and diastolic blood pressure from baseline values at all visits. At all visits, concomitant administration of nicardipine and propranolol produced a greater reduction in systolic and diastolic pressures than did propranolol alone, although the difference between treatments did not always reach statistical significance. Few adverse events were reported, and none was clinically important. We conclude that nicardipine taken concomitantly with propranolol is more effective than propranolol alone in treating patients with hypertension and that the combined regimen is well tolerated.

Adult↗

Prevention of propranolol withdrawal mechanism by prolonged small dose propranolol schedule.

Abrupt withdrawal of propranolol may be followed by a "propranolol withdrawal syndrome "due, at least in part, to enhanced beta adrenergic sensitivity. Tapering propranolol dosage is frequently used in the hope of preventing adverse withdrawal events but the success of such a maneuver has not been shown. The rationale for the dose tapering schedule in this study was based on earlier observations after abrupt withdrawal of propranolol. Nine hypertensive patients were gradually withdrawn from long-term propranolol therapy, either by serial dose reduction for 6 to 9 days (n = 3) or by reduction to a prolonged small dose (30 mg daily) for 2 weeks before complete withdrawal (n = 6). During dose reduction of propranolol and for 2 additional weeks of placebo therapy, serial measurements were made of cardiac sensitivity to isoproterenol, heart rate at rest, blood pressure, plasma catecholamines, serum thyroxine (T4) and triiodothyronine (T3) and symptoms. Serial dose reduction decreased but did not prevent cardiac hypersensitivity in two of three patients. The prolonged small dose therapy largely prevented cardiac hypersensitivity and overshoot in heart rate, blood pressure and plasma catecholamines and symptoms. Serum T4 decreased significantly and T3 tended to increase during and after prolonged small dose treatment. These results indicate that prolonged administration of small dose propranolol before complete withdrawal in hypertensive patients prevents enhanced cardiac beta adrenergic sensitivity and other adverse events.

Adult↗

Comparison of combination nifedipine-propranolol and diltiazem-propranolol with high dose diltiazem monotherapy for stable angina pectoris.

Patients with chronic stable angina are frequently treated with calcium antagonist-beta-blocker combination drug therapy. However, there is a paucity of data comparing such combination therapies with each other and with high dose calcium antagonist monotherapy. Nineteen patients with chronic stable angina pectoris were studied using a prospective, randomized, Latin-square crossover protocol in an effort to determine the differential effects of nifedipine-propranolol combination therapy, diltiazem-propranolol combination therapy and high dose diltiazem monotherapy on exercise treadmill performance. All patients performed exercise tolerance tests after 4 weeks on each of the 3 therapeutic regimens. Both nifedipine (mean daily dose 70 +/- 23 mg) and diltiazem (mean daily dose 237 +/- 12 mg) in combination with propranolol (mean daily dose 146 +/- 58 mg) resulted in significant increases in total exercise time, time to onset of angina and time to maximal ST-segment depression compared with high dose diltiazem (mean daily dose 347 +/- 38 mg) monotherapy (p less than or equal to 0.001). Double-product at rest and the increase observed from rest to the end of stage 1 were significantly decreased during nifedipine-propranolol and diltiazem-propranolol combination therapy compared with high dose diltiazem monotherapy (p less than or equal to 0.001). In patients with chronic stable angina both nifedipine-propranolol and diltiazem-propranolol combination therapy resulted in significantly greater improvement in exercise performance compared with high dose diltiazem monotherapy.

Angina Pectoris↗

Plasma concentrations of propranolol and 4-hydroxypropranolol during chronic oral propranolol therapy.

1 The plasma levels of propranolol and 4-hydroxypropranolol have been measured in 17 hypertensive patients receiving chronic oral therapy with propranolol. 2 The range of plasma propranolol concentrations was from 5.3 to 300 ng/ml, and that of 4-hydroxypropranolol was from 2.1 to 36.0 ng/ml. 3 The mean (+/- s.d.) plasma concentration ratio of 4-hydroxypropranolol to propranolol was 0.130 (+/- 0.005); however, a very wide range was observed with individual values ranging from 0.057 to 0.241. 4 A statistically significant correlation was observed between the plasma concentration of 4-hydroxypropranolol and that of propranolol. 5 Propranolol and 4-hydroxypropranolol plasma concentrations were each significantly, but poorly, correlated with daily propranolol dose. 6 The clinical significance of the results has been discussed.

Adult↗

Comparison of a long-acting form of propranolol and conventional propranolol in the treatment of hypertension in elderly patients.

Nineteen elderly hypertensive patients already being treated with a diuretic and, where necessary, another anti-hypertensive agent, were studied in a double-blind, randomized, crossover comparison of conventional propranolol, 40 mg three times daily, with a long-acting propranolol formulation, 160 mg once daily, as a second line agent. Patients were assessed before taking the morning's allocated medication. This was done as near as possible to 24 h after the last dose of once daily propranolol and as near as possible to 15 h after the last dose of three times daily conventional propranolol. Assessment was carried out at the time of randomization and after 4 weeks' treatment with both propranolol formulations. Heart rate and blood pressures were measured in the supine and standing positions and after exercise. Both propranolol formulations were effective as second line agents in these elderly patients and both were well tolerated. Patient compliance on both propranolol formulations was very good although the long-acting formulation may be of value in improving this still further.

Aged↗

A randomised controlled trial of propranolol for the prevention of initial bleeding in cirrhotic patients with portal hypertension. Preliminary results. The Italian Multicenter Project for Propranolol in the Prevention of Bleeding.

The preliminary analysis of a multicentre, randomised, single-blind trial of propranolol for prophylaxis of first bleeding in cirrhosis is reported. 174 consecutively-chosen patients with large oesophageal varices were randomly assigned to either propranolol, in doses which reduced the resting heart rate by 25% (85 patients), or to vitamin K (89 patients). 25 patients had to be withdrawn from treatment with propranolol because of poor tolerance. The 30-month cumulative proportion of patients free of bleeding was 74% in the propranolol group and 63% in the vitamin K group; corresponding survival figures were 59% and 74%, respectively. These differences were not statistically significant. A retrospective analysis, according to the presence of ascites at randomisation showed that a significantly higher proportion of patients without ascites in the propranolol group were free of bleeding compared with those in the control group (87% vs 64%; p = 0.023). No significant differences were found in patients with ascites at randomisation. Length of survival was not significantly affected by treatment in any subgroup, although it was shorter in ascitic patients given propranolol than in controls (33% vs 63%; p = 0.07). If confirmed on a longer follow-up, these results suggest that propranolol could prevent primary variceal haemorrhage in patients with well-compensated cirrhosis.

Aged↗

[Comparative study of propranolol versus propranolol plus isosorbide 5-mononitrate in portal hypertension in cirrhotics. Evaluating splanchnic hemodynamics with color Doppler ultrasound].

BACKGROUND: Hemorragic portal hypertension (HTP-H) has a mortality of 30-40%. Propranolol alone or in combination with isosorbide-5-mononitrate (5MNI) has been wed as hemorrhage preventive treatment. OBJECTIVE: Compare propranolol vs. propranolol and 5MNI as preventive treatment of HTP-H, evaluating splachnic hemodynamics by color Doppler ultrasound (EDC). METHODOLOGY: We included 20 patients with liver cirrhosis, mean age 53.3 years, 13 female, 10 for primary prevention and assigned them in to 2 groups treatment: l.- Propranolol alone (10 patients), ll.- Propranolol + 5-MNI (10 patients). We carried out EDC to each patient before iniciating and 2 months after treatment. RESULTS: A decrease in splachnic hemodynamics was found in both groups as measured by portal vein (PV), hepatic artery (HA) velocity and flux decreased in group I were: PV velocity from 15.4 to 12.5 cm/seg (p = 0.019089 ) and flux from 1639.8 to 1396.8 mL/min (p = 0.031082), HA velocity from 50.1 to 44.5 cm/seg (p = 0.120385), and flux 547.1 a 470 mL/min (p = 0.069642); in group 11: PV from 16.6 to 12.9 (p = 0.019699) and from 1,786.8 to 1,304.2 (p = 0.004072), in HA from 52.3 to 44.4 (p = 0.003498 ) and 612.5 to 448.8 (p = 0.000285). CONCLUSION: Propranolol and 5-MNI decreases splachnic flux and velocity more than propranolol alone, in consequence it should be better to prevent bleeding from portal hypertension.

Antihypertensive Agents↗

Combined high-performance liquid chromatographic procedure for measuring 4-hydroxypropranolol and propranolol in plasma: pharmacokinetic measurements following conventional and slow-release propranolol administration.

An assay is described for the simultaneous determination of propranolol and its active metabolite, 4-hydroxypropranolol, in human plasma. Both compounds were separated from an ethereal extract by high-performance liquid chromatography employing a C18 bonded-phase column. Detection of the effluent was by fluorescence. Suitable fluorescent spectrometers and wavelength settings that allow optimum detection of both compounds have been described. The limit of sensitivity was 2 ng/ml for both propranolol and 4-hydroxypropranolol. Mean peak plasma levels of propranolol and 4-hydroxypropranolol in six patients receiving a single dose of a slow-release 160-mg formulation of propranolol were 28 and 6 ng/ml, respectively. These levels were about one-tenth the level obtained following a single conventionally prepared dose of propranolol (160 mg). Peak levels were delayed and plasma levels of propranolol persisted for a longer period with the slow-release formulation. Area under the curve estimates suggested that the bioavailability of the slow-release formulation following single-dose administration was about one-third that of the conventional preparation.

Adult↗

Propranolol and blood glucose: simultaneous measurements over a wide range of doses and the effect of propranolol on the glucose tolerance test.

No correlation was found between blood glucose and simultaneous measurements of plasma propranolol concentration in patients with schizophrenia, on a daily dose of 80 mg to 1800 mg of propranolol as an adjunct to phenothiazine medication. The Glucose Tolerance Test (GTT) in ten patients on propranolol and phenothiazines did not differ significantly from those of a matched control group on phenothiazine alone. Two patients with mild diabetes showed no significant change in their GTT after stopping propranolol. These observations accord with the view that relatively high doses of propranolol as an adjunct to phenothiazine medication in schizophrenia are safe from the standpoint of glucose metabolism. This does not apply to the insulin dependent diabetic who is in danger of severe hypoglycaemia when glycogenolysis is blocked by propranolol.

Adipose Tissue↗

Increased responsiveness to histamine after propranolol in subjects with asthma nonresponsive to the bronchoconstrictive effect of propranolol.

Eight nonsmoking subjects with asthma, nonresponsive to the bronchoconstrictive effect of oral propranolol, were studied. The airway response to increasing concentrations of histamine aerosol was assessed by measuring FEV1. The threshold provocative dose of histamine needed to cause a 20% fall in starting FEV1 (PD20) was measured by log dose-response curve. Histamine challenge was performed in duplicate after premedication with placebo or 40 mg of propranolol on separate days. The mean starting FEV1 did not change significantly after placebo and after propranolol administration. The mean PD20 values after propranolol (0.37 mg/ml and 0.32 mg/ml, respectively, for the first and the second challenge) were significantly lower (p less than 0.01) than mean control PD20 values (1.36 mg/ml and 1.48 mg/ml, respectively, for the first and the second challenge). These results indicate that propranolol increases airway responsiveness to histamine, even in those subjects with asthma in whom propranolol has little bronchoconstrictive effect.

Adult↗

Propranolol prevents first gastrointestinal bleeding in non-ascitic cirrhotic patients. Final report of a multicenter randomized trial. The Italian Multicenter Project for Propranolol in Prevention of Bleeding.

We report here the final analysis of a multicentre randomized, single-blind trial of propranolol for prophylaxis of first bleeding in cirrhosis. One hundred and seventy-four consecutive patients with large esophageal varices were randomly assigned to either propranolol in doses reducing the resting heart rate by 25% (85 patients) or to a placebo (vitamin K: 89 patients). Three were lost to follow-up and 26 had to be withdrawn from propranolol because of side effects (n = 23) or low compliance (n = 3). The cumulative value over 42 months of patients free of bleeding was 74% (95% confidence interval = 85%-63%) in the propranolol and 59% (95% CI = 79%-43%) in the control group and the corresponding survival figures were 51% (95% CI = 63%-39%) and 59% (95% CI = 75%-43%): neither of the differences was significant. A retrospective analysis according to the presence of ascites at randomization showed that in the subset without ascites the proportion of patients free of bleeding was significantly higher in the propranolol group than in the control group (83% vs. 61%; 95% CI = 97%-69% and 78%-44%, respectively; P = 0.028); this difference was even more evident in the ascites-free period (94% vs. 58%; 95% CI = 100%-86% and 76%-40%, respectively; P = 0.002). No differences were found in patients with ascites at randomization. Survival was not significantly affected by treatment in any subgroup, although it was shorter in the ascitic patients given propranolol than in controls (33% vs. 49%; 95% CI = 51%-15% and 71%-27%, respectively; P = 0.07).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

Propranolol for prophylaxis of bleeding in cirrhotic patients with large varices: a multicenter, randomized clinical trial. The Italian Multicenter Project for Propranolol in Prevention of Bleeding.

To assess if propranolol prevents the first bleeding in cirrhosis, we randomly assigned 174 patients with large varices to either propranolol in doses reducing the resting heart rate by 25% (85 patients) or to a placebo (oral vitamin K, 89 patients). Sixty-nine patients had alcoholic cirrhosis, 24 posthepatitis cirrhosis and 81 cryptogenic cirrhosis. At the time of inclusion, 75 patients (43%) had ascites and according to the Child-Pugh classification, 103 (59%) had Class A disease, 60 (34%) Class B and 11 (7%) Class C. We report here an interim analysis of the study when all patients had been followed for at least 1 year (mean follow-up = 22 months). At this time, the cumulative proportion of patients free of bleeding was 74% (both differences not significant), respectively. A retrospective analysis showed that the cumulative percentage of patients free of bleeding was significantly higher in the propranolol- than in the control-group in the subsets of patients without ascites or in Child-Pugh Class A: respectively, 87 vs. 64% (p = 0.023) and 88 vs. 64% (p = 0.01). No differences in bleeding incidence were found in patients with ascites or in Child-Pugh Class B or C. Propranolol treatment did not affect survival in any subgroup. Twenty-five patients had to be withdrawn from propranolol because of side effects (n = 23) or low compliance (n = 2). If confirmed on a longer follow-up, these results suggest that propranolol could prevent the first bleeding in patients with well-compensated cirrhosis.

Clinical Trials as Topic↗

Propranolol vs flunarizine vs flunarizine plus propranolol in migraine without aura prophylaxis. A double-blind trial.

Fourty-five migraine without aura patients underwent a parallel double-blind trial aiming the comparison of the effects of propranolol 60 mg/day to flunarizine 10 mg/day and to propranolol 60 mg/day plus flunarizine 10 mg/day simultaneously. There were 3 groups, each one with 15 patients. After a 20-day-baseline period, each group received one kind of treatment during 120 days. Migraine index on propranolol was 23.4*, on flunarizine 18.7* and on both drugs 14.4*, mean frequency of attacks on propranolol was 1.26**, on flunarizine 1.2** and on both drugs 1.13** (*p < 0.05, **p < 0.01 compared to baseline) and global evaluation was reduced with all forms of treatment. It was not found statistical differences between groups, nevertheless there was a trend in the group using two drugs reaching lower values in migraine index, frequency of attacks and global evaluation. In individuals using flunarizine (alone or associated with propranolol) the therapeutic effect was largely maintained up to 45 days after drug withdrawal.

1-Propanol↗