Comparison of the cardiovascular and pulmonary effects of oral celiprolol, propranolol and placebo in normal volunteers.

1. The effects on heart rate, blood pressure and pulmonary function of single oral doses of celiprolol hydrochloride (400 mg), and propranolol (40 mg) were compared with placebo in 12 healthy volunteers, in a double-blind three-period crossover study. 2. Celiprolol had no effect on heart rate while propranolol caused a significant reduction compared with placebo. Systolic blood pressure was reduced by propranolol but not celiprolol, whereas standing diastolic blood pressure was lowered by both drugs. 3. The maximal expiratory flow at 50% vital capacity (MEF.50), was significantly lower after propranolol compared with placebo and celiprolol. Celiprolol had no effect on the flow-volume loop parameters. 4. Effective pulmonary blood flow was significantly increased by celiprolol, but reduced by propranolol. 5. A high incidence of subjective side-effects were experienced on celiprolol (10/12; particularly unpleasant in 5). Side-effects were experienced to a lesser extent on placebo (8/12). Only one volunteer experienced a side-effect on propranolol. 6. Oral celiprolol exerts its hypotensive effect by vasodilatation without reflex tachycardia. It does not cause airways obstruction in healthy subjects.     

An assessment of beta-adrenoceptor blockade in man by prizidilol hydrochloride.

1 Prizidilol hydrochloride (SK&F 92657) is a new compound which causes both arteriolar dilatation and beta-adrenoceptor blockade. The effect of a single oral dose on the responses of heart rate and blood pressure to isoprenaline infusion has been studied in healthy volunteers. 2 Isoprenaline heart rate dose-response curves showed parallel shifts to the right after oral prizidilol, indicating antagonism by this compound at beta-adrenoceptors in the heart. 3 Isoprenaline dose-response curves for decreases in diastolic blood pressure also showed shifts to the right after oral prizidilol, providing evidence of beta-adrenoceptor antagonism by this drug in peripheral resistance vessels. 4 The peak effect of a 40 mg dose of propranolol was greater than that of a 200 mg dose of prizidilol but both drugs caused persistent beta-adrenoceptor blockade for at least 7 h after ingestion.     

Pharmacodynamic and pharmacokinetic studies on prizidilol and nipradilol (K-351), antihypertensive drugs with combined vasodilator and beta-adrenoceptor blocking actions, in rabbits

Effects of prizidilol and nipradilol (K-351), beta-adrenoceptor antagonists with vasodilator action, on blood pressure and heart rate were studied in normotensive conscious rabbits after i.v. administration. In addition, we investigated relationships between plasma drug concentrations and beta-adrenoceptor blocking activity as estimated by the inhibition of isoproterenol-induced tachycardia and vasodilator activity as assessed by the inhibition of pressor response to angiotensin II (ANG II). Prizidilol (4 mg/kg) produced a significant and sustained fall in blood pressure and a slight increase in heart rate, while hydralazine (2 mg/kg) caused the same degree of hypotension and a marked tachycardia. Nipradilol (1 mg/kg) caused a significant reduction of resting heart rate, but had no significant effect on blood pressure. Propranolol (1 mg/kg) did not affect resting blood pressure and heart rate. Hypertensive response to ANG II was significantly attenuated only by hydralazine. Isoproterenol-induced tachycardia was significantly suppressed by prizidilol, nipradilol and propranolol. Good correlations were observed between beta-adrenoceptor blocking activity and plasma drug concentrations. These data suggest that prizidilol has an advantage over hydralazine to induce less tachycardia, but still may cause a certain degree of increase in heart rate. Nipradilol has a more potent beta-adrenoceptor blocking action than propranolol, while its vasodilator action is not obvious, at least in rabbits. Plasma concentrations of prizidilol and nipradilol are good indicators for beta-adrenoceptor blocking activity, but not for vasodilator activity.     

Comparison of prizidilol hydrochloride (SK & F 92657), a new antihypertensive agent with beta-adrenoceptor antagonist and vasodilator activity with propranolol and hydralazine in normal volunteers.

1 Some cardiovascular pharmacology of prizidilol hydrochloride, a new antihypertensive compound with precapillary vasodilator and beta-adrenoceptor antagonist activity, in man is described. 2 To investigate further the pharmacological profile of this drug the effects of a single oral dose of 400 mg prizidilol hydrochloride were compared with propranolol 40 mg in combination with either 25 mg or 50 mg of hydralazine for up to 6 h after dosing, in a placebo controlled in eight healthy subjects. 3 Prizidolol hydrochloride significantly reduced supine and standing diastolic blood pressure and was more effective than propranolol combined with either dose of hydralazine in this respect. 4 Supine heart rate was significantly increased after prizidilol hydrochloride, but was not significantly changed after propranolol combined with either dose of hydralazine. The reasons for the increase in supine heart rate after prizidolol are discussed. 5 beta-adrenoceptor antagonism was assessed in terms of inhibition of exercise induced increases in heart rate and systolic blood pressure. At the doses used, prizidolol hydrochloride was less effective than propranolol and hydralazine combined, particularly during the first 3 h after dosing.     

Acute effects of prizidilol on blood pressure,heart rate,catecholamines, renin and aldosterone in essential hypertension

Summary Prizidilol is a new antihypertensive agent reported to possess combined precapillary vasodilator and betareceptor-blocking properties. To clarify the profile of the acute effects of prizidilol in man, a variable dose study was performed in 8 patients with benign essential hypertension. Blood pressure, heart rate, plasma renin activity, aldosterone, plasma and urinary catecholamines and electrolytes were determined at short intervals before and up to 23 h after oral administration of placebo and prizidilol 150, 300 and 600 mg. The 4 studies were performed at weekly intervals according to a Latin square design. Prizidilol produced dose-dependent decreases in supine and upright blood pressure, with an initial change after about 2 h and maximal effects from 4 to 8 h after drug ingestion. Following a high dose of prizidilol, supine mean blood pressure (average 128 mmHg prior to treatment) was normalised (<107 mmHg) from 3 to 7 h and was still below predose levels 23 h after ingestion. The only reported side effects were postural dizziness in 2 cases (corresponding to a fall in systolic upright blood pressure to <95 mmHg) and headache in one case. A biphasic variation in heart rate and plasma renin activity, with an early drop and a subsequent tendency to a slight rise, was observed after an intermediate or high dose of prizidilol. Plasma norepinephrine levels were increased by a high dose of prizidilol, while plasma epinephrine, aldosterone and plasma and urinary electrolytes were not consistently changed. Prizidilol in a single oral dose appeared to be a potent antihypertensive agent. The profile of heart rate and plasma renin point to early dominance of beta-blockade followed by appearance of the concomitant vasodilator properties of prizidilol.     

Inhaled dopamine induces bronchodilatation in patients with bronchial asthma.

OBJECTIVE: To determine the probable bronchodilating effect of dopamine administered by inhalation route in patients with crisis of bronchial asthma and the effect of dopamine on bronchial motor tone. DESIGN AND METHOD: We have studied eighteen (18) patients with crisis of bronchial asthma, ten (10) subjects with bronchial hyperreactivity and ten (10) healthy subjects. Patients with other pulmonary or cardiac disease were excluded. All received by inhalation placebo (0.9% saline solution), dopamine at 0.5 microg/kg/min (controlled by heart rate and arterial pressure with a dynamap), and placebo. Respiratory parameters: forced vital capacity (FVC), forced expiratory volume at the first second (FEV1), forced maximal expiratory flow (FEFmax) and forced expiratory flow at the 50% of vital capacity (FEF50) were measured in each protocol period. Student's paired t test, Wilcoxon and Mann Whitney analysis were performed. RESULTS: After dopamine inhalation, there was an increase of FVC by 23% (p<0.001); an increase of FEV1 by 39% (p<0.0001); an increase of FEF50 by 33% (p<0.001) and an increase of FEFmax by 31% (p<0.001). There were no respiratory parameter changes in both, subjects with bronchial hyperreactivity and normal after dopamine inhalation. CONCLUSIONS: Inhaled dopamine induces bronchodilatation in patients with crisis of bronchial asthma. Inhaled dopamine neither alters basal bronchial tone in healthy subjects nor in subjects with bronchial hyperreactivity.     

Acute effect of indenolol on human airways

Summary Airways resistance and expiratory flow have been investigated in 6 healthy volunteers given single doses of indenolol, propranolol, atenolol and placebo in a randomized, double-blind, cross over study. The three active drugs significantly decreased the effort-induced rise in systolic pressure, and they also reduced the resting heart rate. The relative potency against exercise-tachicardia was propranolol > atenolol > indenolol. The double and triple product were significantly decreased, too, without any difference between the active treatments. After placebo or indenolol, an exercise-induced increase in the forced expiratory flow at low pulmonary volumes (MEF 50 and MEF 75) was observed. The two control -blockers caused a fall in exercise expiratory flow as compared to the resting values. The non-cardioselective agent (propranolol) was more effective than the cardioselective compound (atenolol) in decreasing the expiratory flow. The mechanism of action of indenolol is discussed in the light of the lack of its acute effect on airways resistance.     

Comparison of the effects of prizidilol and propranolol on renal haemodynamics at rest and during exercise.

Effective renal plasma flow and glomerular filtration rate were measured in 22 mild-to-moderate, uncomplicated, essential hypertensive patients during placebo and after 3 months of randomly assigned treatment either with prizidilol (n = 10) or propranolol (n = 12). Measurements were performed at rest and during cycloergometer exercise. For a comparable effect on blood pressure effective renal plasma flow was significantly increased at rest by prizidilol (+9%) and decreased by propranolol (-13.6%); these patterns were maintained during exercise. Glomerular filtration rate was immodified after the treatment with both drugs. It is concluded that prizidilol is an effective hypotensive agent with no deleterious effects on renal haemodynamics.     

Single-dose efficacy and safety of zindotrine, a new oral bronchodilator

Zindotrine, a new bronchodilator, may be an alternative to theophylline in treating reversible airflow obstruction. Efficacy and cardiovascular effects of a single 300 mg oral dose of zindotrine were compared with placebo in a two-period, double-blind, crossover trial. Twelve subjects with airflow obstruction reversible after isoproterenol and theophylline completed the trial. Improvement in pulmonary function (forced vital capacity [FVC], forced expiratory volume in one second, and forced expiratory flow rate from 25 to 75 percent of FVC) was greater after zindotrine than with placebo. Pulmonary function tests increased 15 percent or more over baseline in 30 minutes after active drug, lasting up to 6 hours. Mild decreases in heart rate and mean blood pressure occurred after both treatments, with changes equal in both treatment groups. Six subjects had mild subjective side effects after zindotrine (headache, dizziness, vertigo, flushing, and heartburn) compared with one report of lightheadedness after placebo. A single dose of zindotrine 300 mg provides effective bronchodilator action with a relatively prolonged response and tolerable side effects.     

Clinical pharmacology and pharmacokinetics of prizidilol in hypertensive patients

We evaluated the clinical pharmacology of prizidilol, a compound with vasodilator and beta-blocking properties, in 12 hypertensive patients with normal renal function. A single dose of 600 mg prizidilol was given orally and blood samples were withdrawn at intervals for high-performance liquid chromatography assay. Blood pressure and heart rate were recorded every hour in supine and standing positions. A nitroglycerin test was performed at the 2nd, 4th, and 6th h for evaluation of cardiac beta-adrenoceptor activity. Results were compared with those after placebo intake the day before. Prizidilol produced a significant decrease in supine systolic and diastolic blood pressures (-22 and -24%, respectively), with a maximum effect 5 h after intake. Blood pressure changes were not different in slow and fast acetylators, suggesting that the acetylated metabolites were active. Heart rate decreased slightly but significantly during the first 2 h, but was similar to control levels thereafter. However, the nitroglycerin test data suggested a prolonged blockade of beta-adrenoceptor activity. Pharmacokinetics showed large variations among patients; several peaks were observed on the curves, indicating irregular absorption. The apparent plasma elimination half-life was 4.4 +/- 0.4 h. Total body clearance was high despite a very low renal clearance, indicating that the drug was eliminated mainly by the metabolic or intestinal route. No significant correlations were found among plasma concentration, blood pressure, and heart rate. In conclusion, prizidilol is a potent antihypertensive drug having equilibrated vasodilator and beta-blocking effects. The pharmacokinetic data suggest a first-pass effect and elimination by extra-renal routes.     

The effect of bucindolol on the airway function of asthmatics

Summary The airway and cardiovascular effects of separate single oral doses of 50, 100 and 200 mg of bucindolol were compared to those of placebo in a double-blind trial in 16 patients with mild to moderately severe asthma. Heart rate (HR), blood pressure (BP), forced vital capacity (FVC), forced expired volume in one second (FEV₁), maximum expiratory flow at 50% of vital capacity (FEF₅₀) and maximum expiratory flow at 75% of expired vital capacity (FEF₇₅) were measured before and at intervals for 4 h, when salbutamol (200 µg) was inhaled and the measurements repeated 15 min later. There was an interval of at least 4 days between each drug treatment day.Four of the 16 patients developed clinically significant bronchoconstriction with 50 mg (3) or 100 mg (1) of bucindolol and were withdrawn from the study. The remaining patients showed impaired bronchodilator response to salbutamol for each bucindolol dose as compared to placebo. No significant BP or HR effects were measured. Two patients withdrew because of circumstances unrelated to bucindolol induced bronchoconstriction. The development of bucindolol induced bronchoconstriction in this group of mild to moderate asthmatics was not predicted by the level of baseline pulmonary function, or the level of histamine responsiveness. However, there was a weak relationship between bucindolol induced bronchoconstriction and salbutamol induced bronchodilation. There was no definitive asthmatic characteristic to predict the likelihood of significant bucindolol induced bronchoconstriction in this asthmatic population.     

Effects of ICI 141,292 on exercise tachycardia and isoprenaline-induced beta-adrenoceptor responses in man.

The beta-adrenoceptor blocking properties and cardioselectivity of ICI 141, 292 were investigated in healthy male subjects. Seven subjects received in random order oral doses of ICI 141,292 20, 50, 100, 200 and 400 mg, atenolol 50 and 100 mg and placebo. ICI 14 292 had no effect on supine heart rate which was reduced by atenolol 100 mg. ICI 141,292 50, 100 and 200 mg had no effect on standing heart rate which was reduced by 400 mg at 2 h. Both doses of atenolol caused greater reductions. The maximum percent reduction of an exercise tachycardia after ICI 141,292 200 mg (23.9 +/- 3.7%) and 400 mg (24.3 +/- 5.2%) were similar to atenolol 50 mg (27.3 +/- 4.7%) but less than atenolol 100 mg (30.8 +/- 2.9%) (P less than 0.02). Six subjects received in random order single oral doses of ICI 141,292 100, 200 and 400 mg, atenolol 50 mg, propranolol 40 mg and placebo. Following each dose each subject received graded infusions of isoprenaline sulphate until heart rate increased by 40 beats min-1. Dose-response curves were constructed for the changes in heart rate, finger tremor, blood pressure and forearm blood flow produced by each infusion. At the 4 micrograms min-1 dose of isoprenaline, ICI 141,292 200 mg caused more attenuation than atenolol 50 mg but less than propranolol 40 mg in the changes of heart rate, diastolic blood pressure and finger tremor (P less than 0.02). ICI 141,292 400 mg caused more attenuation of the changes of all parameters than atenolol 50 mg but less attenuation of the changes in diastolic blood pressure and finger tremor than propranolol 40 mg (P less than 0.02). These results indicate that ICI 141,292 is a cardioselective beta-adrenoceptor antagonist with partial agonist activity.     

A study of pulmonary profile of hypertensive patients--comparison of atenolol vs amlodipine

Two groups of drugs commonly used for the treatment of hypertension are atenolol and amlodipine. These drugs are reported to have conflicting changes on pulmonary responses. In order to study the effect of hypertension and antihypertensive treatment on pulmonary responses, 40 patients with essential hypertension having diastolic blood pressure between 90-114 mmHg on three consecutive weekly visits were taken. Pulmonary responses were tested at the end of 2 weeks of placebo washout period and then at the end of 6 weeks of treatment with either atenolol or amodipine. Using a computerized autospiror along with the weekly recordings of heart rate and blood pressure, the various pulmonary and cardiac parameters were taken. Analysis of the result showed that atenolol treatment resulted in significant decline of forced vital capacity (FVC), % forced vital capacity (%FVC), and forced expiratory volume in first second (FEV1) whereas amlodipine did not show any significant change on pulmonary parameters.     

Changes in heart rate and forearm blood flow following intravenous boluses of isoprenaline in the presence of practolol and propranolol

1 Increases in heart rate and forearm blood flow following graded intravenous bolus injections of isoprenaline sulphate, were measured in a double-blind randomised study of six subjects who received either placebo, practolol 50 mg, practolol 200 mg, propranolol 10 mg or propranolol 40 mg. 2 Dose related increases in forearm blood flow were produced by the graded boluses of isoprenaline sulphate. 3 Practolol 50 mg attenuated the heart rate response to isoprenaline but did not significantly affect the changes in forearm blood flow. Practolol 200 mg further attenuated the heart rate responses but also decreased the forearm blood flow responses. 4 Propranolol 10 mg and propranolol 40 mg significantly attenuated both the heart rate and forearm blood flow responses. The effect on forearm blood flow tended to be greater than the effect on heart rate. 5 Practolol 200 mg had the same effect on heart rate responses as propranolol 10 mg but a significantly smaller effect on the forearm blood flow responses. 6 The measurement of forearm blood flow following intravenous bolus injections of isoprenaline provides useful information about the beta 2-adrenoceptor antagonism of propranolol and practolol. However, application of the technique may be limited by the magnitude of the heart rate response and by the short-lived nature of the increase in forearm blood flow.     

Comparison of the haemodynamic effects of bucindolol, propranolol and pindolol in healthy volunteers.

The effects of single oral doses of bucindolol (50, 100, 200 and 400 mg), pindolol (10 mg), propranolol (160 mg) and placebo on arterial pressure and heart rate in the supine and standing positions and exercise heart rate were compared in 12 healthy male volunteers. Supine heart rate was significantly greater after all four doses of bucindolol and pindolol in comparison to propranolol. Bucindolol had no significant effect on standing heart rate which was significantly reduced by pindolol and propranolol. Bucindolol, pindolol and propranolol significantly reduced an exercise tachycardia for at least 24 h after drug administration. Supine systolic pressure was not affected by any treatment but supine diastolic pressure was significantly reduced by bucindolol (200 and 400 mg) and by pindolol. All doses of bucindolol, propranolol and pindolol significantly reduced standing systolic blood pressure. There was a significant linear trend for reductions in standing systolic blood pressure and increasing doses of bucindolol. Standing diastolic blood pressure was significantly reduced by bucindolol 200 and 400 mg. Faintness and light headedness occurred in 6 of 12 subjects after 200 mg bucindolol and in 8 of 10 subjects after 400 bucindolol. After bucindolol, analysis of plasma samples demonstrated the presence of bucindolol, 5-hydroxy and 6-hydroxy bucindolol and indolyl-t-butylamine. These observations indicate that in man, bucindolol is a beta-adrenoceptor blocking drug with hypotensive activity and probably partial agonist activity. It is unlikely that the hypotensive effects result from blockade of beta-adrenoceptors or from the drug's partial agonist activity.     

Pulmonary and Heart Rate Changes Associated with Nonselective Beta-Blocker Glaucoma Therapy

Abstract

Six ophthalmic beta-blockers-betaxolol, timolol, levobunolol, pindolol, befunolol, and metipranolol-and placebo eyedrops were tested in six normal volunteers for their effect on exercise heart rate, blood pressure, and electrocardiogram tracings. None of the solutions affected blood pressure or electrocardiogram results. Betaxolol and placebo did not affect heart rate. However, all the other agents significantly (p < 0.05) suppressed the heart's ability to respond to exercise.

These same formulations were tested by spirometry in six asdimatic patients. Betaxolol and placebo had no effect on forced expiratory volume at 1 sec (FEV,), whereas all the other agents significantly (p < 0.05) depressed vital lung function.     

Acute effects of combined vasodilation and beta-adrenoceptor blockade with prizidilol on renal function.

1 The effects of a single oral dose of 600 mg of prizidilol on renal function were studied 5 to 6 h after dosing in six normal subjects and eight patients with essential hypertension. 2 Mean arterial blood pressure was reduced to 92% of the control value in normal subjects and to 75% in hypertensive patients. Heart rate increased slightly. 3 In normal subjects, effective renal plasma flow was increased to 107% of control values while glomerular filtration rate (83%), filtration fraction (79%), sodium (84%) and potassium (50%) clearances were significantly decreased. 4 In hypertensive subjects, effective renal plasma flow was increased to 120% of control values, while glomerular filtration rate (67%), filtration fraction (57%), sodium (27%) and potassium (72%) clearances were significantly decreased. 5 Plasma noradrenaline increased significantly in normal subjects (150%) and in patients (173%). Plasma renin activity, aldosterone and epinephrine levels did not change consistently. 6 The results indicate that the acute effects of prizidilol on blood pressure and renal function are more marked in hypertensive than in normotensive subjects. Prizidilol increases renal plasma flow like hydralazine and depresses glomerular filtration rate and fractional sodium excretion like endralazine. In addition to the fall in arterial pressure, efferent vasodilation and/or a specific effect on the glomerular ultrafiltration coefficient Kf may account for the striking decrease in filtration fraction.     

Effects of captopril on blood pressure and respiratory function compared to verapamil in patients with hypertension and asthma.

Seventeen adult patients with moderate and stable bronchial asthma and established essential hypertension (WHO I or II) were evaluated in a randomized, double-blind, crossover study of the effects of captopril (50-100 mg/day) and verapamil (160-240 mg/day) on blood pressure, orthostatic reactions, respiratory function, and asthmatic symptoms. The effect of both drugs on blood pressure was significant. Blood pressure (mean of 161/98 mm Hg initially) decreased to a mean of 147/90 and 160/91 mm Hg on captopril and verapamil, respectively, with normal orthostatic changes. There were no significant differences in forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), maximal expiratory flow at 50% of FVC (MEF50), or peak expiratory flow (PEF) measurements at the end of each treatment period. The subjective severity of asthma did not change significantly during the trial. No significant cough symptoms were reported on captopril.     

The effect of tiotropium on the pulmonary diffusing capacity

To our knowledge, there is no data on the effect of tiotropium on pulmonary gas exchange in healthy subjects. The aim of this study was to assess the effects of tiotropium on pulmonary diffusing capacity. Twenty-one healthy volunteers were enrolled for a prospective, randomized, double-blind, placebo-controlled study. Spirometric measurements, including pulmonary-diffusing capacity, were obtained before and after inhalation of drug or placebo. There was a significant decrease in forced vital capacity (FVC) and, consequently, an increase in the forced expiratory volume in one second (FEV1) to FVC ratio after placebo inhalation (p < 0.05), but no changes were found for percent-predicted FVC, FEV1, percent-predicted FEV1, percent-predicted forced expiratory flow (FEF25%-75%), percent-predicted peak expiratory flow (PEF), diffusing capacity of the lung for carbon monoxide (DLCO), single-breath alveolar volume (VA) and DLCO/VA ratio when compared with the baseline. Tiotropium inhalation caused a significant increase in FVC, percent-predicted FEV1, FEV1/FVC and percent-predicted FEF25%-75%, although the decrease in DLCO was insignificant (12.4 +/- 0.9 to 11.4 +/- 0.9). In conclusion, tiotropium does not change the pulmonary-diffusing capacity in healthy volunteers.     

肺高分辨率CT马赛克样灌注与小气道功能指数的相关分析

目的探讨肺小气道病变时高分辨率CT（HRCT）所示马赛克样灌注与小气道功能指标的相关性。方法选择HRCT上显示马赛克样灌注病例80例,由3位放射诊断医师对马赛克样灌注与小气道功能指标的相关性进行分析。结果马赛克样灌注与FEF 25%呈负相关（r=-0.48,P〈0.05）,与FEV1、FEF50%无相关性（r值分别为-0.27和-0.19,P〉0.05）。而空气潴留的程度与FEF25%、FEV1呈负相关（r值分别为-0.62和-0.41,P〈0.05）,与FEF 50%无相关性（r=-0.29,P〉0.05）。结论马赛克样灌注作为小气道病变的主要征象,其与FEF 25%具有良好的相关性,而空气潴留作为小气道阻塞的直接后果,其程度与FEV1、FEF 25%具显著相关性,即使肺功能检查结果正常时,也可以辅助诊断临床可疑的小气道阻塞。