Do beta-adrenergic blocking agents increase asthma exacerbation? A network meta-analysis of randomized controlled trials.

Beta-adrenergic blocking agents (abbreviated as beta-blockers) have been used for treating various cardiovascular diseases. However, the potential for asthma exacerbation is one of the major adverse effects of beta-blockers. This study aimed to compare the level of risk for an asthma attack in patients receiving various beta-blockers. We searched for randomized controlled trials (RCTs) of either placebo-controlled or active-controlled design. The current network meta-analysis (NMA) was conducted under a frequentist model. The primary outcome was the incidence of asthmatic attack. A total of 24 RCTs were included. Overall NMA revealed that only oral timolol [risk ratio (RR) = 3.35 (95% confidence interval (CI) 1.04-10.85)] and infusion of propranolol [RR = 10.19 (95% CI 1.29-80.41)] were associated with significantly higher incidences of asthma attack than the placebo, whereas oral celiprolol [RR = 0.39 (95% CI 0.04-4.11)], oral celiprolol and propranolol [RR = 0.46 (95% CI 0.02-11.65)], oral bisoprolol [RR = 0.46 (95% CI 0.02-11.65)], oral atenolol [RR = 0.51 (95% CI 0.20-1.28)], infusion of practolol [RR = 0.80 (95% CI 0.03-25.14)], and infusion of sotalol [RR = 0.91 (95% CI 0.08-10.65)] were associated with relatively lower incidences of asthma attack than the placebo. In participants with a baseline asthma history, in addition to oral timolol and infusion of propranolol, oral labetalol, oxprenolol, propranolol, and metoprolol exhibited significantly higher incidences of asthma attack than did the placebo. In conclusion, oral timolol and infusion of propranolol were associated with a significantly higher risk of developing an asthma attack in patients, especially in those with a baseline asthma history, and should be avoided in patients who present a risk of asthma.Trial registration: PROSPERO CRD42020190540.

X indening oral liquid improves cardiac function of rats with chronic cardiac failure via TGF-ß1/Smad3 and p38 MAPK pathway.

OBJECTIVE: Xindening oral liquid (Xin) is a widely used traditional Chinese medicine for the treatment of chronic heart failure (CHF). However, the exact mechanisms related to its therapeutic effects against CHF remain unclear. In the present study, we investigate the effects of Xin on cardiac function in CHF rats and the possible mechanisms involved. METHODS: Transverse aortic constriction (TAC) was conducted to induce a CHF rat model in this study. Sixty male Wistar rats were randomly assigned to six groups 28 days after TAC: sham; CHF model; Xin at concentrations of 5 ml/kg, 10 mL/kg, and 20 mL/kg; and QiLi 0.6 g/kg. After four weeks, the rats were treated with Xin (5, 10, or 20 mL/kg/d) for six weeks consecutively. At the end of the study, the cardiac function, heart weight index (HWI) and left ventricular mass index (LVMI), serum level of LDH, B-type natriuretic peptide (BNP), cTnI and CK-MB, and collagen volume fraction were studied. The expression of transforming growth factor-ß1 (TGF-ß1), drosophila mothers against decapentaplegic protein 3 (Smad3), and p38 mitogen activated protein kinase (p38 MAPK) were detected. RESULTS: The results showed that Xin treatment significantly improved cardiac function but decreased the serum level of LDH, BNP, cTnI, and CKMB of CHF rats. In addition, it reduced the HWI, LVMI, and collagen volume fraction compared with the model group. Xin treatment significantly improved cardiac function and attenuated cardiac fibrosis by suppressing the p38 MAPK and TGF-ß1/Smad3 signaling pathway in CHF rats. CONCLUSION: These results suggested that Xin might be a promising complementary treatment for CHF. More detailed experimental studies will be carried out in our subsequent research.

Changes of small bowel motility and noradrenaline content of the intestinal wall in response to alpha- and beta-adrenergic blockade in dog.

In experiments on dogs, the spontaneous movements of the small bowel were in all cases enhanced by the alpha 2-blocker phentolamine, while they were not influenced, or were slightly decreased, by the beta 1-blocker practolol. Neither drug caused a change in the noradrenaline content of the intestinal wall. In the same animals, the joint administration of phentolamine and practolol led to a considerable increased small bowel motility, and to a significant decrease in the noradrenaline level of the intestinal wall. The results are in agreement with experimental data indicating that presynaptic alpha-receptors play a primary role in the sympathetic regulation of small bowel motility.

The pharmacokinetics of oral and intravenous prenalterol in young, healthy volunteers.

The pharmacokinetics of prenalterol in healthy young volunteers after i.v. and oral dosing has been studied. There is evidence of non-linearity following the i.v. dosing. Evidence of dose-dependent pharmacokinetics following i.v. dosing has been obtained. The sustained-release formulation is very effective: almost 12 h were needed to achieve 50 per cent of the total AUC.

High-dose prenalterol in beta-blockade intoxication.

This study presents a case of beta-blocker intoxication due to massive overdose of metoprolol (7.5 g). Prenalterol in a dose of 420 mg was given as antidote, in combination with epinephrine in intermittent doses. Resuscitation was performed during 4 hours because of mechanical asystole. The patient regained health in 24 hours after further repeated doses of 30 mg prenalterol. Prenalterol is valuable in the management of toxic doses of beta-blocking drugs, and a titration to extremely high doses of prenalterol might be necessary.

Intravenous and oral prenalterol in congestive heart failure. Effects on systemic and coronary hemodynamics and myocardial catecholamine balance.

Systemic and coronary hemodynamic effects of prenalterol, a beta-1 receptor agonist, were determined in patients with chronic congestive heart failure, initially after intravenous administration (10 patients) and then after oral administration (eight patients). Cardiac index increased by 33 percent and 30 percent after intravenous and oral prenalterol, respectively. The increase in stroke volume index and stroke work index and decrease in pulmonary capillary wedge pressure and systemic vascular resistance were not significant. Myocardial oxygen consumption and coronary sinus blood flow increased in the majority of patients, although these changes were not statistically significant. There were no significant changes in transmyocardial norepinephrine or epinephrine balance. The systemic and coronary hemodynamic effects of both intravenous and oral prenalterol were similar. Major side effects included sudden death (two patients) and hypotension and bradycardia (three patients) during oral prenalterol treatment. It is concluded that improved left ventricular function following both intravenous and oral prenalterol may be associated with increased myocardial oxygen consumption, and serious adverse effects may occur during prenalterol therapy.

Prenalterol in cardiogenic shock following acute myocardial infarction.

Eleven patients with cardiogenic shock following acute myocardial infarction (AMI) have been treated with prenalterol. This drug was administered in seven patients once dobutamine or dopamine proved to be ineffective or poorly effective, and it was the first inotropic drug employed in four patients. Therapeutic dose of intravenous infusion ranged from 2.2 to 18 micrograms/kg/min (mean dose: 7 micrograms/kg/min), and was maintained for 2 to 4 hours. Since two patients received the infusion on two different occasions, a total of 13 cases were considered for statistical analysis. Prenalterol produced an increase in cardiac index (p less than 0.01), mean aortic pressure (p less than 0.02), net work index (p less than 0.01), net/stroke work index (p less than 0.01), pressure rate product (p less than 0.05), and myocardial perfusion gradient (p less than 0.02). It decreased systemic (p less than 0.02) and pulmonary (p less than 0.01) vascular resistances, pulmonary artery (p less than 0.01) and pulmonary capillary (p less than 0.05) pressures. Heart rate and right atrial pressure were not significantly changed. The drug acted as a relatively selective inotropic agent without a chronotropic effect and with minimal peripheral actions. It was effective in seven patients and ineffective in four patients. Thus prenalterol appears to be a useful drug in cardiogenic shock and further studies are warranted.

Marked relief of acute exacerbation of congestive cardiomyopathy by intravenous practolol--report of a case.

This paper reports a case of severe low output cardiac failure due to congestive (alcoholic) cardiomyopathy which was unresponsive to dopamine infusion, but which improved rapidly on intravenous practolol therapy. The therapeutic range of beta-blockade turned out to be quite narrow.

Beta-adrenergic stimulation of the failing ventricle: a double-blind, randomized trial of sustained oral therapy with prenalterol.

Eleven patients with severe left ventricular impairment (mean ejection fraction 24%) and moderate impairment of exercise tolerance underwent a double-blind, placebo-controlled, cross-over trial of the orally administered beta-agonist prenalterol. Exercise hemodynamics and tolerance were measured during bicycle and treadmill exercise after 2 weeks of therapy with placebo or prenalterol. Cardiac index, ejection fraction, and stroke work index were not improved and exercise duration and peak oxygen consumption were not significantly different during the two treatments. During prenalterol treatment heart rate during exercise was consistently reduced. These results show that prolonged therapy with prenalterol does not improve hemodynamics or exercise tolerance and is associated with a diminished heart rate response to exercise.

Contractile, coronary, and metabolic effects of the acute and long-term treatment of cardiac failure with prenalterol.

Prenalterol was examined with regard to its acute intravenous effects on left ventricular function, coronary hemodynamics, and myocardial oxygen consumption, as well as for its long-term effects, by oral therapy, on left ventricular function and systemic hemodynamics. Intravenous prenalterol enhances myocardial contractility and left ventricular ejection function significantly. A decrease in total peripheral vascular resistance is effected. Myocardial oxygen consumption is only moderately increased, most probably because of the decrease in the systolic integrated wall stress of the left ventricle. The changes of coronary circulation (blood flow, resistance, arteriovenous, oxygen difference) indicate benign and metabolically induced coronary vasodilation. Long-term oral treatment of patients with severe cardiac failure by prenalterol effects significant enhancement in-left ventricular performance within the first 1-2 months of treatment; however, this effect is not present at longer therapy intervals (16-28 weeks). Tolerance development as well as the natural history of these patients may be responsible for this inotropic amelioration. There were no clinical side effects with either intravenous or oral application. It may be concluded that prenalterol is highly effective in acute cardiac failure (intravenous administration) and also in chronic heart disease (long-term oral application). However, the long-term effects are unpredictable, and tolerance development has to be considered.

Acute intravenous and sustained oral treatment with the beta1 agonist prenalterol in patients with chronic severe cardiac failure.

Prenalterol, a beta1 agonist, was given in a single blind acute intravenous study to seven patients with cardiac failure (New York Heart Association class II and III). It was then given in a double blind crossover study of sustained oral prenalterol to six of them. As a result of dose titration studies the oral dose of prenalterol given was 100 mg twice a day in all patients. Erect bicycle sprint tests were performed to exercise tolerance before and after treatment had been started. Cardiac function was assessed at rest and during graded supine bicycle exercise by determining haemodynamic indices using a Swan-Ganz catheter and radionuclide left ventricular ejection fractions. In the intravenous study cardiac function was assessed at rest and during exercise after a control infusion of dextrose and after an infusion of 5 mg prenalterol. In the oral crossover study a placebo or prenalterol were given for two periods of two weeks; at the end of each period exercise tolerance was measured and cardiac function assessed at rest and during exercise. Throughout the study period there was no change in symptoms, medication, or exercise tolerance. Intravenous prenalterol significantly improved cardiac function; left ventricular ejection fraction and cardiac index increased and left ventricular filling pressure fell both at rest and during exercise. Sustained oral treatment with prenalterol, however, did not improve resting left ventricular filling pressure or left ventricular ejection fraction at rest or during exercise but did increase heart rate at rest, and mean blood pressure and peripheral vascular resistance at rest and during exercise; in fact, during exercise left ventricular filling pressure was significantly increased while cardiac index and stroke volume index were decreased by prenalterol. Sustained oral treatment with prenalterol did not have the beneficial effects on cardiac function produced by intravenous treatment and in fact had deleterious effect on the measured indices of cardiac function during exercise.

Prenalterol in the treatment of orthostatic hypotension in Shy-Drager syndrome.

The effects of prenalterol, a selective beta 1-adrenoreceptor agonist, were studied in a patient with the Shy-Drager syndrome, presenting with incapacitating orthostatic hypotension. The main haemodynamic defect was an impressive postural fall in stroke volume and cardiac output pointing to denervation of the capacitance vessels. Prenalterol 4 X 30 mg orally produced a marked increase in supine and standing blood pressure, along with substantial symptomatic improvement. Notable positive chronotropic and inotropic effects were observed. Association of fludrocortisone 0.5 mg/day resulted in further haemodynamic and symptomatic improvement, presumably due to plasma volume expansion. Haemodynamically, prenalterol and fludrocortisone resulted in a substantial increase in standing cardiac output, primarily due to the chronotropic effects of prenalterol. In addition to the haemodynamic effects, prenalterol stimulated the renin-aldosterone system and restored the normal diurnal pattern of water and sodium excretion, the latter may have contributed to the improvement of orthostatic tolerance. Prenalterol could be a valuable adjunct to the existing treatment schedules of neurogenic orthostatic hypotension.

Haemodynamic and cardiac metabolic effects of the new beta 1 agonist prenalterol in patients with cardiac failure.

Prenalterol, a beta 1 selective agonist, exerts a positive inotropic action in animal studies as well as in human volunteers and is effective when administered orally. To assess its immediate haemodynamic and myocardial metabolic effects, we studied the response to prenalterol (50 and 100 micrograms kg-1 given intravenously by cardiac catheterization) in 15 patients with congestive heart failure secondary to coronary artery disease or non-ischaemic cardiomyopathy. At peak effect, cardiac index increased from 2.6 +/- 0.5 to 3.2 +/- 0.8 l min-1 m2 (mean +/- S.D.) (P less than 0.001); peak rate of left ventricular pressure development rose from 963 +/- 242 to 1335 +/- 411 mmHg s-1 (P less than 0.001); left ventricular end-diastolic pressure fell from 25 +/- 6 to 17 +/- 7 mgHg (P less than 0.001); coronary sinus blood flow increased from 113 +/- 39 to 148 +/- 55 ml min-1 (P less than 0.01); myocardial oxygen consumption was augmented from 12.7 +/- 3.9 to 16.4 +/- 5.8 ml min-1 (P less than 0.001); and heart rate increased slightly (from 76 +/- 12 to 86 +/- 14 beats min-1; (P less than 0.05)). No significant changes occurred in left ventricular systolic pressure, stroke volume index, myocardial lactate extraction rate and myocardial arteriovenous oxygen difference, and no patients developed angina, ECG changes or ventricular arrhythmias. Infusion of prenalterol effectively improved haemodynamic function and cardiac metabolism in cardiomyopathy. Therefore this agent deserves further investigation to evaluate its possible role for the long-term therapy of patients with chronic heart failure.

Prenalterol in primary dilated cardiomyopathy: hemodynamic and angiographic evaluation.

The hemodynamic effects of an acute infusion of prenalterol (PN), a new inotropic beta-adrenoceptor agonist, have been evaluated by cardiac catheterization in 10 patients with primary dilated (congestive) cardiomyopathy. A single dose of 20 micrograms/kg was administered over 5 min after basal hemodynamic and angiographic measurements. The administration of prenalterol caused a significant increase in mean cardiac index, from 2.3 to 3.3 l/min/m2 (P less than 0.01) and mean stroke volume, from 47 to 62 ml (P less than 0.01) without a change in heart rate. Mean left ventricular end-diastolic pressure was reduced from 19 to 13 mm Hg (P less than 0.05) and left ventricular dp/dt rose from 902 to 1089 mm Hg/s (P less than 0.01). Stroke work index increased from 27 to 40 g m/m2 (P less than 0.01) and ejection fraction from 31 to 36% (P less than 0.05). Mean blood pressure did not change and the systemic vascular resistance decreased from 24 to 17 RU (P less than 0.01). The favorable effect of prenalterol on left ventricular relaxation was shown by an increase of peak negative left ventricular dp/dt from 946 to 1159 mm Hg/s and by a decrease of the time constant of left ventricular pressure fall from 49 to 39 s. These results demonstrated a positive inotropic effect of prenalterol on patients with diffuse and severely reduced contractility.

Hemodynamic, hormonal and electrolyte responses to prenalterol infusion in heart failure.

The hemodynamic, hormonal and electrolyte effects of prenalterol, a synthetic selective beta 1 agonist, were studied in six patients with New York Heart Association functional class II and III heart failure. Prenalterol was infused incrementally at 60, 120 and 240 nmol/min, each rate for 24 hours, producing steady-state plasma prenalterol levels of 52 +/- 3, 121 +/- 6 and 194 +/- 9 nmol/1, respectively (mean +/- SEM). Hemodynamic and hormonal measurements were performed before, during and after prenalterol administration under conditions of constant body posture and a regulated intake of dietary sodium and potassium. Prenalterol induced a statistically significant increase in cardiac index (from 2.6 +/- 0.2 to 3.1 +/- 0.3 1/min/m2), with parallel increases in stroke index (from 28 +/- 2 to 34 +/- 2 ml/beat/m2). Forearm blood flow measurements increased (from 2.9 +/- 0.5 to 4.1 +/- 0.6 ml/min/100 g), while calculated systemic vascular resistance fell, as did pulmonary capillary wedge pressure (from 13.7 +/- 1.6 to 10.5 +/- 1.7 mm Hg). The drug did not alter heart rate, arterial pressure, right heart pressures or the frequency of ventricular premature beats. Prenalterol increased plasma renin activity (from 2.9 +/- 0.8 to 6.6 +/- 1.8 nmol/1/hour), angiotensin II (from 59 +/- 12 to 89 +/- 22 pmol/1), urinary aldosterone excretion (from 41 +/- 10 to 78 +/- 34 nmol/day) and plasma insulin (from 10.6 +/- 2.2 to 19.8 +/- 3.9 mU/1). Circulating catecholamines, cortisol, glucose, glucagon or pancreatic polypeptide did not change. Dose-response studies in five patients showed dose-dependent increments in hemodynamic variables, while hormonal changes plateaued at the second dose level. We conclude that prenalterol infusion augments myocardial contractility, reduces systemic vascular resistance, and stimulates insulin release and the renin-angiotensin-aldosterone system.

Ultrastructural changes in rat parotid acinar cells after selective beta 1-adrenoceptor agonist treatment.

Administration of the selective beta 1-adrenoceptor agonist, prenalterol, affects the acinar cell of the rat parotid in a manner similar to that observed after isoprenaline (IPR) treatment. Sixty minutes after injection of prenalterol, many cells are depleted of their zymogen granules and there is evidence of secretory protein resynthesis. Long term treatment leads to cellular hypertrophy and marked structural changes in the granule population. The cellular alterations are, however, not as pronounced as those observed after IPR injections. This may be due to the combined beta 1- and beta 2-adrenoceptor effect of IPR. With prenalterol, cell damage is obvious in acute experiments. In long term treated animals numerous characteristic autophagic vacuoles are observed, reflecting a reorganization of cytoplasmic components in superstimulated glands. Although prenalterol and IPR give rise to rather similar structural changes in parotid glands, marked differences between effects of the two drugs on gland biochemistry have been noted. It seems evident that different biochemical pathways involved in secretory activity have actions in common with respect to effects on submicroscopical structures.

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.