Zero-Order Release Formulation of Oxprenolol Hydrochloride with Swelling and Erosion Control

Zero-order release of oxprenolol hydrochloride was obtained by controlling the swelling and erosion of the matrix. This formulation involves only mixing of drug, hydroxypropylmethylcellulose (HPMC), and sodium carboxymethylcellulose (Na CMC) at the ratio of 1:0.4:1.6, respectively, and compressing the mixture directly into tablets. The in vitro release pattern from this optimized matrix tablet was reproducible. Accelerated stability studies revealed that the optimized formulation remains stable for an approximately 2-year shelf life. This sustained-release (SR) tablet was evaluated in dogs, and for comparison a conventional (CV) formulation was also given at the same dose level. Plasma oxprenolol levels were monitored by a sensitive and specific high-performance liquid chromatographic (HPLC) method. Significant differences in the pharmacokinetic parameters, i.e., lower C _max, higher values of t _max, MRT, AUC, and plasma concentration at 24 hr, and nearly constant plasma levels over 12 hr, indicated that the SR matrix tablet is superior to the CV rapid-releasing formulation. The in vitro release parameters and in vivo pharmacokinetics correlated well.     

Binding ofβ-adrenoceptor blocking drugs to human serum albumin,to α1-acid glycoprotein and to human serum

Summary The binding of 8 -adrenergic blocking drugs to human serum albumin, to ₁-acid glycoprotein and to serum from normal volunteers and from patients with rheumatoid arthritis was studied. Protein binding was determined in vitro using equilibrium dialysis of labelled drug at 25° C. Oxprenolol and propranolol were highly bound to serum, alprenolol, pindolol and timolol to a lesser degree, and atenolol, metoprolol and sotalol were negligibly bound. For the five compounds which were appreciably bound, the mean binding was significantly higher in serum from patients with rheumatoid arthritis than in serum from normal volunteers. For those drugs, binding to ₁-acid glycoprotein was higher than to human serum albumin, and binding to a mixture of both proteins approached that to serum from healthy volunteers. For each of these drugs there was a strong correlation between the serum ₁-glycoprotein concentration and the percentage binding.     

The Influence of Monotherapy with Oxprenolol and Nitrendipine on Ambulatory Blood Pressure in Hypertensives

We investigated whether beta-blockers or calcium-antagonists might be preferred in baseline antihypertensive therapy. In middle-aged male patients with essential BP readings did not differ between patients on Oxpranolol or on Nitrendipine (average BP: 123 12/81 14 vs. 129 17/80 10 mmHg), when clinical casual BP was within the normotensive range. Average BP at work was lower than clinical casual BP taken at the same day (125 14/80 12 vs. 133 12/87 13 mmHg). A linear dependency between SBP at work and level of self reported physical activity (F(3,413) = 7.6; p 0.001) and arousal was found (F(3, 374) = 5.2; p 0.02). Patients on Oxprenolol consistently had lower SBP at a particular level of physical activity and at lower levels of arousal than patients on Nitrendipine. We conclude that both regimen were equally effective as baseline antihypertensive monotherapy.     

Interference by sulphinpyrazone with the antihypertensive effects of oxprenolol

Summary The interfering effect of sulphinpyrazone, a uricosuric agent which reduces the activity of cyclo-oxygenase, with the antihypertensive activity of oxprenolol, a non-cardioselective beta-blocker with sympathomimetic activity, has been evaluated. Ten patients with primary arterial hypertension of mild to moderate degree entered a randomized doubleblind cross-over study versus placebo. They were given oxprenolol + placebo or oxprenolol + sulphinpyrazone for 15 days, and then the treatments were crossed-over for a further 15 days. Oxprenolol significantly reduced blood pressure (161±3/101±1 vs 149±4/96±2 mmHg) and heart rate (72±3 vs 66±3 beats/min). During administration of the combination with sulphinpyrazone the blood pressure increased to its pretreatment level (156±5/101±2 mmHg). The effect of oxprenolol on heart rate was not influenced by the combined treatment (67±6 beats/min). The results may be explained by 1) sulphinpyrazone-induced inhibition of prostaglandin synthesis, which could interfere with the antihypertensive activity of oxprenolol, or 2) sulphinpyrazone-induced acceleration of the metabolism of oxprenolol.     

Effect of oxprenolol and metoprolol on serum lipid concentration

Summary The aim of the present study was to evaluate whether a reduction in HDL-cholesterol is peculiar to non cardioselective beta blockers or whether it is also produced by cardioselective beta₁-blockers. 16 patients with primary arterial hypertension on a balanced isocaloric diet were given oxprenolol 120 to 240 mg/day or metoprolol 100 to 200 mg/day in a random cross-over study. No significant change was observed after either treatment in fasting blood glucose, serum total cholesterol and triglycerides. HDL-cholesterol concentration was significantly decreased on metoprolol, from 41 to 36 mg/dl (p<0.05), while oxprenolol did not affect it at all. The difference might depend on intrinsic sympathomimetic activity which is possessed by oxprenolol and which metoprolol lacks.     

Blockade of 5-hydroxytryptamine receptors in the central nervous system by beta-adrenoceptor antagonists.

(±)-propranolol, oxprenolol and pindolol in doses ranging from 0.5 to 5 mg/kg antagonised the head twitch produced in mice by 5HTP. These doses had no effect on the pinna reflex. (+) propranolol was inactive. These β-adrenoceptor antagonists also prevented the induction of sleep in 5-day old chicks by 5HT. Their activities in the two tests were similar to their 5HT receptor blocking potencies in the rat fundus preparation. It is suggested that these β-adrenoceptor antagonists may block some 5HT receptors in the central nervous system.     

Effects of beta-adrenergic blocking drugs on ventilatory function in asthmatics

Summary The effects on respiratory function have been compared of five different beta-blocking drugs injected intravenously in asthmatic patients. In all groups but one there was a decrease in FEV₁ and an increased nitrogen washout time. After practiolol, only two cases of increase of nitrogen washout time were observed without a fall in FEV₁. Thus practolol seems much safer than the other agents in patients prone to respiratory distress.     

An application of receptor models to the analysis of data on β-adrenoceptor blockade

1. The classical single receptor competitive occupancy model accurately describes the joint action of an agonist (isoprenaline) and a β-adrenoceptor antagonist (propranolol) or some partial agonists (dichlorisoprenaline, practolol) on the positive chronotropic response in rats which have been depleted of catacholamines. 2. The mathematical form of the model suggests that the dissociation constants of classical competitive partial agonists may be assessed using dose ratios by exactly the same method as that currently used for agonist-antagonist interactions, provided that the log dose-response curves are first suitably normalized. 3. Close agreement between the theoretical mathematical models and the experimental data can be demonstrated by statistical fitting for certain β-adrenoceptor antagonists (propranolol, dichlorisoprenaline, practolol). 4. The model fails to describe the behaviour of other β-adrenoceptor antagonists (oxprenolol, pindolol). A possible extension of the model to include these drugs is proposed.     

Haemodynamic effects,plasma concentrations and tolerance of orally administered prenalterol in man

Summary Prenalterol was studied in six healthy volunteers given single oral doses of 2.5, 5 and 10 mg and placebo. It displayed a distinct positive inotropic action, manifested as a dose-related reduction of 16.5–27.2 msec in the pre-ejection period (PEP_c; systolic time-intervals), and an increase of 4.2–5.9 /sec² in the Heather index (impedance cardiography). There was also a dose-related increase of 17.6–34.0 mmHg in systolic blood pressure, whereas diastolic pressure showed a slight, transient decrease, not related to the dose given. Heart rate rose by 5–12 beats/min. Stroke volume, as determined by impedance cardiography, increased by 24.2–28.5 ml at all three dose-levels. The effects of the drug developed rapidly, reaching their maximum within 30–60 min and lasting for about 4 h. The time-course of the effects corresponded to the plasma concentrations of the drug. The increases in systolic pressure and contractility were linearly correlated with the plasma concentrations (r=0.8–0.9,p<0.001). The activity of prenalterol was also tested in the same volunteers after blockade of -receptors with oxprenolol 80 mg. Under these conditions, oral doses of 25, 50 and 100 mg produced effects similar to or slightly less marked than those recorded after doses ten times lower in the absence of -blockade. In a further 10 healthy volunteers, in whom tolerance to prenalterol was studied by repeated administration for 10 days of 5 mg four times daily, no change in blood chemistry, haematological parameters or urine values was found. The positive inotropic effect of a single oral dose of prenalterol 5 mg was also demonstrated by reference to the systolic time-intervals and the echocardiogram, in six patients with chronic heart failure, five of whom were digitalized. Prenalterol did not give rise to premature concentrations or other arrhythmias. The only untoward effect definitely attributable to the drug was palpitation, which was dose-related and as a rule was not unduly distressing; in one volunteer, however, the palpitations were unbearable. Prenalterol is a cardiostimulant agent with no direct effect on the peripheral circulation. On the basis of its pharmacological activity, it might well be of therapeutic benefit in all conditions in which an improvement in the pumping efficiency of the heart is required.     

The effects of beta-adrenergic blocking agents on blood lipid levels

This review examines the effects of beta-adrenergic blocking agents on blood lipids. These agents have been effective in the treatment of angina and hypertension and in the reduction of recurrence of ischemic cardiac disease, such as myocardial infarction. Many beta blockers, however, have an adverse effect on blood lipids, especially by reducing high-density lipoprotein (HDL) cholesterol and increasing triglycerides. One result is an unfavorable influence on the cholesterol ratio (expressed either as low-density lipoprotein [LDL]/HDL or total cholesterol/HDL). These cholesterol parameters have been shown to have a strong influence on coronary heart disease (CHD) risk. Studies have shown that antihypertensive therapy has reduced the incidence of cerebrovascular disease but, in many instances, has not reduced the incidence of CHD. A hypothesis for this lesser effect on coronary disease is that antihypertensive agents may be adversely affecting blood lipids. Thus, while one major risk factor for CHD is reduced, another may be somewhat enhanced. Pharmacologic properties of some beta blockers such as peripheral alpha blockade (e.g., with labetalol) or intrinsic sympathomimetic activity (ISA) (e.g., with pindolol) may counteract some of these negative lipid effects. An investigational beta blocker, bevantolol, which will be marketed shortly in the United States, has been effective in antihypertensive therapy. Bevantolol has been shown to lower LDL cholesterol and not adversely affect HDL cholesterol; in this way, bevantolol favorably influences the serum lipoprotein profile. Whether this effect will have clinical significance remains to be seen.