Oxprenolol vs propranolol: a randomized, double-blind, multiclinic trial in hypertensive patients taking hydrochlorothiazide. Veterans Administration Cooperative Study Group.

Oxprenolol (O) or propranolol (P) was randomly added double-blind to the regimen of 260 patients with mild and moderate hypertension who had not responded to hydrochlorothiazide (H) alone. Both beta-adrenergic blocking agents were titrated over a range of 120 to 360 mg per day while H was continued. After 6 months of treatment, reduction of diastolic blood pressure (DBP) to below 90 mm Hg and at least 5 mm Hg less than the initial DBP was achieved in 50% of patients receiving P+H and 27% of patients taking O+H (p less than 0.001). P+H lowered BP an additional 10.5/9.8 mm Hg compared with 6.8/7.0 mm Hg for O+H (p less than 0.02). Reduction in heart rate was less after O+H (average, 8.4/min) than after P+H (average, 12.3/min, p less than 0.01). The number of dropouts, morbid events, and reported side effects between the two regimens was not significantly different except that more patients complained of impotence with P+H than with O+H (p less than 0.05).

Antihypertensive effectiveness of oxprenolol administered twice daily.

Oxprenolol, a beta-blocker, is an effective antihypertensive when administered 3 or 4 times daily. We evaluated the antihypertensive effect of oxprenololgiven twice daily (bid). The subjects were 15 ambulatory men whose standing diastolic blood pressure (BP) was at least 100 mm Hg after 3 wk of treatment with hydrochlorothiazide and oxprenolol placebo. Oxprenolol 40 mg twice daily was then substituted for the placebo. On subsequent weekly vists oxprenolol was titrated to 80 and 160 mg bid if the standing diastolic BP was greater than 90 mm Hg. BLood pressures on the last visit on placebo were compared to those on the last visit on oxprenolol. Standing BP declined from 145 +/- 4/108 +/- 1 to 130 +/- 4/98 +/- 4 on a mean dose of 256 mg of oxprenolol (p less than 0.001 syst.; p less than 0.01 diast.). Recumbent BP fell from 146 +/- 4/107 +/- 1 to 138 +/- 5/93 +/- 2 (p less than 0.06 syst.; p less than 0.01 diast.). During the final week, 13 of the 15 patients were admitted to the hospital for 24-hr monitoring of BP. The 24-hr BP readings showed a mean coefficient of variation of 6.6% recumbent and 7.2% standing. we conclude that bid oxprenolol will maintain 24 hr BP control in most patients.

Pharmacokinetics of oxprenolol in normal subjects.

The effect of oxprenolol administered intravenously (10 and 20 mg) and orally (20, 40, 80, and 160 mg) on plasma concentrations of the drug, resting heart rate, exercise-induced tachycardia, and arterial blood pressure was assessed as a function of time in 6 healthy subjects. The pharmacokinetics of oxprenolol following intravenous administration are best described as 2-compartnent open model with dose-dependent parameters. The mean (+/-SD) plasma half-life for oral doses is 1.94 +/- 0.37 and for intravenous doses is 2.31 +/- 0.64 hr. After oral administration, peak plasma concentrations are reached within 30 to 90 min, and the area under the plasma concentration-time curve varies linearly with the dose. Comparison of oral and intravenous data reveals the variation in bioavailabilty of orally administered oxprenolol to range from 19% to 74%. Unlike propranolol, oxprenolol does not show a saturable "first-pass" elimination effect. Blockade of beta-receptors occurs at plasma levels in excess of 60 ng/ml as evidenced by significant reductions in resting heart rate and exercise-induced tachycardia. Higher plasma concentrations of oxprenolol are required to lower blood pressure compared to those necessary to slow heart rate. These data suggest significant pharmacokinetic differences between oxprenolol and other beta-adrenergic receptor antagonists.

Oxprenolol in the treatment of anxiety due to environmental stress.

The author conducted two trial studies to evaluate the use of oxprenolol in the treatment of symptoms resulting from environmental stress. Results indicated that on a three-times-a-day regimen, 80 mg of oxprenolol was superior to 20 mg of oxprenolol and equally as effective as 5 mg of diazepam. The author discusses the benefit of beta-blocking drugs and points to the need for further studies.

Effect of slow oxprenolol and a combination of slow oxprenolol and cyclopenthiazide on plasma lipoproteins.

The effect of slow oxprenolol on plasma lipoprotein concentrations was compared to that of combined therapy with slow oxprenolol and cyclopenthiazide. The design of the study was a double blind between patient investigation in which 9 subjects with mild hypertension received slow oxprenolol and 11 slow oxprenolol and cyclopenthiazide. Plasma lipoproteins were analysed at 0, 2, 4, 8, 12 and 16 weeks. Slow oxprenolol given alone resulted in a significant rise in plasma and low density lipoprotein (LDL) cholesterol concentration whereas combined therapy with slow oxprenolol and cyclopenthiazide produced significant rises in plasma and very low density lipoprotein (VLDL) triglyceride. If one accepts that a rise in plasma or LDL cholesterol increases atherogenic risk more than a rise in plasma or VLDL triglyceride combined therapy is preferable.

Comparison of five beta-adrenoreceptor antagonists with different ancillary properties during sustained twice daily therapy in angina pectoris.

The effects of five beta-adrenoreceptor blocking agents and placebo during twice daily sustained therapy were compared in 23 patients with stable, exertional angina pectoris. The study was double blind in design, and each drug was prescribed for a period of one month in a random fashion. The number of anginal attacks and consumption of glyceryl trinitrate tablets during the one month period were significantly reduced by a similar degree during therapy with all five beta blocking drugs in comparison to the placebo (P less than 0.01). Exercise tolerance, when assessed 12 hours after a previous dose had been given and 1 hour after the morning dose was given, also improved by a similar degree with all five drugs in comparison to the placebo (P less than 0.01). The increase in exercise duration was associated with a significant reduction in the S-T segment depression, heart rate, systolic blood pressure, and the product of heart rate and systolic blood pressure, with each of the five drugs--effects markedly different from those obtained with the placebo (P less than 0.01). These data show that noncardioselective (propranolol and oxprenolol) and cardioselective (practolol, metoprolol and tolamolol) agents, as well as drugs with intrinsic sympathomimetic activity (oxprenolol and practolol), were equally effective antianginal agents during sustained therapy. Furthermore, twice daily therapy with any of these drugs was effective in the management of patients with angina pectoris.

Clinical responses to oxprenolol in the elderly.

Data from 6 controlled clinical trials of oxprenolol carried out in the United States were reviewed to determine the efficacy and tolerability of oxprenolol in patients aged greater than or equal to 55 years. All study designs but 1 called for dosage to be increased to a maximum of 480 mg/day. In a 10-week trial of oxprenolol versus placebo given twice daily, oxprenolol reduced diastolic pressure by 8 mm Hg, while placebo reduced it by 3 mm Hg. A comparison of once-daily with twice-daily dosing showed similar results for both groups: -12/-6 mm Hg for once-daily and -9/-8 mm Hg for twice-daily. There were 2 short-term studies comparing oxprenolol and placebo, both given in addition to hydrochlorothiazide. In the first, the change in blood pressure with oxprenolol was -18/-14 mm Hg and with placebo was +6/-3 mm Hg; only 3 of 14 patients receiving oxprenolol received a maximal dosage. In the follow-up study, most of the dosages were titrated to maximum; reductions were -9/-9 mm Hg with oxprenolol treatment and 0/-12 mm Hg with placebo. Two long-term studies compared oxprenolol and propranolol, also as combination therapy with hydrochlorothiazide. In the 14-week study, the reduction in blood pressure was slightly better with oxprenolol: -15/-15 versus -12/-11 mm Hg. In the 27-week study, almost half of the patients in the oxprenolol group received the maximal dosage. Blood pressure was reduced 2 or 3 mm Hg less with oxprenolol than with propranolol. Oxprenolol was well tolerated in the elderly; it produced a low incidence of typical beta-blocker side effects even when given in a once-daily regimen.

Pharmacokinetics of oxprenolol in the elderly.

This paper is a brief review of the problems associated with drug therapy in the elderly. Although the elderly are more prone to suffer adverse reactions to drugs and to respond abnormally, impaired drug handling should not be blamed for these problems until other factors have been evaluated. Renal function deteriorates as people grow older, but the absorption, metabolism and distribution of most drugs may not be adversely affected by advancing age. Evidence to the contrary is sometimes based on studies of convalescent patients in whom an effect of disease or drug therapy cannot be excluded. For an assessment of the effects of aging on the pharmacokinetics of oxprenolol, 2 groups of 8 healthy females, mean age 21 and 68 years, respectively, were studied. Oxprenolol, 80 mg, was given orally in a single dose on day 1 and day 8 of a course of treatment; on the intervening days, oxprenolol, 80 mg, was given twice daily. The mean plasma concentration:time curves for both day 1 and day 8 for the 2 age groups were comparable. Thus, age alone does not affect the pharmacokinetics of oxprenolol.

United States experience with oxprenolol in hypertension.

Double-blind, randomized, parallel-group studies have confirmed that oxprenolol, either alone or in combination with a thiazide, is effective in reducing elevated blood pressure. In 2 of 3 comparisons with placebo, the blood pressure reduction was significantly more effective with oxprenolol; in 1 study, even though the placebo response was pronounced, oxprenolol was still more effective than placebo. In 2 studies propranolol reduced blood pressure by about 2 mm Hg more than oxprenolol. In the larger, longer-term study this difference was significant at the end of the dose-titration period, but there were no significant differences between the 2 treatment groups at study end. Moreover, oxprenolol reduced heart rate less and was associated with fewer side effects. Oxprenolol effectively lowered blood pressure when given once daily and was well tolerated, even in large doses. Blood pressure was reduced less with oxprenolol than with hydrochlorothiazide, -14/-11 versus -20/-13 mm Hg. The mean reduction with oxprenolol was less for black patients than for white. In a 1-year safety study, 86% of the patients continued to have a diastolic pressure of less than 90 mm Hg at study end.

Slow release oxprenolol in angina pectoris: study comparing oxprenolol, once daily, with propranolol, four times daily.

Oxprenolol and propranolol are noncardioselective beta adrenoreceptor blocking agents known to be equally effective in the management of patients with angina pectoris. Both are usually prescribed four times daily. Slow release formulation of oxprenolol administered once daily has been shown to maintain therapeutic effects for 24 hours. In a double-blind crossover study in 23 patients with stable angina pectoris, the effects of 160 mg slow release oxprenolol, administered once daily for 1 month, were compared with those of 40 mg of propranolol given four times daily for a similar period. No adverse effects occurred when patients were switched between treatment schedules. The average number of anginal attacks experienced were 11/month during oxprenolol therapy and 8/month during propranolol therapy (difference not significant). The resting values for heart rate were higher 7 1/2 nd 24 hours after oxprenolol than they were 4 and 12 hours after propranolol (p less than 0.01). The treadmill walking time to the onset of angina and to the development of moderate angina 24 hours after oxprenolol was less than that observed 7 1/2 hours after the drug or 4 and 12 hours after propranolol (p less than 0.01). In contrast, the values for walking time to the onset of angina and to the development of moderate angina at 4 and 12 hours after propranolol were similar. This decreased exercise tolerance 24 hours after oxprenolol was associated with a lesser degree of beta adrenoreceptor blockade than that present after propranolol as documented by higher levels of heart rate (p less than 0.05), systolic blood pressure (p less than 0.05) and rate-pressure product (p less than 0.05) during exercise after oxprenolol therapy. It is concluded that in the doses used, slow release oxprenolol administered once daily does not exert as consistent a beneficial effect on exercise tolerance throughout the dosing schedule as does propranolol given four times daily.

Oxprenolol: clinical pharmacology, pharmacokinetics, and pharmacodynamics.

Oxprenolol is clinically a well-established beta blocker that shares with other members of this group the ability to control a variety of disorders, in particular, hypertension and angina. Pharmacologically it is a nonselective beta blocker that possesses partial agonist activity (intrinsic sympathomimetic activity). Pharmacokinetically, oxprenolol behaves as a moderately lipophilic agent. This means that it is well absorbed, but then undergoes considerable first-pass loss. It penetrates well into most tissues, including the central nervous system. About 80% of oxprenolol is bound to protein in the blood, and when acute-phase proteins increase, as, for example, in patients with inflammatory disease, total plasma concentrations of oxprenolol also increase. Apart from this, the plasma concentration:time profile produced after the oral administration of oxprenolol is remarkably consistent and reproducible. Intrasubject and intersubject variability is small, and the administration of the drug after food or with many other drugs has very little effect. The beta-blocking effects of oxprenolol correlate well with the plasma concentrations, but as with other beta blockers, it has not been possible to correlate plasma concentrations directly with its therapeutic actions such as lowering blood pressure or controlling arrhythmias.

Serial measurements of systolic time intervals during treatment with hydrochlorothiazide alone and combined with other antihypertensive agents.

As part of the Veterans Administration cooperative studies on antihypertensive agents, systolic time intervals (STIs) were recorded before and after 2 or 4 weeks of treatment with hydrochlorothiazide (HCTZ) alone in 320 asymptomatic patients with mild to moderate hypertension. After treatment with HCTZ, left ventricular ejection time corrected for heart rate (delta LVET) was significantly reduced. This decrease is consistent with other hemodynamic observations indicating a reduced preload and stroke volume after administration of thiazides. Electromechanical systole corrected for heart rate (delta QS2) decreased, while the ratio of preejection period to LVET (PEP/LVET) increased, reflecting reduced left ventricular function. PEP did not change. Four step 2 drugs--hydralazine, prazosin, oxprenolol and propranolol--were then added randomly to HCTZ and further recordings of STIs were taken at 1 and 6 months after administration of these drugs. The delta LVET and delta QS2 increased and PEP/LVET decreased, suggesting improved left ventricular function after administration of all 4 agents. These changes may have been due to the added agents or to the recovery of cardiac output that occurs independently during long-term treatment with thiazide diuretic drugs alone. PEP decreased slightly after hydralazine and prazosin and increased slightly after treatment with the beta-blocking drugs, although none of these changes were significant except those during hydralazine treatment. Processing of the STIs was greatly facilitated by the automated system for recording and analyzing the measurements.

Evaluation of L-tryptophan for treatment of insomnia: a review.

Sleep laboratory and outpatient studies of the hypnotic efficacy of the amino acid L-tryptophan are reviewed, with particular emphasis on evaluation of therapeutic effectiveness in the treatment of insomnia. In younger situational insomniacs, whose sleep problem consists solely of longer than usual sleep latencies, L-tryptophan is effective in reducing sleep onset time on the first night of administration in doses ranging from 1 to 15 g. In more chronic, well-established sleep-onset insomnia or in more severe insomnias characterized by both sleep onset and sleep maintenance problems, repeated administration of low doses of L-tryptophan over time may be required for therapeutic improvement. In these patients, hypnotic effects appear late in the treatment period or, as shown in some studies, even after discontinuation of treatment. The improvement in sleep measures post-treatment has given rise to use of a treatment regimen known as "interval therapy", in which L-tryptophan treatment alternates with an L-tryptophan-free interval until improvement occurs. The absence of side effects and lack of development of tolerance in long-term use are important factors in the decision to embark upon a trial of L-tryptophan treatment. In addition, L-tryptophan administration is not associated with impairment of visuomotor, cognitive, or memory performance, nor does it elevate threshold for arousal from sleep.

Captopril and oxprenolol in a fixed combination with thiazide diuretics: comparison of their antihypertensive efficacy and metabolic effects.

After receiving placebo for two weeks, 20 patients with essential hypertension were randomly divided into two groups. Those in group 1 received a combination of 25 mg of captopril (CPT) and 25 mg of hydrochlorothiazide (HCT) BID. Those in group 2 received a combination of 80 mg of oxprenolol (OXP) and 10 mg of chlorthalidone (CHLT) BID. Patients whose recumbent diastolic blood pressure was less than 95 mmHg after four weeks of treatment continued with the same regimen for six more weeks, while the dosages were doubled for nonresponders. All the patients in group 1 had satisfactory blood pressure readings after the first four weeks of therapy; six patients in group 2 required double dosages to control their blood pressure. Both drug combinations reduced patients' recumbent systolic blood pressure, but CPT + HCT reduced their diastolic and standing systolic blood pressure more effectively. Doubling the dosages of OXP + CHLT was only slightly more effective in controlling patients' blood pressure. In addition, patients who received CPT + HCT showed a significant decrease in serum sodium level, whereas patients who received the double dosages of OXP + CHLT showed a significant increase in serum cholesterol and creatinine levels. The data suggest that low dosages of CPT + HCT control blood pressure more effectively than high dosages of OXP + CHLT and, in addition, do not have any negative metabolic effects.

Hydrochlorothiazide and triamterene with sustained-release oxprenolol in the treatment of hypertension.

A single-blind, three-way Latin square crossover study without wash-out periods was performed in a general practice. Thirty moderately hypertensive patients were studied to compare the antihypertensive effect of 160 mg sustained-release oxprenolol once daily, 25 mg hydrochlorothiazide/50 mg triamterene once daily or a combination of the two preparations once daily, each treatment being given for 1 month. Blood pressure control was significantly better with the combination than with either agent used separately. Pulse rates, as expected, were lower when sustained-release oxprenolol was taken either alone or in the combination. Adverse events led to withdrawal in 1 patient only. Otherwise, all treatments were well tolerated and compliance was excellent. Renal function tests indicated a slight increase in creatinine, urate and urea levels after the treatments which included hydrochlorothiazide compared with oxprenolol alone, although the results were of no clinical significance.

Experience with a sustained-release formulation of oxprenolol in the management of angina pectoris in hospital out-patient departments.

One hundred and two patients with angina pectoris under treatment with beta-receptor antagonists prescribed on a multi-dose basis were openly switched to treatment with once-daily sustained-release oxprenolol (160 mg per tablet). Eighty-eight patients were successfully managed on once-daily oxprenolol and 70% achieved significant benefit with a single morning dose of 160 mg. The mean number of anginal attacks and the mean glyceryl trinitrate consumption were both significantly reduced. It is concluded that once-daily treatment with oxprenolol in sustained-release form offers the advantage of reduced tablet ingestion without symptomatic detriment in the management of angina pectoris.

Beta-adrenergic blocking drugs in anxiety and stress.

A series of controlled studies have demonstrated an antianxiety effect of beta-adrenergic blocking drugs in patients with anxiety. Also, in certain performance situations, beta-blocking drugs may block the autonomic response to stress and reduce anxiety. However, because these drugs are less effective than the benzodiazepines, their role in the treatment of anxiety and phobic disorders appears to be limited.

Novel approach to zero-order drug delivery via immobilized nonuniform drug distribution in glassy hydrogels.

A novel approach to zero-order drug delivery from glassy hydrogel matrices via an immobilized, sigmoidal, initial drug distribution has been developed. The method utilizes a controlled-extraction process on initially dry, drug-loaded hydrogels to generate an inflection-point-containing drug concentration profile followed by a vacuum freeze-drying step to rapidly remove the swelling solvent and immobilize in situ a nonuniform drug distribution. The drug release from such a system generally exhibits typical zero-order characteristics similar to that of a membrane-reservoir device. However, a saturated reservoir of active ingredient as in the membrane-reservoir device is not required because the constant release is achieved via an initially nonuniform concentration distribution instead of the constant activity in a reservoir. The applicability of the present concept and process has been demonstrated experimentally with the release of oxprenolol hydrochloride from hydrogel beads based on 2-hydroxyethyl methacrylate polymerized with a polymeric cross-linking agent.

Constant-rate drug release from novel anionic gel beads with transient composite structure.

A new anionic composite bead system with a transient membrane-matrix structure, capable of prolonged constant-rate drug release, has been developed from suspension-polymerized poly(methyl methacrylate-co-methacrylic acid) (PMMA/MAA). These composite beads have a thin PMMA/MAA surface layer and a core consisting of the sodium salt form of the polymer (PMMA/MANa). The high loading (> 20%) of a model drug (oxprenolol HCl) that is achievable in this system from a loading solution concentration as low as 0.5% suggests the formation of a drug-polymer complex in the form of an ionic salt in the core. The release of oxprenolol from such composite beads shows an initial burst effect followed by an extended constant-rate region before leveling off. Apparently, the surface PMMA/MAA layer functions as a transient rate-controlling membrane before it is completely ionized. Because the ionization process is slow, the rate-controlling characteristics of the surface layer and the resulting constant rate of drug release are both sustained for an extended period. The unique feature of the present system is not only its high drug loading capability, but also the transient nature of the rate-controlling surface layer, which is completely ionized towards the latter part of the drug release, thus avoiding prolonged tailing of drug release that is normally associated with permanent membrane-matrix systems.

The pharmacokinetics and dynamics of oxprenolol: a simulation study with six subjects.

Experimental results of plasma concentration determinations and lowering of exercise heart rate for six subjects taking a conventional tablet and a sustained release preparation of oxprenolol have been analysed by a comprehensive computer simulation model. Individual plasma values were simulated using a lest squares procedure and the results were applied to evaluate individual release patterns following dosage with the sustained release preparation. Application of the model to the lowering of exercise heart rate indicated that the response is in a steady state with the plasma values and that the response-concentration relation is of the saturable, Emax, type. The parameters for this were evaluated for each subject for the results after a dose of a conventional tablet. These parameters were applicable to the results after dosage with a sustained release preparation. The method should be applicable to other sustained release preparations.