Drug treatment during pregnancy and isolated orofacial clefts in hungary.

OBJECTIVE: To evaluate the possible association between all kinds of drug treatments during pregnancy and isolated cleft lip with or without cleft palate (CL/P) and posterior cleft palate (PCP) in the offspring. SETTING: The dataset of the large population-based Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996, was evaluated. PARTICIPANTS: One thousand three hundred seventy-four cases with isolated CL/P and 601 with PCP, plus 38,151 population controls (without birth defects) and 20,868 malformed controls with other defects. INTERVENTION: In this observation case-control study the data collection was based on prospective medical records particularly prenatal logbook, retrospective maternal data via a self-reported questionnaire, and home visits of nonresponding mothers. MAIN OUTCOME MEASURES: Isolated CL/P and PCP associated with drug treatments during pregnancy. RESULTS: An increased risk for isolated CL/P was found in cases born to mothers treated with amoxicillin, phenytoin, oxprenolol, and thiethylperazine during the second and third month of pregnancy, i.e., the critical period of isolated CL/P. Risk of isolated PCP was increased in mothers with oxytetracycline and carbamazepine treatment during the third and fourth month of pregnancy, i.e., the critical period of PCP. CONCLUSIONS: This study confirmed the orofacial cleft (OFC) inducing effect of phenytoin, carbamazepine, oxytetracycline, and thiethylperazine and suggested a possible association between OFCs and oxprenolol and amoxicillin. However, drugs may have only a limited role in the origin of isolated OFCs.

Iontophoretic in vivo transdermal delivery of beta-blockers in hairless rats and reduced skin irritation by liposomal formulation.

PURPOSE: To demonstrate the in vivo transdermal delivery and establish the comparative pharmacokinetics of five beta-blockers in hairless rat. METHODS: Intravenous dosing was initially done via jugular cannula. For iontophoretic delivery, current (0.1 mA/cm2) was applied for 2 h through a drug reservoir patch containing the beta-blocker (10 mg/ml). Blood samples were collected and analyzed by stereoselective HPLC assays. Any irritation resulting from patch application was quantified by a chromameter. Multilamellar liposomal formulation was prepared by the thin-film hydration method and converted to unilamellar liposomes by extrusion. RESULTS: With transdermal iontophoresis, therapeutically relevant amounts of propranolol (83.78 +/- 7.4 ng/ml) were delivered within an hour and lasted for up to 4 h. Cmax (185.1 +/- 56.8 ng/ml) was reached at hour 3. A significantly higher amount (p < 0.05) of sotalol HCl was delivered compared to other beta-blockers. There was no significant difference in the S/R ratio of AUC0-t for enantiomers after both intravenous and transdermal delivery. Skin irritation was significantly reduced (p < 0.05) when a liposomal formulation of the propranolol base was used rather than the base itself. CONCLUSIONS: The comparative pharmacokinetics of intravenous and transdermal iontophoretic delivery of five beta-blockers in hairless rats was established. It was shown that there is no stereoselective permeation.

Efficacy and tolerability of long term oxprenolol and chlorthalidone singly and in combination in hypertensive blacks.

Sixty two black patients who had confirmed but untreated hypertension participated in a double blind clinical trial of the efficacy and tolerability of slow-release oxprenolol in a daily dose of 160 mg initially and 320 mg subsequently versus chlorthalidone 50 mg daily. Thereafter, a combination of oxprenolol with chlorthalidone in an initial dose of 160 mg and 25 mg and a subsequent dose of 320 mg and 50 mg, respectively, was administered and the effects compared with those of the same drugs given singly. The trial lasted for 3 years, but each participant took active medication for 1 year. Oxprenolol as monotherapy had no effect on the blood pressure, irrespective of the dose. Chlorthalidone as monotherapy produced a significant fall in blood pressure (p less than 0.01). Combining the 2 drugs enhanced their blood pressure lowering effects (p less than 0.001). Oxprenolol as monotherapy and as part of combination therapy was well tolerated by all patients. Chlorthalidone as monotherapy was well tolerated by most patients while a fraction of the patients developed biochemical derangements. These results confirm the findings that a beta-blocker alone may be ineffective in lowering blood pressure in hypertensive blacks. The results also show that the efficacy and tolerability of a beta-blocker and a diuretic are enhanced by their combined administration. Finally, the results show that increasing the dose of a beta-blocker or a diuretic does not produce a further increase in its blood pressure lowering effect.

ACE-inhibitors and quality of life.

A review of the literature concerning quality of life aspects on ACE-inhibitors in hypertensive patients is given. In the first part of the eighties two prospective multi-center randomised trials were conducted to determine the effect of captopril in comparison to methyldopa or an unselective beta-blocker on the quality of life in patients with mild to moderate hypertension (Hill et al. and Croog et al.). Both studies revealed slight but significant positive effects on indices of quality of life in captopril treated patients compared to those who had methyldopa or an unselective beta-blocker. Later, another ACE-inhibitor, enalapril, has been compared with a selective beta-blocker (Edmonds et al. and Herrick et al.) with respect to side-effects and the quality of life. The measurements of the quality of life tended to favour enalapril, but the differences were small and the over-all tolerability of the two drugs was similar. In conclusion, comparisons with more long standing forms of antihypertensive therapy suggest a slightly more favourable effect of ACE-inhibitors on the quality of life.

Effects of chronic administration of the fixed combination slow-release oxprenolol-chlorthalidone on left ventricular hypertrophy in hypertensive patients. Echocardiographic study.

To evaluate the effects of the chronic administration of the fixed combination slow-release, oxprenolol 160 mg and chlorthalidone 20 mg on left ventricular hypertrophy, ten hypertensive out-patients, with left ventricular hypertrophy documented by left ventricular mass index (LVMI) greater than 130 g/m2, were studied. After a two-week placebo period, patients were given the study medication, once daily for six months. Blood pressure and heart rate were measured, 24 h after-dosing, at the end of placebo and thereafter every month. A m-mode echocardiographic examination was performed at the end of the placebo period, after 1 month of active treatment and at the end of the study. In comparison with placebo, the study medication induced a significant reduction (p less than 0.01) of systolic and diastolic blood pressure, 24 h after dosing, after 1 month of treatment (from 181.0 +/- 18.5/108.5 +/- 12.0 to 146.5 +/- 10.8/94.0 +/- 7.7 mmHg), and this reduction was maintained until the end of the study (142.0 +/- 14.0/90.0 +/- 8.2 mmHg). At the 6th month and in comparison with placebo, a significant (p less than 0.01) reduction of left ventricular mass (LVM) and of LVMI was observed (LVM: from 295.9 +/- 113.8 to 221.5 +/- 66.1 g; LVMI: from 158.1 +/- 39.0 to 126.2 +/- 35.8 g/m2. In conclusion, our results confirm the good antihypertensive efficacy of the fixed combination slow-release oxprenolol and chlorthalidone and show that the study medication is able to induce a regression of left ventricular hypertrophy, in hypertensive patients.

Evaluation of oxprenolol slow release and osmotic release by exercise testing and ambulatory electrocardiographic monitoring in patients with chronic stable angina pectoris.

We have treated eleven patients with chronic stable angina pectoris with slow-release oxprenolol (160 mg and 320 mg) in a double-blind crossover study and evaluated its efficacy objectively by exercise testing between 180 and 240 min after dosing. The mean exercise time increased significantly from 6.2 min on placebo to 7.2 min and 7.3 min on oxprenolol 160 mg and 320 mg respectively. No overall beneficial effects could be demonstrated for the higher dose. A further 20 patients received slow release oxprenolol 160 mg and 10/170 mg "Oros" (osmotic release) oxprenolol in a double-blind crossover study using exercise testing and ambulatory electrocardiographic monitoring at 21-23 h after dosing. The mean exercise time increased significantly from 7.0 min on placebo to 8.3 min on slow-release oxprenolol and to 8.1 min on "Oros" oxprenolol. The effects of the 2 treatments on exercise and ambulatory heart rates were comparable. Two patients were withdrawn during the double-blind treatment period while receiving oxprenolol slow-release, one because of unstable angina and another because of throbbing headache. These findings confirm that slow-release oxprenolol is effective in treating chronic stable angina pectoris at the 160-mg dose. "Oros" oxprenolol 10/170 mg has a profile of action closely similar to but without any additional benefit over slow-release oxprenolol 160 mg.

Respiratory effects of four adrenergic blocking agents combined with a diuretic in treating hypertension with concurrent chronic obstructive lung disease.

The study was a comparison of the effects on respiratory function produced by four antihypertensive agents with receptor-blocking properties (atenolol, oxprenolol, labetalol, metoprolol), when used in combination with a diuretic (chlorthalidone) in four homogeneous groups of hypertensive patients also suffering from chronic obstructive lung disease. All the agents with the exception of labetalol caused systematic and considerable worsening of functional parameters monitored in the trial. Treatment with labetalol, on the other hand, led to an improvement in respiratory function. Labetalol thus proved to be the most reliable and selective of the drugs tested for administration to patients with severe chronic airflow limitation.

Predictors of blood pressure increases after withdrawal of antihypertensive therapy.

We examined possible predictors of the recurrence of high blood pressure (BP) in patients who remained normotensive after withdrawal of drug therapy. Thirty untreated male patients with WHO stage I essential hypertension (mean age 43 +/- 6 years) were randomly allocated to oxprenolol or nitrendipine groups. Before therapy, BP at rest, during mental arithmetic (MA) and during the cold pressor (CP) test was assessed. After 6 months of effective monotherapy, all drugs were withdrawn and casual BP was followed up for 5 months. Two weeks after cessation of therapy 26% were hypertensive again, after 4 weeks 28%, after 12 weeks 48% and after 21 weeks 74%. The two therapeutic groups did not differ in their BP increase after discontinuation of therapy. Predictors for the return of high BP were age, pretreatment BP, systolic and diastolic BP increase to the CP test. Analyses of covariance for age and pretreatment BP confirmed that reactivity to the CP test was a predictor of the return of hypertension.

Angiotensin converting enzyme inhibitors and quality of life: the European trial.

Two prospective multi-centre randomized trials were initiated to compare the relative efficacy and influence on quality of life of captopril, alone or in combination with hydrochlorothiazide, against either methyldopa, alone or in combination with hydrochlorothiazide, or oxprenolol in combination with chlorothalidone. The complaint rate, activity index and psychiatric morbidity were evaluated as indices of quality of life. Captopril was associated with a significantly (P less than 0.05) greater reduction in complaint rate compared with methyldopa and a tendency for less symptoms of depression compared with oxprenolol (P = 0.06), the latter drug being associated with an increase in depression scores. The trends in quality of life indices in the captopril-treated patients would suggest the need for double-blind placebo-controlled trials to investigate these apparent benefits.

A comparison of single doses of bucindolol and oxprenolol in hypertensive patients.

Single doses of bucindolol 50, 100 and 200 mg were compared to placebo and single doses of oxprenolol 40, 80 and 160 mg in seven patients with mild hypertension, in a double-blind randomized study. Both bucindolol and oxprenolol inhibited exercise induced tachycardia. The mean maximum inhibition of exercise heart rate was similar after each dose of both drugs (20%, P less than 0.001). Bucindolol produced a significantly greater reduction in blood pressure than either oxprenolol or placebo. This was most apparent in standing systolic and diastolic and post-exercise systolic blood pressures between 1 and 2 h after dosing and was dose-related. All seven patients experienced adverse effects related to hypotension within the first 2 h after ingestion of bucindolol 200 mg. Plasma concentrations of oxprenolol, bucindolol or 5-hydroxy-bucindolol, sampled 2 h after dosing, could not be related to either the changes in blood pressure or to the occurrence of symptoms. The results emphasise the need for careful dose-finding of new drugs prior to their more widespread evaluation in phase 3 studies.

Cardiovascular risk and risk factors in a randomized trial of treatment based on the beta-blocker oxprenolol: the International Prospective Primary Prevention Study in Hypertension (IPPPSH). The IPPPSH Collaborative Group.

Myocardial infarction, sudden cardiac death, cerebrovascular accidents, blood pressure control and treatment tolerability were studied in a randomized double-blind trial conducted in 6357 men and women aged 40-64 years with uncomplicated essential hypertension (diastolic blood pressures 100-125 mmHg). At the start of the trial 3185 patients received treatment based on a beta-blocker (oxprenolol), while in the remaining 3172 placebo replaced oxprenolol. Supplementary drugs, excluding beta-blockers, were used as necessary in both treatment groups, with the aim of reducing diastolic pressure to 95 mmHg or less. Patients were followed for 3-5 years, a total of 25 651 patient years at risk. In most respects the two groups fared equally well; sudden death (relative risk [RR] 1.08; 95% confidence interval [Cl] 0.68 and 1.72), myocardial infarction (RR 0.83; Cl 0.59 and 1.16) and cerebrovascular accident (RR 0.97; Cl 0.64 and 1.47) rates were similar. Beta-blocker based therapy was associated with significantly lower average blood pressures, earlier ECG normalization, less hypokalaemia and fewer withdrawals from double-blind treatment for uncontrolled hypertension. Doctor-elicited and patient-assessed unwanted effects demonstrated overall good tolerability. In smokers the cardiac event rate was doubled. We propose that beta-blocker treatment effects depend on smoking status, with a significant interaction benefiting non-smoking men. Lower blood pressures during treatment were associated with substantially lower rates for cardiac as well as cerebrovascular events. Proportional hazards analysis also underlines the importance of other cardiovascular risk factors. The IPPPSH stresses the need for a comprehensive approach to the management of blood pressure and other risk factors in hypertensive patients.

The relative antihypertensive potency of propranolol, oxprenolol, atenolol, and metoprolol given once daily. A double-blind, crossover, placebo-controlled study in ambulatory patients.

The antihypertensive effect of four beta-blocking agents given once daily was compared with that of placebo in a prospective, crossover, double-blind study of 150 patients. The preparations tested were slow-release propranolol hydrochloride, 160 mg, atenolol, 100 mg, slow-release oxprenolol hydrochloride, 160 mg, and metoprolol, 200 mg. Propranolol and atenolol produced a significant decline in lying, standing, and postexercise blood pressure and pulse rate values. The effects of oxprenolol and metoprolol were not significantly different from that of placebo.

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.

Side-effects of beta-adrenoceptor blocking drugs assessed by visual analogue scales.

A series of visual analogue scales (VAS) was used to examine the prevalence of side-effects among hypertensive patients taking beta-adrenoceptor blocking drugs. When compared to untreated non-hypertensive control subjects, patients taking beta-adrenoceptor blockers had a greater prevalence of tired legs (P less than 0.001), cold digits (P less than 0.01), insomnia (P less than 0.01) and loss of overall wellbeing (P less than 0.01). Side-effects did not differ significantly between patients taking atenolol (n = 30), oxprenolol (n = 16), propranolol (n = 15) or metoprolol (n = 10). If there is an important difference in the prevalence of side-effects between different beta-adrenoceptor blockers, a much larger study will be needed to demonstrate it.

Side-effects of beta-blockers assessed using visual analogue scales.

Visual analogue scales were used in a pilot study to compare side-effects in patients receiving antihypertensive drugs either including or excluding beta-blockers. Compared with symptom scores for patients receiving antihypertensive medication other than a beta-blocker, symptom scores (when combined) for patients receiving a beta-blocker were significantly higher for tired legs (p less than 0.001), cold digits (p less than 0.005), and vivid dreams (p less than 0.01). These methods were also applied in a postal survey which was designed to compare the incidence of symptoms in patients receiving different beta-blockers with symptoms in subjects receiving no drugs. When compared with symptom scores for subjects receiving no drugs, symptom scores (when combined) for patients receiving beta-blockers were significantly higher for tired legs (p less than 0.001), cold digits (p less than 0.01), insomnia (p less than 0.01), and lack of well-being (p less than 0.01). These two studies were consistent in showing higher symptom scores for tired legs and cold digits in patients receiving beta-blockers. However, there were inconsistencies regarding sleep disturbance. Increased dreaming was apparent in the pilot study whereas increased insomnia was apparent from the postal survey. These inconsistencies cannot be explained. No significant differences in side-effects were apparent between different beta-blockers.