Double-blind comparison of amlodipine and hydrochlorothiazide in patients with mild to moderate hypertension.

In the final analysis of this study at Week 26, 26% of the patients randomized to receive amlodipine attained blood pressure control with amlodipine alone compared with 33% of the patients allocated to hydrochlorothiazide (HCTZ). Neither amlodipine nor HCTZ produced clinically significant changes in pulse rate or in the electrocardiogram. Amlodipine treatment did not appear to produce clinically significant changes in blood lipids; HCTZ, however, produced an increase in total plasma cholesterol (delta 22.9 +/- 8.6 mg/dl). The incidence of side effects and the rate of patient withdrawal in the amlodipine and HCTZ groups were comparable. As expected, HCTZ therapy caused well-recognized biochemical alterations in cholesterol and potassium levels, whereas amlodipine was metabolically neutral.

Bisoprolol, a once-a-day beta-blocking agent for patients with mild to moderate hypertension.

The 24-h blood pressure control of bisoprolol, a new beta-selective, beta-blocking agent, was studied in 240 mild to moderate hypertensive patients in this 4-week, randomized, double-blind, placebo-controlled trial. A once-daily dosing schedule was evaluated by comparing bisoprolol's antihypertensive effectivness and safety at 24 h postdose and 3 h postdose, the latter time intended to correspond to peak effectiveness. Results from this trial demonstrated the antihypertensive effectiveness of once-daily bisprolol at doses ranging from 5-20 mg. Mean reductions from baseline diastolic blood pressure, measured 24 h postdose, were 6.3, 8.8, and 10.1 mmHg for patients receiving bisoprolol 5, 10, and 20 mg, respectively, compared with 1.6 mmHg for placebo-treated patients (p < 0.01); mean reductions from baseline systolic blood pressure for the bisoprolol groups were 8.6, 8.6, and 10.9 mmHg, respectively, versus 3.3 mmHg for placebo (p < or = 0.01); and mean reductions from baseline heart rate for the bisoprolol groups were 5.1, 7.1, and 10.2 beats/min, respectively, compared with a 0.9 beats/min increase in heart rate for the placebo group (p < 0.01). The response rates for bisoprolol-treated patients ranged from 47 to 70% compared with 18% for patients on placebo (p < 0.01). Antihypertensive effects were dose-related and sustained over the 24-h dosing interval. Near maximal antihypertensive effects were achieved within 1 week of initiation of therapy with bisoprolol and were sustained over the course of the trial.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the antihypertensive effects of betaxolol and chlorthalidone as monotherapy and in combination.

In this multicenter, double-blind, parallel study, the antihypertensive effects of betaxolol (20 mg once daily) and/or chlorthalidone (25 mg once daily) were analyzed in 186 patients with essential hypertension. Following a 2- to 4-week placebo baseline period, patients were randomized to one of two treatment groups (betaxolol or chlorthalidone) and studied for 6 weeks while receiving single therapy and an additional 6 weeks with a combination of the two agents. Significant decreases from baseline supine diastolic blood pressure (SDBP) were observed in both groups at the end of the single-therapy phase (11 mm Hg in SDBP for betaxolol and 12 mm Hg in SDBP for chlorthalidone); a further significant decrease (7 mm Hg for betaxolol and 8 mm Hg for chlorthalidone in SDBP) was observed from the end of the single-therapy phase to the end of the combination-therapy phase. Changes in supine systolic blood pressure (SSBP) from baseline to the end of the single-therapy phase were 10 mm Hg for the betaxolol and 16 mm Hg for the chlorthalidone group. In all cases, within-group changes were statistically significant. From the end of single therapy to end of combination therapy there was an additional 14-mm Hg and 13-mm Hg reduction in SSBP in the betaxolol and chlorthalidone groups, respectively. Overall, 89% of the randomized patients completed the single-treatment phase (phase I), and 89% of those patients completed the combined therapy phase (phase II). There was no significant difference between treatment groups in the clinical response rate (SDBP at or below 90 mm Hg or a decrease from baseline of at least 10 mm Hg). A substantial percentage of patients completing phase I responded to either single agent (58% for betaxolol and 65% for chlorthalidone). Among patients completing phase II therapy, the combination of the two agents produced a greater response rate (83% for the betaxolol-first group and 85% for the chlorthalidone-first group). In conclusion, both agents were effective and well tolerated. The most frequent adverse events in the single-therapy phase were headache, arthralgia, and dizziness, while bradycardia, rhinitis, arthralgia, and dizziness were most frequent in the combination-therapy phase. The combination of betaxolol (20 mg) and chlorthalidone (25 mg) once daily produced an additive antihypertensive effect regardless of which drug was administered first.

A multicenter double-blind study of the efficacy and safety of once and twice daily dilevalol compared to propranolol.

Dilevalol, the R,R isomer of labetalol, is a non-selective beta-adrenergic blocking drug with vasodilator properties which differ from those of labetalol in that they are attributable to beta-2 agonism rather than alpha-1 blockade. This multicenter, double-blind, randomized study compares the antihypertensive efficacy and safety of dilevalol with propranolol and, in addition, compares the efficacy of dilevalol when given once daily with twice daily. Caucasian patients with mild and moderate essential uncomplicated hypertension were divided into three treatment groups and received either propranolol twice daily (N = 59), dilevalol twice daily (N = 60), or dilevalol once daily (N = 53). Patients were given increasing doses of these medications over a 2 to 10 week period to achieve a supine diastolic blood pressure (SuDBP) of less than 90 mm Hg. The three regimens were equally effective in lowering supine blood pressure (dilevalol daily and twice daily reduced SuDBP by 14 Hg and propranolol by 13 mm Hg). Patients with at least a 5 mm Hg reduction in SuDBP then entered a two month maintenance phase. Dilevalol, whether given once (N = 40) or twice daily (N = 55) maintained the supine systolic blood pressure more effectively (dilevalol daily--15 mm Hg, twice daily--13 mm Hg, P less than .05) than propranolol (N = 53, 11 mm Hg) and dilevalol given once daily maintained diastolic blood pressure more effectively than propranolol (17 mm Hg v 14 mm Hg, P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Dilevalol compared with propranolol and placebo for systemic hypertension.

Dilevalol is a new antihypertensive agent that is both a vasodilator, through its beta 2-agonist action, and a nonselective beta antagonist. Two multicenter, double-blind studies were performed: study 1 compared dilevalol administered once-daily with either dilevalol or propranolol every 12 hours; study 2 compared dilevalol administered once daily with placebo. Both studies had a placebo run-in period to establish that the baseline supine diastolic blood pressures were consistent in the mild to moderate severity range (95 to 115 mm Hg) at 2 consecutive visits for study 1 and in the mild severity range (95 to 105 mm Hg) in study 2. Patients then were randomized to the double-blind titration phase, during which doses were titrated over a 9-week period to achieve a supine diastolic blood pressure of less than 90 mm Hg and a decrease from baseline of greater than or equal to 10 mm Hg. Patients were then maintained on a fixed dose for 2 months (study 1) or for 1 month (study 2). Dilevalol given once daily was as effective in reducing supine diastolic blood pressure as dilevalol every 12 hours and propranolol every 12 hours (study 1) and was superior to placebo (p less than 0.001) (study 2). In both studies, dilevalol given once daily was effective and well tolerated. The side-effect profile of dilevalol was similar to that of placebo and different from that of propranolol. Treatment with dilevalol resulted in significantly less fatigue (p less than 0.05), bradycardia (less than 50 beats/minute) and mental depression than with propranolol, but significantly (p less than 0.05) more diarrhea/loose stools.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of betaxolol, a new beta 1-adrenergic antagonist, to propranolol in the treatment of mild to moderate hypertension.

A double-blind, multicenter study compared the safety and efficacy of oral betaxolol 10 to 40 mg once daily (n = 68) with propranolol 40 to 160 mg twice daily (n = 73) in the treatment of mild to moderate essential hypertension. Both agents produced significant (P less than 0.01) and comparable reductions in mean supine systolic and diastolic blood pressures (7/11 mm Hg on betaxolol and 9/10 mm Hg on propranolol). Both betaxolol and propranolol significantly (P less than 0.01) reduced mean supine heart rate by 9 beats per minute. Patients achieved a more significant (P less than 0.01) reduction in blood pressure earlier (weeks 2 and 4 of the titration period) with betaxolol. By the end of treatment there was no significant difference in response between treatment groups. A higher incidence of central nervous system side effects (insomnia, bizarre dreams, depression, hallucinations, dizziness), however, was seen with propranolol than with betaxolol. Overall, the data show that in patients with mild to moderate essential hypertension, betaxolol 10 to 40 mg administered once daily is as effective as and better tolerated than propranolol 40 to 160 mg administered twice daily.

Double-blind comparison of amlodipine and hydrochlorothiazide in patients with mild to moderate hypertension.

Amlodipine, a new long-acting dihydropyridine calcium antagonist, was compared with hydrochlorothiazie (HCTZ) in 145 patients with mild to moderate hypertension. After 4 weeks of single-blind placebo runin, patients were randomly allocated to receive amlodipine (2.5-10 mg once daily, n = 97) or HCTZ (25-100 mg once daily, n = 48). At study week 12 response rates for amlodipine and HCTZ were 61.5 and 60.5%, respectively. There were clinically significant reductions in 24-h postdose blood pressures with both amlodipine (-18/-11 mm Hg supine: -14/-10 mm Hg standing) and HCTZ (-18/-10 mm Hg supine, -18/-9 mm Hg standing). After study week 12, atenolol (50-100 mg once daily) was added to the regimen of those patients whose hypertension was not controlled with monotherapy. Neither amlodipine nor HCTZ produced clinically significant changes in pulse rate, electrocardiogram, or chest x-ray film. Although amlodipine increased and HCTZ decreased the high-density lipoprotein (HDL)/total cholesterol ratio and the HDL/(low-density lipoprotein + very-low-density lipoprotein) ratio, the difference between the two treatments was not statistically significant. The incidence of side effects and the rate of patient withdrawal was comparable in the two groups. The incidence of laboratory abnormalities was 56% with HCTZ (mainly hypokalemia and hyperuricemia) and 16% with amlodipine. Amlodipine was an effective, well-tolerated agent for treatment of mild-to-moderate hypertension in this study, as single-daily-dose monotherapy and in combination with atenolol.

Serum magnesium and potassium levels in hypertensive patients after a therapeutic switch from hydrochlorothiazide plus a potassium supplement to maxzide.

Determinations of serum magnesium and potassium levels and blood pressure were made in 40 hypertensive patients in whom daily therapy with 50 mg of hydrochlorothiazide plus potassium supplements was switched to a once-daily regimen of 50 mg of hydrochlorothiazide plus 75 mg of triamterene (Maxzide). Patients showed no clinically significant changes in blood pressure or in serum magnesium or serum potassium values following the switch. It is concluded that therapy in patients receiving hydrochlorothiazide and up to 60 meq of potassium can be safely switched to Maxzide without adversely affecting serum magnesium levels, serum potassium levels, or blood pressure control.

Monotherapy with labetalol in the treatment of mild hypertension: a double-blind study.

The antihypertensive effects of oral labetalol compared with placebo were evaluated in 74 mildly hypertensive patients (standing diastolic blood pressure 95 to 110 mm Hg) in a bicentric double-blind parallel group study. Following a four-week placebo phase, 36 patients were randomly assigned to receive labetalol and 38 to receive placebo. A five-week titration phase followed during which the dose of labetalol was increased weekly from 100 mg twice a day to 600 mg twice a day to achieve a standing diastolic blood pressure of less than 90 mm Hg and decreased 10 mm Hg or more from baseline. A matching number of placebo capsules for each dose of labetalol was dispensed for blinding purposes. Patients then entered a two-month maintenance phase. A thiazide diuretic could be added when the standing diastolic blood pressure was 100 mm Hg or greater at the highest dose of the study drug. At the end of this phase, the administration of labetalol (or placebo) was abruptly discontinued and patients were given the same number of placebo capsules twice a day taken during maintenance. Blood pressure and heart rate in the supine and standing position were measured eight to 10 hours after a dose at each visit. This study demonstrated that labetalol (median daily doses of 600 mg) was significantly more effective than placebo (p less than 0.05) in lowering the supine and standing blood pressures. Significantly more (p less than 0.001) placebo-treated patients than labetalol-treated patients (six versus 20) required the addition of a thiazide diuretic. Control of hypertension (that is, standing diastolic blood pressure less than 90 mm Hg) was achieved in significantly (p less than 0.001) more labetalol-treated patients than placebo-treated patients at the monotherapy endpoint (26 of 36; 72 percent versus six of 38; 16 percent). Blood pressure overshoot did not occur when labetalol was abruptly discontinued. Not one labetalol-treated patient discontinued the study because of adverse experiences. Labetalol is a safe and effective treatment for patients with mild hypertension.

Nitroglycerin prophylaxis in angina pectoris. Effect of sustained release nitroglycerin capsules on anginal frequency and exercise capacity.

Since the pharmacological effects of sublingual nitroglycerin are of short duration, attempts have been made over a number of years to prolong the activity of nitroglycerin by various means, viz. : (1) topical applications of nitroglycerin ointments, relying upon percutaneous absorption; (2) changes in chemical structure leading to such derivatives as isosorbide dinitrate or pentaerythritol tetranitrate; and (3) development of pharmaceutical preparations devised to disintegrate slowly, thus releasing the active substance over a long period. The purpose of the present study was to determine the effects of such a sustained-release nitroglycerin preparation on the frequency of painful paroxysms and on exercise capacity in patients with angina pectoris. In a double-blind trial comparing the preparation with a placebo 25 patients were observed during 24 weeks. The active substance significantly reduced the number of anginal attacks and increased exercise capacity in all cases. It would therefore seem that sustained-release nitroglycerin capsules deserve to have a place in the treatment of angor pectoris. However, further studies involving a larger number of patients are required to support these conclusions.

Sodium intake and furosemide administration in hypertensive patients with renal insufficiency.

The effects of various levels of sodium intake and loop diuretic (furosemide) administration upon arterial pressure and renal function were studied in 11 patients with impaired renal function and essential hypertension. The patients were hospitalized in a metabolic ward and continued taking their usual antihypertensive medications. After a stabilization period, all patients followed the following regiments for 5 to 7 days: period I, 20 mEq sodium diet without diuretic administration; period II, 80 mEq sodium diet and furosemide, 80 mg daily; and period III, 200 mEq sodium diet and furosemide, 240 mg daily. Supine diastolic pressure was lower (P is less than 0.05) during period II than during period I and both supine and standing systolic and diastolic pressures were significantly lower in period III than in period I (P is less than 0.01). No significant differences in the renal clearance of inulin were noted between any of the study periods. In patients with essential hypertension and impaired renal function, consumption of a moderate or liberal sodium diet combined with administration of a loop diuretic agent (furosemide) appears to result in better control of arterial pressure without significant changes in renal function than does strict sodium restriction without diuretic administration.

Vasodilator administration in the presence of beta-adrenergic blockade.

To explore the possibility that the presence of propranolol-induced beta-adrenergic blockade might have an adverse effect upon homeostatic circulatory reflexes activated by the administration of a potent vasodilator agent, arterial blood pressure and pulse rate response to rapid intravenous diazoxide injection was monitored before and after pretreatment with propranolol in ten hypertensive patients. It appeared that beta-adrenergic blockade had no clinically significant effect on the magnitude of hypotension or the degree of heart rate acceleration induced by the administration of the potent vasodilator diazoxide. This reflex vasodilator-induced cardio-acceleration after propranolol adminstration could be the result of incomplete blockade of endogenously released neurotransmitter, inhibition of the parasympathetic nervous system, or a direct pharmacologic action of diazoxide. Diazoxide administration to hypertensive patients in the presence of beta-adrenergic blockade was not associated with any clinically significant hemodynamic consequences.