Randomized placebo-controlled trial of amlodipine in vasospastic angina. Amlodipine Study 160 Group.

OBJECTIVES: This study was designed to assess the efficacy and safety of amlodipine, a long-acting calcium channel blocker, in patients with vasospastic angina. BACKGROUND: Previous studies have established the value of short-acting calcium channel blockers in the treatment of coronary spasm. METHODS: Fifty-two patients with well documented vasospastic angina were entered into the present study. After a single-blind placebo run-in period, patients were randomized (in a double-blind protocol) to receive either amlodipine (10 mg) or placebo every morning for 4 weeks. Twenty-four patients received amlodipine and 28 received placebo. All patients were given diaries in which to record both the frequency, severity, duration and circumstances of anginal episodes and their intake of sublingual nitroglycerin tablets. RESULTS: The rate of anginal episodes decreased significantly (p = 0.009) with amlodipine treatment compared with placebo and the intake of nitroglycerin tablets showed a similar trend. Peripheral edema was the only adverse event seen more frequently in amlodipine-treated patients. No patient was withdrawn from the double-blind phase of the study because of an adverse event. Patients who completed the double-blind phase as responders to amlodipine or as nonresponders to placebo were offered the option of receiving amlodipine in a long-term, open label extension phase. During the extension, the daily dose of amlodipine was adjusted to 5 or 15 mg if needed and the rate of both anginal episodes and nitroglycerin tablet consumption showed statistically significant decreases between baseline and final assessment. CONCLUSION: This study suggests that amlodipine given once daily is efficacious and safe in the treatment of vasospastic angina.

The safety of nitrendipine in the treatment of essential hypertension--a review of 61 clinical studies.

To assess the safety of the calcium channel blocker nitrendipine, data from 61 clinical studies conducted in the United States and involving 1,245 patients were reviewed. The drug appeared to be tolerated in the majority of patients and the dropout rate was low. The most common side effects associated with nitrendipine administration were headache and edema. Most side effects were mild and were tolerated or disappeared with continued therapy. No serious adverse biochemical, hemodynamic, renal, or humoral effects of nitrendipine were apparent. Nitrendipine produced a prompt, smooth, and sustained reduction in systolic and diastolic blood pressures in both the supine and standing positions. The blood pressure response was maintained for six months to one year with no evidence of resistance or tachyphylaxis. Sex and race had no influence on the antihypertensive effect of nitrendipine, but patients sixty years of age and older appeared to respond better to the drug than younger patients.

Safety aspects of long-term nitrendipine therapy.

More than 1,700 patients with essential or renal hypertension were treated with nitrendipine; data from 967 of these were included in a data pool, and safety data were evaluated. Treatment duration was between 7 days and 2 years. The most frequent side-effects were headache, flush, oedema, dizziness, and palpitations due to the pharmacodynamic effect of the drug. All other side-effects had an incidence below 2%. Eighty-two of the 967 patients stopped therapy before the end of the trial. In 33 of these patients, this was probably due to the side-effects of nitrendipine. Hematological and clinical chemistry data did not indicate any systemic or organ damage. When nitrendipine was combined with thiazides, a lowering of plasma potassium levels could be found, which, however, did not necessitate any therapy.

Comparison of nitrendipine combined with low-dose hydrochlorothiazide to hydrochlorothiazide alone in mild to moderate essential hypertension.

Patients with mild to moderate essential hypertension were treated in four centers with hydrochlorothiazide (HCTZ) 25 mg daily for 4 weeks. Those patients failing to achieve control (supine diastolic blood pressure (DBP) 90 mm Hg or lower) were randomly assigned to nitrendipine (NTP) 5 mg or placebo (PLA) b.i.d. NTP or PLA was increased stepwise to 20 mg b.i.d. as needed to achieve control. Treatment with HCTZ was maintained at 25 mg daily. Eighty-six patients completed the study: 41 in NTP + HCTZ and 45 in PLA + HCTZ groups. Both groups were comparable in baseline characteristics. Supine systolic blood pressure (SBP) was 148.6 +/- 14.4 and DBP was 96.0 +/- 5.4 mm Hg in the NTP + HCTZ group. SBP was 147.4 +/- 16.6 and DBP was 96.4 +/- 5.6 mm Hg in the PLA + HCTZ group. At the end of 7 weeks of titration and treatment with NTP or PLA combined with HCTZ, SBP had fallen to 133.4 +/- 15.1 and DBP to 85.4 +/- 5.9 mm Hg in the NTP + HCTZ group. SBP fell to 138.8 +/- 16.2 and DBP to 90.7 +/- 6.3 mm Hg in the PLA + HCTZ group. The increment in lowering of both SBP and DBP was significantly greater (p = 0.002 and p = 0.0007, respectively) in the NTP + HCTZ group compared to the PLA + HCTZ group.

Steady-state pharmacokinetics of nitrendipine in hepatic insufficiency.

As a calcium antagonist, nitrendipine will be used in the treatment of various diseases in patients with hepatic insufficiency, and it is important to know if they require modified dosing schedules. In this study, six patients with biopsy-confirmed cirrhosis and six age/sex-matched normal healthy subjects were given 10 mg nitrendipine as a single dose on day 1 and 10 mg nitrendipine every 12 h from day 3 through the first dose on day 8. Blood levels of nitrendipine were determined to confirm the attainment of steady state and evaluate the pharmacokinetics in each group. Nitrendipine concentrations were consistently higher in the hepatic group. On day 1, the maximum concentration (Cmax) in the normals was 4.67 +/- 2.60 ng/ml and in the hepatic patients 16.87 +/- 9.42 ng/ml. On day 8, these values were 8.60 +/- 8.82 ng/ml and 27.37 +/- 8.56 ng/ml, respectively. The time to Cmax was not significantly different in the two groups. The elimination half-life was only slightly prolonged from 15.29 +/- 7.25 h in the normals to 19.57 +/- 4.28 h in the hepatic impairment group. This resulted in a marked increase in the area under the concentration-time curve from 28.71 +/- 28.92 ng . h/ml for the normals to 119.56 +/- 34.39 ng . h/ml for the hepatic patients on day 1 and similar results on day 8. Trough levels at steady state were expectedly higher in the hepatic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Guanabenz and methyldopa on hypertension and cardiac performance.

In previous placebo-controlled studies, guanabenz was shown to be a safe and effective antihypertensive drug without acute effects on cardiac function. In view of its therapeutic advantages, a double-blind comparison of guanabenz with methyldopa was performed in a group of 36 patients over 6 mo. Both drugs produced statistically and clinically significant decreases in blood pressure with similar side effects. No laboratory or electrocardiographic abnormalities were found other than positive Coombs' tests which developed in 3 patients during methyldopa therapy. Cardiac performance in 26 of the patients, as measured by noninvasive techniques, showed no significant changes from either drug except for a progressive and statistically significant increase in systolic time interval (QS2) and the ratio of the pre-ejection period to left ventricular ejection time (PEP/LVET) during methyldopa therapy. For an additional 6 mo, continued efficacy and safety were shown under open conditions in those patients who had received guanabenz. The study suggests that guanabenz may be an important new antihypertensive drug because of effectiveness, absence of adverse cardiac effects, and paucity of side effects.

Guanabenz in essential hypertension.

Fifty-five patients with mild to moderately severe essential hypertension were treated with guanabenz (2, 6-dichlorobenzylidene aminoguanidine acetate) in doses from 4 to 16 mg twice daily in a randomized, placebo-controlled study. The patients treated with placebo in the initial phase of the study were subsequently treated with guanabenz. The mean arterial pressure in the guanabenz group decreased from 130.6 to 107.6; that in the placebo group decreased from 129.6 to 126.6 standing and from 126.6 tp 109.9 and 128.8 to 120.5, respectively, supine. The principle adverse effects included sedation, dry mouth, weakness, and tiredness. Of the guanabenz-treated patients 84% had sustained decrease in supine diastolic blood pressure of 10 mm Hg or more, whereas in the placebo-treated patients only 32% had such a response. There was no significant orthostatic hypotension. Guanabenz thus appears to be an effective antihypertensive drug in patients with mild to moderately severe hypertension.

Guanabenz effects on blood pressure and noninvasive parameters of cardiac performance in patients with hypertension.

Guanabenz (2,6 dichlorobenzylidene amino guanidine acetate) is a new antihypertensive whose mechanism of action appears to involve both central alpha adrenergic stimulation leading to suppression of sympathetic nervous system activity from bulbar vasoconstriction centers as well as peripheral adrenergic neuron blockade. In this study, the drug was shown to produce a statistically and clinically significant decrease in blood pressure during a 4-wk placebo-controlled double-blind study. For three additional months continued efficacy and safety were shown under open conditions in 17 hypertensive patients. Mild sedation occurred, but there were no postural hypotension, tachycardia, evidence of sodium retention, gastrointestinal disturbances, or electrocardiographic (ECB) abnormalities. Noninvasive parameters of cardiac performance in 10 patients after single doses of guanabenz showed no significant changes. Although the numbers of patients were relatively small, the data suggest that this new drug may be a useful antihypertensive agent that warrants further investigation.