A multicenter comparison of isradipine and prazosin for treatment of essential hypertension.

Isradipine is a dihydropyridine calcium-entry blocking agent with pronounced vasodilator activity and no significant cardiac effects at clinical doses, a desirable profile for an antihypertensive drug. Prazosin, a post-junctional alpha-adrenoceptor blocking agent, may produce a similar hemodynamic pattern. Therefore, we compared the effects of isradipine (2.5-10 mg bid) with those of prazosin (2-8 mg bid) in 83 patients with established essential hypertension, using a randomized, double-blind, parallel-group design. Patients received a placebo for 3-5 weeks, then either isradipine or prazosin over a 6-week titration period, followed by a 4-week plateau phase. During the plateau period, isradipine therapy lowered sitting blood pressure more effectively than did the administration of prazosin: Mean systolic BP fell 16.7 versus 8.1 mmHg (p less than 0.001) and mean diastolic BP was reduced 15.6 versus 12.6 mmHg (p less than 0.01). In the dosing range used (while also noting that prazosin is occasionally titrated up to doses of 30 mg qd), 83% of isradipine-treated patients had at least a 10 mmHg reduction in diastolic BP, compared with 64% of prazosin-treated patients (p = 0.05, FET). Tachyphylaxis did not occur with either drug. The rate of occurrence of side effects was similar in both treatment groups; the most common adverse event seen with isradipine was headache (20%) and with prazosin, dizziness (19%).

Isradipine vs propranolol in hydrochlorothiazide-treated hypertensives. A multicenter evaluation.

A randomized, parallel, controlled study was conducted to evaluate the safety and efficacy of isradipine, 2.5 to 10 mg orally twice a day, compared with propranolol hydrochloride, 60 to 240 mg orally twice a day, in 78 hypertensives whose supine diastolic blood pressure was greater than 95 mm Hg while receiving 50 mg/d or more of hydrochlorothiazide. Isradipine or propranolol was titrated during a 10-week double-blind phase to achieve a supine diastolic blood pressure below 90 mm Hg while a fixed dose of hydrochlorothiazide was maintained. Supine diastolic blood pressure was reduced by 10 mm Hg in 88% of the isradipine/hydrochlorothiazide-treated and 83% of the propranolol/hydrochlorothiazide-treated groups and to less than 90 mm Hg in 55% of the isradipine/hydrochlorothiazide-treated and 69% of the propranolol/hydrochlorothiazide-treated patients. There was no significant difference in supine blood pressure reduction between either group, but there was a 3-to 4-beats per minute increase in supine heart rate in isradipine-treated patients and an expected 15- to 20-beats per minute decrease in heart rate in propranolol-treated patients. Five of 7 patients in the isradipine-treated group and 8 of 9 patients in the propranolol-treated group discontinued the therapy because of adverse reactions or treatment failure. Using Fisher's Exact Test, we found no significant difference in the relative frequency of individual adverse reactions between groups, although the absolute adverse reaction frequency was significantly higher with isradipine. This study demonstrates the effectiveness and safety of supplemental isradipine in the treatment of hypertension not controlled by hydrochlorothiazide alone.

The effects of renal function on the disposition of isradipine.

The effect of renal function on isradipine kinetics was examined in four groups of subjects (N = 55) who had normal or impaired renal function. Each subject received isradipine orally as a 10-mg capsule. Serial blood samples were obtained from 0 to 48 hours postdose and the isradipine plasma concentrations determined by radioimmunoassay. Kinetic parameters, Cmax, lambda 3, t 1/2, AUC, CL'o (oral clearance), and CLo (oral clearance standardized to body weight) were determined. Marked intersubject variability of the pharmacokinetic parameters was observed. No statistically significant differences (P greater than .05) were found for AUC, Cl'o, and Clo parameters when renal impairment groups were compared with controls. AUC values were lower (P less than .05), however, for the group with severe renal function impairment than for groups with mild or moderate renal function impairment. No significant correlations (r = -.23, P greater than .05; and r = .13, P greater than .05, respectively) were found between creatinine clearance (CLCR) and CLo and between age and CLo. Considering the interpatient variability in isradipine disposition and the lack of significant differences in CLo between groups, no clear-cut dosing regimen alterations, based on single-dose data, are warranted in renal impairment.

Effects of isradipine, a new calcium antagonist, versus hydrochlorothiazide on serum lipids and apolipoproteins in patients with systemic hypertension.

The effect of isradipine versus hydrochlorothiazide on the lipid profile of 44 hypertensive patients was investigated in a double-blind, randomized, 2-center trial. Lipid profiles included total cholesterol, serum triglycerides, high density lipoprotein (HDL) cholesterol, HDL subclasses, (HDL2 and HDL3), low density lipoprotein cholesterol, very low density lipoprotein cholesterol, apolipoprotein A-1 and apolipoprotein B. Isradipine had no effect on the lipid profile in short- (4 and 10 week) or long-term (52 week) studies. Hydrochlorothiazide increased serum triglycerides in 11 of 13 patients by a mean of 8% for the group (p less than 0.05) in long-term (52 week) studies, and total cholesterol by a mean of 9 and 16%, respectively (p less than 0.01) in 2 of 13 patients, with no difference in other lipid or lipoprotein parameters in short- or long-term studies.

Isradipine (PN 200-110) versus hydrochlorothiazide in mild to moderate hypertension. A multicenter study.

The effects of 10 weeks of treatment with isradipine (ISRP), a new dihydropyridine Ca antagonist, was evaluated in a prospective, randomized, double-blind, parallel group, hydrochlorothiazide (HCTZ) controlled study in patients with mild to moderate hypertension. Of 98 patients enrolled, 73 completed the study and were deemed valid for efficacy analyses; 36 in the ISRP group and 37 in the HCTZ group. Monotherapy with ISRP significantly (P less than 0.001) decreased (mean +/- SD) sitting systolic blood pressure (BP) from 146 +/- 11 mm Hg to 128 +/- 11 mm Hg and diastolic BP from 100 +/- 4 mm Hg to 83 +/- 5 mm Hg. Heart rate during the plateau period was not significantly different (76 +/- 11 vs 78 +/- 11 bpm) between the ISRP and HCTZ groups. These reductions in BP were comparable to monotherapy with HCTZ. The mean reduction in diastolic BP with ISRP (17 +/- 6 mm Hg) was significantly (P less than 0.05) greater than that with HCTZ (14 +/- 5 mm Hg). The mean doses for ISRP and HCTZ were 12 mg/day and 60 mg/day, respectively. There was no significant difference in frequency of common side effects (headache, nausea, fatigue, dizziness, palpitations) between the two groups. However, transient or intermittent peripheral edema occurred more frequently in ISRP group. Four patients in ISRP group (two due to edema and two due to palpitations) and two patients in HCTZ group (due to poor BP control) were discontinued from the study. Our results indicate that ISRP in doses of 5 to 10 mg bid is as effective as HCTZ as monotherapy in the treatment of mild to moderate hypertension.

The pharmacokinetics of oral isradipine in normal volunteers.

The pharmacokinetics and relative bioavailability of oral isradipine, a dihydropyridine calcium channel blocking agent, were determined in 42 normal male volunteers participating in two separate studies. Eighteen of the subjects received 2.5-, 5-, and 10-mg oral doses of isradipine solution (Study 1). The remaining 24 subjects received four 2.5-mg capsules, one 10-mg capsule, and 10 mg of isradipine as an oral solution (Study 2). Venous blood samples were obtained prior to and at frequent intervals after administration of each dose form. Plasma isradipine concentrations were measured by radioimmunoassay. No significant dose effect occurred with respect to any pharmacokinetic parameter except AUC and Cmax in Study 1. In Study 2, Cmax, tmax, and MRT were significantly different after the solution compared with the capsular formulations. The respective pharmacokinetic parameters (mean +/- SD) for the 10-mg solution and 10-mg capsule in Study 2 were time to maximum concentration, 0.40 +/- .28 and 1.57 +/- 0.44 hours; oral clearance, 284.9 +/- 105.3 and 317.0 +/- 138.4 L/hr; elimination half-life, 5.36 +/- 1.8 and 6.63 +/- 2.4 hrs, respectively. Headache, dizziness, and tachycardia were the most frequent adverse effects in both studies.

Improvement of the lipid profile during long-term administration of pindolol and hydrochlorothiazide in patients with hypertension.

The effect of the combined administration of pindolol (10 or 20 mg daily) and hydrochlorothiazide (50 mg daily) on the serum lipid and lipoprotein levels of 34 hypertensive patients was investigated for 6 to 18.5 months (mean 13.3). Placebo control data were compared with the results obtained during treatment periods in each patient by paired t tests. Mean levels of high-density lipoprotein cholesterol increased by 17% (p less than 0.01), low-density lipoprotein cholesterol decreased by 4% (p less than 0.01) and the high-density lipoprotein: low-density lipoprotein cholesterol ratio increased by 28% (p less than 0.01). Total serum cholesterol, serum triglycerides and very low-density lipoprotein cholesterol showed no statistically significant changes from control values. These findings suggest that the long-term administration of this beta blocker combined with a diuretic results in serum lipid changes considered beneficial in the evaluation of risk factors for coronary artery disease.

Adverse reactions to pindolol administration.

More than 1200 patients who received pindolol for the treatment of hypertension, angina pectoris, and various arrhythmias in studies conducted in the United States were included in the New Drug Application submitted to the FDA. Nearly 1000 of these patients received pindolol as monotherapy. The side effects reported were generally transient and of mild or moderate severity. The most frequently reported side effects seen after pindolol administration, compared to those seen after placebo, were in decreasing order of incidence: headache, dizziness, insomnia, muscle pain, fatigue, weakness, nervousness, joint pain, edema, nausea, and muscle cramps. Other side effects that occurred more frequently with pindolol than with placebo but at a rather low incidence induced weight gain, bizarre dreams, visual disturbances, lethargy, and diarrhea. Nasal congestion, throat discomfort, nocturia, impotence, pruritus, anxiety, hypotension, bradycardia, and heart failure occurred only rarely. Of the 323 patients who received pindolol alone for the treatment of mild to moderate hypertension, only 20 (6.2%) were withdrawn from the study because of side effects. Overall, 3.4% of the patients treated with pindolol were withdrawn because of side effects, most of which involved the central nervous system, that is, insomnia, anxiety, dizziness, and headache. However, a few patients manifested some edema and weight gain while receiving pindolol alone. Review of the side effects data did not reveal a tendency for the incidence of side effects to be dose related. One placebo-controlled, double-blind study designed to evaluate the fixed dosages of 15, 30, and 60 mg in the treatment of mild to moderate hypertension suggested that only the incidences of insomnia and nervousness increased with increasing doses. However, these side effects were generally transient and of mild or moderate severity. The evidence indicates that pindolol has an acceptable safety profile and that any side effects that appear are generally well tolerated and disappear with continued treatment.