The safety and efficacy, as measured by peak/trough blood pressure reduction, of a new, once-daily, controlled-release formulation of isradipine (isradipine-CR, ICR) were evaluated in patients with mild to moderate essential hypertension during a nine-week trial. After a 3-week placebo washout period, patients with a sitting diastolic blood pressure between 100 and 114 mm Hg were randomized to either 1 of 4 ICR treatment groups or placebo. Of 402 randomized patients, 384 completed the study (placebo = 77, ICR-5 mg = 76, ICR 10 mg = 76, ICR-15 mg = 78, and ICR-20 mg = 77). Peak and trough post-dose blood pressure responses and heart rates were monitored for both the sitting and upright positions. Blood chemistries, urinalyses, complete blood counts, and electrocardiograms were done during the study. Both sitting and upright blood pressure decreased with the 5-(P < .05), 10-, 15-, and 20-mg (P < .001) once-daily ICR doses. The peak blood pressure reduction for all ICR doses occurred at 8 to 10 hours post-dose. Maximum peak/trough blood pressure response, achieved with the 10-mg dose, was similar with that of 15 and 20 mg of ICR. No serious clinical or metabolic side effect were noted, except ankle edema, which was dose dependent but did not require discontinuation of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

One hundred seventy-eight patients, aged 30 to 85, with mild-to-moderate hypertension entered a multicenter double-blind, randomized, between-patient comparison of isradipine (0.5, 1.25, or 2.5 mg twice daily) and placebo. Patients were assessed after three weeks of placebo treatment (for baseline) and after two and five weeks of active therapy. Despite a marked placebo effect, isradipine at 1.25 mg and 2.5 mg twice daily reduced blood pressure to a significantly lower level. The lowest blood pressures were recorded at four hours post-dose, and the residual antihypertensive effect at 12 hours was between 70 and 79 percent of the four-hour measurements. Isradipine did not produce more laboratory, electrocardiographic, or clinical abnormalities, or adverse events than did placebo. It is concluded that isradipine in doses of 1.25 mg and 2.5 mg twice daily is effective and well tolerated in the treatment of mild-to-moderate hypertension.

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OBJECTIVES:

</b>We sought to determine the efficacy of isradipine in reducing left ventricular (LV) mass and wall thickness in hypertensive patients.<b>

BACKGROUND:

</b>LV hypertrophy on the echocardiogram is a strong predictor of cardiovascular events. Reduction of LV mass may be a desirable goal of drug therapy for hypertension. However, although thiazide diuretic drugs have been advocated as first-line therapy for hypertension, their efficacy in reducing LV mass has been questioned.<b>

METHODS:

</b>Patients with mild to moderate diastolic hypertension and LV mass in excess of 1 SD of normal values were randomized to isradipine (n = 89) or hydrochlorothiazide therapy (n = 45). Evaluations were obtained at baseline, after 3 and 6 months of treatment and 2 weeks after treatment was stopped.<b>

RESULTS:

</b>At 6 months, LV mass decreased by 43 +/- 45 g (mean +/- SD) with hydrochlorothiazide (p < 0.001) but only by 11 +/- 48 g with isradipine (p = NS; between-group comparison, p < 0.001). Two weeks after drug therapy was stopped, LV mass remained 24 +/- 41 g lower than that at baseline in the hydrochlorothiazide group (p = 0.003) but only 7 +/- 50 g lower in the isradipine group (p = NS). Septal and posterior wall thicknesses were significantly and equally reduced with both isradipine and hydrochlorothiazide. Greater LV mass reduction with hydrochlorothiazide was related to a 2.8 +/- 3.3-mm reduction of LV cavity size with hydrochlorothiazide but no reduction with isradipine. At 6 months of treatment, diastolic blood pressure (BP) by design was equally reduced in both treatment groups. At 3 months, systolic BP was reduced by 17 +/- 15 mm Hg with isradipine and by 26 +/- 15 and 25 +/- 17 mm Hg at 3 and 6 months, respectively, with hydrochlorothiazide (p = 0.003, between-group comparison). However, on stepwise multivariable regression analysis, treatment selection (partial r2 = 0.082, p = 0.001), change in average 24-h systolic BP (partial r2 = 0.032, p = 0.029) and change in average sitting systolic BP (partial r2 = 0.017, p = 0.096) were predictive of LV mass reduction.<b>

CONCLUSIONS:

</b>Despite an equivalent reduction of diastolic BP, 6 months of therapy with hydrochlorothiazide is associated with a substantial reduction of LV mass, greater than that with isradipine. The superior efficacy of hydrochlorothiazide for LV mass reduction is associated with a greater reduction of systolic BP as well as drug selection itself. These data may have important therapeutic implications.

In animal studies calcium channel blockers (CCB's) and especially isradipine, a second generation dihydropyridine, interrupt the sequence of events culminating in the formation of atherosclerotic lesions. The effect of 4 weeks isradipine treatment (5mg daily) on blood pressure and in-vivo platelet function (measured with 111Indium-oxine labeled autologous platelets) were investigated in a randomized, double-blind and placebo controlled trial in 40 patients with mild to moderate hypertension and scintigraphically diagnosed active atherosclerotic lesions of the carotid arteries. The average supine systolic/diastolic blood pressure was significantly reduced at the end of the treatment period in the isradipine group (group 1; p < 0.0001) but remained unchanged in the placebo group (group P). The heart rate was not significantly altered in either group. There were no serious side effects. The platelet uptake ratio (PUR) measured over the atherosclerotic region of the carotid artery on 4 consecutive days before and after treatment decreased significantly in group I from 1.20 to 1.15 (within groups: p < 0.0001) but remained unchanged in group P. Platelet survival increased significantly in group I (mean 5.70 hours, lower quartile 4.50, upper quartile 4.50 hours, within groups: p < 0.0001) and remained unchanged in group P. Isradipine has a beneficial effect on in-vivo platelet function as evidenced by a decreased platelet deposition on vascular lesion sites and an associated prolonged platelet survival in patients with hypertension and active atherosclerotic lesions.

A meta-analysis was performed to compare the risk of serious adverse events associated with the use of all formulations of isradipine, when used as monotherapy in hypertension, to active drug or placebo controls. Eligible studies totalled 65 published and unpublished randomised controlled trials involving 9903 subjects and 10,675 treatment exposures: 4492 to isradipine, 1473 to isradipine sustained release, 2768 to other active drugs, and 1942 to placebo. Mortality, cardiovascular outcomes, other serious incident illnesses, such as cancer, and withdrawals were sought. Seventy-five per cent of the isradipine exposures were to standard-release formulations and 25% were to sustained-release formulations. Overall, isradipine therapy shows no difference in risk of major adverse events or withdrawals compared to other active controls or placebo (odds ratios [OR] 0.9; 95% CI 0.7-1.46 and 0.5; 95% CI 0.2-1.3). These major adverse events included angina, fatal and non-fatal myocardial infarction, stroke and overall mortality. Isradipine sustained release could be compared only to placebo, based on available data, and shows a lower risk of withdrawals (OR 0.5; 95% CI 0.3-0.9), and a similar trend was observed for major adverse events, (OR 0.8; 95% CI 0.3-2.5). Published and unpublished randomised controlled trials were analysed in separate meta-analyses and later combined when this sensitivity analysis of risk showed no differences between the groups. In conclusion, we find no evidence for increased risk of serious adverse events in patients receiving isradipine as monotherapy for hypertension.

Most antihypertensive drugs have negative effects on metabolic control in diabetic patients. Calcium antagonists have been widely used in antihypertensive treatment of diabetics, although a possible influence on glucose tolerance, insulin secretion, and insulin action is unknown. Therefore, the effect of the calcium antagonist isradipine on glucose tolerance and insulin secretion (75 g oral glucose tolerance test) and on peripheral and hepatic insulin action (euglycemic clamp) was evaluated in 11 type II diabetic patients. All patients were treated with placebo or isradipine for 8 weeks (double-blind, crossover design). A second group of six diabetic patients received a thiazide diuretic, hydrochlorothiazide, according to the same protocol. Systolic blood pressure was significantly lowered after isradipine and hydrochlorothiazide compared with placebo (127 +/- 3 versus 139 +/- 6 mm Hg and 129 +/- 4 versus 142 +/- 4, respectively; p less than 0.05). Fasting blood glucose (190 +/- 21 versus 152 +/- 15 mg/dl; p less than 0.01), glucose levels, basal and glucose-stimulated insulin levels were significantly higher after hydrochlorothiazide compared with placebo but remained unchanged after calcium antagonist treatment. Basal hepatic glucose production and peripheral insulin resistance were significantly elevated after hydrochlorothiazide compared with placebo or calcium antagonist therapy. These data indicate that the calcium antagonist isradipine has no effect on glucose tolerance, insulin secretion, and insulin action in type II diabetic patients and might therefore be a useful drug for antihypertensive treatment in diabetes mellitus. However, diuretic treatment can lead to impairment of metabolic control and reduction of insulin action in type II diabetes mellitus.

Isradipine, a new calcium channel blocker, was given to 32 patients with mild to moderate essential hypertension. After a run-in period of three weeks, 32 patients were randomized double-blindly to six weeks' treatment with either isradipine 2.5 mg twice daily or isradipine 5.0 mg once daily in a modified release formulation. Based on conventional 'clinic' BP measurements 12 or 24 hours postdose, the two treatments resulted in clinically relevant BP reduction (16/11 and 19/15 mmHg) without reflex tachycardia. No differences were seen between the groups. Efficacy increased throughout the study period. By determination of the 24 hour BP profile with a noninvasive method, the two groups were comparable during the placebo period, and no differences were seen between the two treatments. Both treatments resulted in satisfactory BP reduction during 24 hours (daily reduction of 4/6 and 12/9 mmHg twice daily and once daily dosing respectively). One third of the patients had 'white-coat' hypertension based on ambulatory daytime mean BPs, compared with conventional measurements. No relationship was found between the initial BP lowering effect and the effect after long-term treatment with isradipine in either dose.

The antihypertensive efficacy and tolerability of the new calcium antagonist isradipine was assessed in 86 hypertensive patients who had pretreatment diastolic blood pressures (DBP) greater than or equal to 105 mm Hg and who were randomly allocated to a double-blind comparison of three different dosage regimens: 1.25 mg, 2.5 mg, and 5 mg b.i.d., and placebo. A 2-week run-in period was followed by a 4-week course of treatment. Isradipine reduced systolic and diastolic blood pressures dose-dependently; the normalization rate (DBP less than or equal to 90 mm Hg) was 5% with placebo and 29, 55, and 64% with isradipine 1.25, 2.5, and 5 mg b.i.d., respectively. The proportion of patients experiencing at least a 10 mm Hg reduction in sitting DBP was 29, 67, 86, and 91%, respectively. All three dosages proved to be significantly effective compared to placebo. Neither heart rate nor blood pressure regulation in orthostasis were influenced. The main side effects were headache, dizziness, and flushing; isradipine 1.25 and 2.5 mg b.i.d. were well tolerated (not significantly different from placebo). In conclusion, isradipine 2.5 mg b.i.d. appears to be the potential dose of first choice, exhibiting a favorable benefit-risk profile.

Isradipine, 2.5 mg twice daily and placebo were administered for 4 weeks to 11 untreated essential hypertensives in a double-blind, random order, crossover study. At the end of each phase patients were assessed by 36 h of continuous intra-arterial blood pressure monitoring, surface electrocardiography, and measurement of endogenous creatinine clearance, serum biochemistry and plasma renin activity. Arterial pressure was significantly reduced by isradipine, with mean reduction in systolic blood pressure of 11.0 mmHg and diastolic pressure of 13.2 mmHg over 24 h. There was no significant change in heart rate, endogenous creatinine clearance, serum biochemistry or plasma renin activity.

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