Anti-angina effect of the calcium antagonist bepridil in stable angina pectoris

Twelve patients with angiographically proven coronary artery disease and stable, exercise-induced angina pectoris were treated in a randomized sequence with placebo (PL) and bepridil tablets in maintenance doses of 200 mg, 400 mg and 600 mg per day for one week each, according to a double blind-protocol with intra-individual cross-over. The four treatment phases were separated by 2-week wash-out periods (placebo). On day 7 of each treatment phase and at the end of each wash-out period heart rate and blood pressure were measured 2 and 5 hours after drug intake and exercise stress testing was performed. The mean plasma concentrations at the end of the 1-week treatment periods 2 hours after drug intake were: 375 +/- 202 ng/ml (200 mg/day), 844 +/- 273 ng/ml (400 ng/day) and 1378 +/- 538 ng/ml (600 mg/day). Systolic blood pressure was not influenced by either bepridil dose. Diastolic blood pressure was slightly reduced (-6%) after 600 mg bepridil/day (p less than 0.05). While heart rate at rest in the upright position tended to lower values with regard to bepridil dosages, it was significantly lowered at the end of stress testing (2 hours/5 hours):400 mg: -7% (p less than 0.05)/-15% (p less than 0.05); 600 mg: -11% (p less than 0.001)/-10% (p less than 0.05). Myocardial ischemia (sum of ST-segment depressions) was improved in a dose-dependent manner (2 hours/5 hours):200 mg: -21% (p less than 0.05)/-31% (n.s.); 400 mg: -27% (n.s.)/-31% (p less than 0.01); 600 mg: -56% (p les than 0.001)/-55% (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of the calcium antagonist nifedipine on stress-induced bronchial asthma

Studies of the efficiency of the calcium antagonist nifedepine on the exercise-induced asthma bronchiale (EIA) were carried out in 15 cases of asthmatics (11 men, 5 women; average age 28.5 years; average time of illness 6.4 years). Duration of exercise was 6 minutes at 80-85% of the maximal age related heart frequency, either on the bicycle ergometer or free running. Rtot, TGV, MEF50, MEF25 and arterial pO2 were measured, Rtot and TGV with air breathing as well as with He/O2 (80% He, 20% O2). Nifedepine reduces significantly the exercise-induced obstruction of the large and the peripheral airways. Possible mechanisms are discussed. Prophylactic treatment with nifedepine is possible. The development of a selective calcium antagonist is desirable.     

Myocardial properties of the new dihydropyridine calcium antagonist isradipine compared to nifedipine with or without additional beta blockade in coronary artery disease

Isradipine is a new dihydropyridine calcium antagonist with myocardial effects significantly different from those of nifedipine, as shown by in vitro and animal experimental data. Isradipine selectively inhibits the sinus node but not the atrioventricular conduction and its negative inotropic action is much less if administered in a dose of comparable peripheral effects. To study these effects in man, 40 patients with coronary artery disease were divided into 2 groups receiving either a continuous 30-minute intravenous infusion of 2 mg of nifedipine or 0.5 mg of isradipine, doses that resulted in a comparable afterload reduction (decrease of systemic vascular resistance: nifedipine -22.1%, isradipine -25%, p less than 0.001). Ten patients in each group received an additional intravenous bolus of 5 mg of propranolol at the end of the calcium antagonist administration to antagonize its induced adrenergic reflex mechanisms. The heart rate significantly increased after nifedipine only (+9.2%, p less than 0.001), experienced no change after isradipine and the nifedipine and propranolol combination and decreased after the combination of isradipine and propranolol (-9.6%, p less than 0.001). This resulted in a significant decrease of the rate pressure product with isradipine (-12.5%, p less than 0.001) but not with nifedipine. As a result of the afterload-induced adrenergic reflex mechanisms, the maximal derivative of the left ventricular pressure increased after isradipine administration (+13.5%, p less than 0.001) and was unchanged after nifedipine, which demonstrates the significantly less negative inotropic properties of isradipine as compared with nifedipine.     

Unstable coronary plaque and its relation to coronary calcium

Coronary calcium is intimately associated with coronary atherosclerotic plaque development. The use of electron-beam computed tomography (EBCT) for accurate quantitative measurements has led to an increased interest in understanding the clinical importance of coronary calcium, particularly in terms of the ability to identify unstable coronary plaques that underlie the clinical acute coronary syndromes. Histopathologic studies have demonstrated that calcium is a frequent feature of ruptured plaques, but the presence or absence of calcium does not allow for reliable distinction between unstable versus stable plaques. This issue is complicated by the lack of a prospective definition for "unstable." Plaque rupture is sometimes found in apparently healthy subjects and in patients with clinically stable disease. Coronary atherosclerosis is a coronary systemic disease process. Imaging of coronary calcium, although unable to identify a localized unstable plaque, potentially can identify the more clinically pertinent "unstable patient." Almost all patients with a recent acute coronary syndrome have measurable coronary calcium because moderate-to-advanced coronary plaque disease is already present, although obstructive disease frequently is not. Prospective studies have demonstrated that extensive coronary calcium detected by EBCT is associated with a significantly increased incidence of subsequent myocardial infarction, need for revascularization, and coronary death. The incremental prognostic value of coronary calcium compared with that of risk factor assessment remains to be fully defined. The occurrence of an acute coronary syndrome is determined by many factors apart from the extent of atherosclerotic plaque disease. Large prospective trials in the general population are needed to define the subgroups that will benefit most from quantitative assessment of coronary calcium.     

Effect of a calcium antagonist, nifedipine, in exercise-induced asthma

The nifedipine effect was studied in 8 extrinsic asthmatic subjects with exercise-induced asthma. Before the exercise the patients received, in a randomized double-blind manner, either 20 mg nifedipine, sublingually or sodium cromoglycate by inhalation on 2 separate days. Nifedipine and sodium cromoglycate in all patients inhibited the exercise fall in FEV1. No differences were found between the two drugs. Nifedipine is a potent antagonist of calcium ion influx in smooth muscle and secretory cells, and these studies suggest that it may inhibit release of mast cell mediators and reduce bronchial smooth muscle contractility in asthma.     

The calcium antagonist nifedipine inhibits arterial smooth muscle cell proliferation

Migration of smooth muscle cells from the media to the intima of the arterial wall and proliferation of intimal smooth muscle are major early events in the formation of an atherosclerotic lesion. The start of proliferation requires that the cells have passed through a modulation from contractile to synthetic phenotype and that they are stimulated with growth factors. Here, we have examined the effects of the calcium antagonist nifedipine on phenotypic modulation and growth of isolated rat arterial smooth muscle cells cultivated in vitro. The results indicate that micromolar concentrations of nifedipine slow down the rate of transformation of the cells from a contractile to a synthetic phenotype and inhibit initiation of DNA synthesis as well as cellular proliferation. The inhibitory effect on DNA synthesis was seen both in cells stimulated with whole blood serum and with purified platelet-derived growth factor. The results raise the possibility that nifedipine may be used to prevent atherogenesis and to inhibit progression of fibromuscular lesions by interfering with the proliferation of arterial smooth muscle cells.     

The effect of the calcium antagonist nifedipine on peripheral nerve function in streptozotocin-diabetic rats

Summary Recent data suggests that reduced nerve blood flow is implicated in the aetiology of experimental diabetic neuropathy, which may be prevented by manipulations that reduce receptor-mediated vasoconstrictor activity. This investigation examines the effects of nifedipine, a voltage-sensitive calcium channel antagonist which has a direct vasodilatory effect on vessels, on nerve conduction, hypoxic resistance and capillary density in streptozotocin-induced diabetic rats. Treated and non-treated non-diabetic and diabetic groups were employed. Diabetes duration was 2 months. Treatment was preventive, groups received a nifedipine dietary supplement (40 mg · kg^–1 · day^–1) for 2 months from the start of the study. Conduction was measured in sciatic motor branches supplying tibialis anterior and gastrocnemius muscles, and sensory saphenous nerve. Diabetes resulted in a 23–28 % reduction in motor conduction velocity (p<0.001), and a 15% deficit for sensory saphenous nerve (p<0.001). In the nifedipine-treated diabetic group, motor and sensory conduction deficits were minimal compared with non-treated diabetes (p<0.001). Nifedipine treatment had no significant effect on conduction velocity in nondiabetic rats. In vitro measurement of sciatic nerve hypoxic resistance revealed a 60 % increase in the time taken for compound action potential amplitude to reach half its initial value with diabetes (p<0.001). This was not significantly affected by nifedipine treatment. Experimental diabetes or nifedipine treatment did not significantly alter sciatic nerve endoneurial capillary density. We conclude that nifedipine, a vasodilator which acts directly on vascular smooth muscle, prevents nerve conduction deficits in experimental diabetes.     

The effects of nifedipine,a calcium antagonist,on platelet function

Platelet function was studied before and 1 hour after ingestion of 20 mg nifedipine, a new calcium antagonist, in 20 patients with coronary heart disease. Platelet counts remained unchanged. Platelet adhesiveness, measured as retention in glass bead columns with hellem's method for native blood, did not drop significantly either when 0.9 or 3.6 ml of blood was used. Platelet aggregation, which is dependent on extracellular calcium, was induced in citrated platelet-rich plasma. The mean maximal rate of primary aggregation, initiated with three different concentrations of adenosine diphosphate, was reduced by 20% to 26%. The rate of irreversible collagen-induced aggregation was on average 23% lower after nifedipine. The mean bleeding time was 36 seconds, or 12%, longer after ingestion of the drug. The moderate, but significant reduction of platelet aggregation and prolongation of the bleeding time by nifedipine may be mediated through inhibition of calcium transport across the platelet membrane.     

Similarities and differences in the antihypertensive effect of two calcium antagonist drugs, verapamil and nifedipine

The short- and long-term effects of two calcium channel blocking drugs, verapamil and nifedipine, on blood pressure, heart rate, plasma catecholamines, plasma renin activity, plasma volume and cardiac performance (echocardiography) were studied in essential hypertensive patients and in normal subjects. Verapamil, 160 mg orally, reduced blood pressure within 60 minutes in 22 hypertensive patients, but not in 12 normotensive subjects. Nifedipine, 10 mg sublingually, reduced blood pressure within 15 minutes in 19 hypertensive patients, but not in 7 normotensive subjects. Plasma noradrenaline was significantly increased both in normal subjects and in hypertensive patients only after nifedipine was administered. Verapamil (80 mg three times a day) first, and nifedipine (10 mg three times a day) thereafter, or vice versa, were given to 12 hospitalized hypertensive patients on a fixed sodium and potassium intake; the drugs produced similar blood pressure reductions, but heart rate and plasma catecholamines were increased only after nifedipine (p less than 0.05). Neither drug affected plasma volume, aldosterone or plasma renin activity. Long-term ambulatory treatment with verapamil (80 or 160 mg three times a day for 2 to 4 months) or nifedipine (10 mg three times a day for 2 months) produced changes in all variables that were similar to those observed in the hospital (controlled) study. Shortening fraction was significantly increased after nifedipine (p less than 0.05) but no change was observed after verapamil. In conclusion, blood pressure is effectively reduced by both verapamil and nifedipine; an appreciable adrenergic stimulation may be caused by nifedipine, but usually not by verapamil, and fluid retention, renin release or myocardial depression is not observed during verapamil or nifedipine treatment.     

Effectiveness of once-daily monotherapy with a new nifedipine sustained release calcium antagonist.

Data from 2 separate multicenter, double-blind clinical studies following the same protocol, except for the selection of doses, were pooled to evaluate the efficacy and tolerability of fixed doses of a new sustained-release (SR) formulation of nifedipine compared with placebo in 388 patients with mild to moderate uncomplicated essential hypertension. After a 3-6 week placebo washout period, the patients were randomized to receive either placebo or nifedipine SR-20 mg (study I only), 50 mg, 100 mg, or 150 mg (study II only). Among the 278 patients who completed 6 weeks of active therapy, mean supine diastolic blood pressure reductions from pretreatment baseline were 5.9, 9.3, 9.2, 11.1, and 13.2 mm Hg in the placebo, 20-, 50-, 100-, and 150-mg groups, respectively. The reductions achieved in each of the nifedipine SR groups were statistically significant versus baseline values (p less than 0.001). All nifedipine-SR doses reduced supine systolic blood pressure significantly more than placebo (p less than 0.001). In addition, there was a significant linear relationship between the log of the dose and the blood pressure reduction (p less than 0.05). Automated ambulatory blood pressure recordings performed in 221 of the patients showed that the blood pressure was lowered evenly through the entire 24-hour dosing period. The doses that were effective and associated with the fewest adverse reactions were 20 mg and 50 mg once daily.     

Effect of the calcium antagonist nifedipine on blood pressure and its circadian rhythm in patients with hypertension

In 74 patients with hypertension with an average age of 60 years on the basis of 8 measuring values the behaviour of blood pressure and frequency was controlled between 6 a.m. and 11 p.m. during the administration of the calcium antagonist nifedipine. The average blood pressure decreased from 198/106 to 178/89 mm Hg during the nifedipine treatment. The scope of the decrease of blood pressure was significantly higher in the patients older than 60 years than in the younger patients. At the same time the blood pressure values very much decreased in patients with the higher values. The heart rate increased only in patients of older age under the administration of nifedipine. The circadian rhythm of the blood pressure, in particular the matutinal increase of blood pressure, could not be influenced.     

Left ventricular response to exercise in coronary artery disease: relation to myocardial ischaemia and effects of nifedipine

To assess the relationship between left ventricular (LV) responseto exercise and myocardial ischaemia, 40 patients with coronaryartery disease (CAD) and 17 control subjects underwent radionuclideventriculo-graphy at rest and during semiupright exercise. In14 of the 40 patients with CAD, radionuclide exercise studieswere repeated 20 min after 20 mg of sublingual nifedipine. Patientswith CAD had increases in both LV end-diastolic and end-systolicvolumes and no change in ejection fraction during exercise.End-systolic volume increased and ejection fraction decreasedsignificantly more in patients with multivessel disease, exercise-inducedangina and/or ischaemic ST segment depression. Nifedipine reducedangina and ST-segment depression during exercise, attenuatedexercise-induced increase in end-diastolic and end-systolicvolumes and improved eject ion fraction. This study suggests that in patients with CAD, the responseof LV volumes and ejection fraction to exercise is related tothe degree of exercise-induced myocardial ischaemia and nifedipineimproves exercise LV performance     

Effect of the calcium antagonist nisoldipine on coronary circulation and myocardial ischemia in temporary coronary occlusion

Sixteen patients undergoing PTCA of a significant lesion of the left anterior descending coronary artery received either 0.3 mg nisoldipine or placebo intravenously. Immediately before and during balloon inflation the following parameters were measured: aortic pressure, post-stenotic pressure, coronary occlusion pressure, diastolic pulmonary artery pressure, coronary sinus flow (thermodilution), and intracoronary ECG. After placebo there were no statistically significant changes. Nisoldipine led to a decrease in aortic pressure from 109 +/- 12 to 93 +/- 11 mm Hg (p less than 0.05) before, and from 103 +/- 14 to 92 +/- 8 mm Hg (NS) during balloon inflation. In contrast, coronary occlusion pressure remained unchanged. Heart rate increased from 80 +/- 13 to 96 +/- 16/min before (p less than 0.05), and from 87 +/- 18 to 97 +/- 17/min during balloon inflation (NS). Coronary sinus flow was increased from 95 +/- 16 to 116 +/- 13 ml/min before balloon inflation (p less than 0.01), and from 70 +/- 25 to 86 +/- 26 ml/min during balloon inflation (NS). ST-segment depression or elevation, severity of angina pectoris, and the diastolic pulmonary artery pressure remained unchanged. Thus, 0.3 mg nisoldipine led to a peripheral vasodilatation. While the aortic pressure decreased, coronary occlusion pressure remained unaffected. This could be explained by a marked dilatation of collateral vessels due to nisoldipine. However, myocardial ischemia remained unaffected as a result of the constant coronary occlusion pressure.     

Anti-angina therapy of coronary heart disease. Mono- or combination treatment]

Applying a metaanalysis, it was examined whether a combination of drugs is superior to monotherapy in the treatment of angina pectoris. The three classical groups of anti-anginal drugs, nitrates, calcium channel blockers and beta-receptor blockers were investigated. For data analysis, patients were divided in those suffering from "angina pectoris" and those suffering from "angina pectoris despite monotherapy." In patients with the inclusion criterium "angina pectoris" combination of drugs is not superior to monotherapy. This applies to the evaluation criteria "improvement of symptoms" and "reduction of ischemia". In patients with the inclusion criterium "angina pectoris despite monotherapy" however, there is a clear superiority of drug combination as compared to monotherapy. Again this applies to the evaluation criteria "improvement of symptoms" and "reduction in myocardial ischemia". With respect to antianginal efficacy all three possible combinations appear to be similar. If the evaluation criterium is "improvement of prognosis" no data are available with regard to drug combination. Furthermore no data are available on the prognostic effect of an anti-anginal therapy in patients with stable angina pectoris. A significant improvement of prognosis could be demonstrated for beta-receptor blocking agents without ISA in unstable angina, acute myocardial infarction, and in the postinfarction period. The effect of calcium channel blockers on prognosis depends on the substance class applied and on the presence or absence of signs of congestive heart failure. Monotherapy with nifedipine in instable angina and acute myocardial infarction fails to improve prognosis, and there even may be a tendency to adverse effects. In the absence of signs of congestive heart failure verapamil has been demonstrated to improve prognosis in the post infarction period. Likewise, improvement of prognosis by the administration of diltiazem in acute myocardial infarction only could be demonstrated in patients without signs of heart failure. In contrast, in patients with signs of congestive heart failure diltiazem increased the rate of reinfarction and mortality. For nitrates only in acute myocardial infarction a trend towards improved prognosis has been shown. Especially for nitrates the data on prognosis in coronary heart disease available so far are not convincing.     

Safety of acute calcium antagonist withdrawal: studies in patients with unstable angina withdrawn from nifedipine

The acute effects of nifedipine withdrawal were studied in 81 patients with angina at rest who had completed a prospective, double-blind, randomized trial of nifedipine versus placebo. Thirty-nine of the 81 patients (group 1) were withdrawn from nifedipine or placebo at the time of coronary artery bypass surgery for uncontrolled angina or left main coronary artery disease. When the patients withdrawn from nifedipine were compared with those withdrawn from placebo, no significant differences were seen in the incidence of hypotension, myocardial infarction, significant arrhythmias or vasopressor or vasodilator requirements during the perioperative period. Forty-two patients (group 2) completed 2 years on a protocol consisting of nitrates and propranolol, in addition to nifedipine or placebo. These patients were hospitalized for a controlled withdrawal of the study drug (nifedipine or placebo), and no significant difference was noted in either exercise performance on serial treadmill testing or the number or duration of episodes of ischemic ST-segment changes during continuous electrocardiographic monitoring. Eight patients continued to experience occasional episodes of angina at rest. Angina at rest recurred during the withdrawal period in 5 of these 8 patients. Four of these 5 patients were withdrawn from nifedipine. Of the 34 stable patients in group 2 who were not experiencing angina at rest before withdrawal, none had angina at rest during the withdrawal study period. Thus, there were no early untoward effects of acute nifedipine withdrawal either in patients undergoing coronary bypass surgery or in stable patients on long-term medical therapy. However, patients with persistent symptoms of angina at rest may experience early recurrent ischemia upon withdrawal from nifedipine.     

The antihypertensive efficacy of the novel calcium antagonist mibefradil in comparison with nifedipine GITS in moderate to severe hypertensives with ambulatory hypertension

Mibefradil is a novel calcium antagonist that blocks selectively the T-type calcium channels. In this double-blind forced titration study design we compared the effects of mibefradil 50, 100, and 150 mg and nifedipine GITS 30, 60, and 90 mg monotherapies or combined with lisinopril 20 mg in 71 moderate to severe hypertensives (59 men and 12 women) with confirmed ambulatory hypertension. An incremental dose-response effect was observed both in clinic and ambulatory blood pressure parameters during treatment with mibefradil and nifedipine GITS alone and combined with lisinopril. At maximal dosage, patients treated with mibefradil experienced a greater (P < .05) reduction in clinic and ambulatory diastolic blood pressures as well as a greater response rate (86% ν 69%). Trough:peak ratios for systolic and diastolic blood pressures were > 90% at each dose level. Significant decrease in baseline heart rate was observed with mibefradil 150 mg alone or combined with lisinopril, but no patients experienced clinically significant atrioventricular conduction abnormalities. Adverse events related to vasodilation were more prevalent in the nifedipine GITS group. Consequently, the results of the present study demonstrate that the novel calcium channel blocker mibefradil, either alone or in combination with lisinopril, is effective in reducing clinic and 24-h blood pressures while decreasing heart rate and is well tolerated in patients with moderate to severe hypertension.     

Comparative efficacy of nicardipine, a new calcium antagonist, versus nifedipine in stable effort angina

The relative efficacy of nicardipine and nifedipine was examined in a double-blind placebo-controlled randomized crossover trial. We studied 12 patients with chronic effort angina involving reproducible angina and greater than or equal to 1.5 mm of ST-segment depression on exercise treadmill test performed before and after a 1-week control period of single-blind placebo administration. Subsequently, indistinguishably prepared nicardipine 20 mg, nifedipine 10 mg, or placebo, four times a day, was administered in a randomized double-blind crossover fashion for 3 weeks (total study period 9 weeks). Exercise treadmill test was performed at the end of each 3-week period. Both nicardipine and nifedipine significantly reduced the frequency of anginal attacks and nitroglycerin consumption. Compared with placebo both drugs caused a comparable increase of the duration of exercise, of the time to angina and to the appearance of 1.5 mm ST-segment depression (P less than 0.05 placebo versus nicardipine; P less than 0.01 placebo versus nifedipine respectively). No significant side effects were observed with either drug. We conclude that nicardipine and nifedipine produce similar hemodynamic and clinical effects in patients with stable effort angina.     

Comparative efficacy of nicardipine, a new calcium antagonist, versus nifedipine in effort stable angina

The relative efficacy of nicardipine and nifedipine was examined in a double-blind randomized trial. We studied 12 patients with chronic effort angina who had reproducible chest pain and greater than or equal to 1.5 mm of ST-segment depression on treadmill exercise testing performed before and after 1-week control period of single-blind placebo administration. Subsequently over a 9-week period, nicardipine 20 mg or nifedipine 10 mg or an identical placebo four times a day, was administered in a randomized double-blind crossover fashion. Treadmill exercise testing was performed at the end of each 3-week period. Both nicardipine and nifedipine reduced the frequency of anginal attacks and trinitrate consumption. Compared with placebo both drugs caused a comparable increase of the total duration of exercise (p less than 0.05 placebo versus nicardipine; p less than 0.01 placebo versus nifedipine) and of the time to the onset of angina (p less than 0.05 placebo versus nicardipine; p less than 0.01 placebo versus nifedipine) and to the appearance of 1.5 mm ST depression (p less than 0.05 placebo versus nicardipine; p less than 0.01 placebo versus nifedipine). Moreover 4 patients no longer had angina with either drug and only 1 patient with placebo. Both drugs increased resting heart rate and reduced systolic blood pressure at resting (p less than 0.01) and submaximal exercise (p less than 0.01). Peak heart rate, systolic blood pressure and rate-pressure product were similar with placebo, nicardipine and nifedipine. No important side effects were observed with either drug. We conclude that nicardipine and nifedipine produce similar haemodynamic and clinical effects in patients with stable angina.