Effectiveness of a new calcium antagonist in severe hypertension

Nitrendipine is a new nifedipine-like calcium antagonist antihypertensive agent. In this study, nitrendipine 5-40 mg orally bid was administered for up to three months to 16 patients with severe essential hypertension (untreated supine diastolic blood pressure greater than or equal to 115 mm Hg). Hydrochlorothiazide or propranolol or both were also given to patients who did not achieve goal blood pressure with nitrendipine alone. Five patients achieved goal blood pressure (supine less than or equal to 90 mm Hg) with nitrendipine alone and six more after the addition of a second drug, and only four required triple-drug therapy. One patient was terminated from the study because of headaches, a common nitrendipine side effect. This study demonstrates that nitrendipine is an effective and well-tolerated agent in the treatment of severe hypertension.     

Clinical evaluation of amlodipine, a new long-acting calcium antagonist, in mild and moderate hypertension.

The antihypertensive efficacy of amlodipine was studied in 22 patients (16 female, six male) with mild-to-moderate hypertension. Following an initial two-week placebo run in, patients with a sitting diastolic blood pressure in the range 95-115 mmHg (12.7-15.3 kPa) began the 12-week active treatment phase with amlodipine at a dose of 5 mg once daily. If the sitting diastolic blood pressure was not reduced to less than or equal to 90 mmHg (12.0 kPa) after four weeks' treatment, the amlodipine dose could be adjusted to 10 mg once daily. The final four weeks of active treatment comprised of a maintenance phase during which the dose, which had produced the desired therapeutic response in each patient, remained constant. At the end of the trial, 18 patients (85.7%) were classified as therapeutic successes (reduction in diastolic blood pressure to less than or equal to 90 mmHg [12.0 kPa] with a greater than or equal to 5 mmHg [0.7 kPa] from baseline values or a greater than or equal to 10 mmHg [1.3 kPa] decrease from baseline). Of these patients, 16 received the 5 mg dose throughout the study and only two required an increase to 10 mg once daily. Patients generally tolerated amlodipine treatment well.     

Effect of FR 7534, a new calcium antagonist, on myocardial oxygen demand.

The actions of FR 7534, a new calcium antagonist, nitroglycerin, and dipyridamole on myocardial oxygen demand have been compared. Six anaesthetized dogs received two infusion levels of each drug which produced equivalent arterial hypotension. All three compounds reduced the tension-time index (TTI). FR 7534 and nitroglycerin but not dipyridamole produced significant decreases in myocardial oxygen consumption (MVO2). FR 7534 demonstrated oxygen-sparing actions comparable to nitroglycerin. FR 7534 may prove beneficial in alleviating myocardial ischemia.     

Cardiac electrophysiologic effects of a new calcium antagonist, lacidipine.

Lacidipine is a new 1,4-dihydropyridine derivative with potent and long-lasting antihypertensive activity. We used intracellular microelectrodes to characterize the electrophysiologic properties of lacidipine on different cardiac preparations. Lacidipine (10(-8) -10(-6) M) dose-dependently decreased contractility of driven sheep Purkinje fibers. For concentrations less than or equal to 10(-7) M, this effect was associated with a selective decrease of the plateau height. Higher concentrations (3 X 10(-7) and 10(-6) M), however, affected action potential amplitude, overshoot, and maximum rate of depolarization. In the same range of concentrations, lacidipine did not affect normal automaticity of guinea-pig sinus node and sheep Purkinje fibers. Lacidipine (10(-6) M) consistently blocked barium-induced abnormal automaticity in Purkinje fibers and reduced the amplitude and Vmax of the slow action potentials induced by histamine (10(-5) M) in guinea pig papillary muscle depolarized by potassium (22 mM). The effect of lacidipine on the slow inward current (Isi) was studied in shortened Purkinje fibers under voltage-clamp conditions. Lacidipine (10(-7)-10(-6) M) reduced the Isi without affecting the I-V relationship. None of the effects of lacidipine was reversed by 2-h washout. The results indicate that lacidipine has calcium-antagonistic properties in cardiac tissues. Its cardiac effects occur at concentrations 100 times higher than those active in the vascular smooth muscle. The lack of recovery of the lacidipine effects suggests that its interaction with the calcium channel may occur at an inner site of the cell membrane.     

Antihypertensive effect of CV-4093.2HCl, a new calcium antagonist, in three rat models of hypertension

The hypotensive action of CV-4093.2HCl (CV-4093), a new calcium antagonist, was studied in spontaneously hypertensive, renal hypertensive, DOCA-salt hypertensive and normotensive rats. CV-4093 (3 and 10 mg/kg, p.o.) dose-dependently decreased systolic blood pressure in the three types of hypertensive rats. At the dose of 10 mg/kg, the compound decreased the blood pressure to the normotensive level between 1 and 3 hr after it was administered; the antihypertensive effect lasted for at least 8 hr. The systolic blood pressure in normotensive rats was also decreased at 3 and 10 mg/kg, p.o., but less evidently than in the hypertensive rats. When the antihypertensive effect of CV-4093 was compared with that of seven known calcium antagonists in spontaneously hypertensive rats, it was the most potent and the most long-lasting.     

Ambulatory blood pressure monitoring in elderly hypertensives treated with the new calcium antagonist,nilvadipine

Summary. A newly developed calcium antagonist, nilvadipine, was administered to 7 hypertensive patients aged 75.6 y.Nilvadipine 4 mg b.d. decreased the average 24-h blood pressure significantly from 169/89 mm Hg to 152/81 mm Hg after 7 to 14 days without any change in the pulse rate. The circadian patterns of blood pressure and pulse rate were not affected by nilvadipine.Although the present study was a preliminary one done over a short period in a small number of patients, the results suggest that nilvadipine exerts an antihypertensive effect without altering the circadian pattern or the variability of blood pressure in elderly hypertensive patients.     

Effect of amlodipine, a new calcium antagonist on isolated blood vessels]

Amlodipine (AML), a new 1,4-dihydropyridine derivative, similar to nifedipine (NIF), dose-dependently relaxed or inhibited the KCL-contraction (cont.) of dog coronary artery (DCA) and rat aorta (RA) and the spontaneous motility of rat portal vein (RPV). However, in contrast to the case of NIF, the maximum effect was obtained at 1-2 hr following an addition of AML, and the recovery of KCl-cont. after removal of AML was very slow. Similar effects of AML on KCl-cont. were observed in dog femoral artery (DFA), dog basilar artery (DBA) and rabbit aorta (RBA). The IC50 values of AML for producing the half-maximal effect were 6.5 x 10(-9) M, 6.5 x 10(-9) M, 1.1 x 10(-8) M, 1.7 x 10(-8) M and 4.8 x 10(-8) M in DCA, DFA, RPV, DBA and RBA, respectively. In these vessels, the potency of AML was slightly less than the potency of NIF. On the other hand, AML (10(-7), 10(-6) M) only slightly attenuated norepinephrine (NE)-induced cont. in DFA and RA. Based on the ratio of IC50 values in DFA, AML exhibited 846-fold higher selectivity toward KCl-cont. than NE-cont., and it was much higher than the selectivity of NIF. In calcium-free medium, AML failed to inhibit the NE-cont. in RA, but it markedly inhibited CaCl2-induced cont. These results indicate that AML significantly inhibits KCl-cont. in blood vessels at lower doses with slightly less potency than NIF, but with a higher selectivity than NIF in comparison with the potency against NE-cont., and they also confirmed that the effect of AML is of slow onset and long-lasting.     

Effect of MCI-176, a new calcium antagonist, on the calcium induced contraction of isolated porcine coronary arteries

Calcium antagonistic activity of MCI-176, a new calcium antagonist, was compared with those of diltiazem and nifedipine in isolated depolarized porcine coronary arteries. MCI-176, diltiazem and nifedipine competitively inhibited calcium contraction of the large coronary arteries, and their pA2 values were 7.49, 6.89 and 9.55, respectively. Similar competitive inhibition by MCI-176, diltiazem and nifedipine of calcium contraction was also observed in the small coronary arteries, and their pA2 values were 7.38, 6.83 and 9.91, respectively. Although calcium antagonistic activity of nifedipine was several hundreds times more potent than MCI-176 and diltiazem, the action of nifedipine, unlike MCI-176 and diltiazem, favored the small coronary arteries rather than the large coronary arteries.     

Effect of lacidipine,a long-acting calcium antagonist,on hypertension and lipids: a 1 year follow-up

Summary The effect of lacidipine, a dihydropyridine calcium antagonist on lipid metabolism, has been followed in 8 patients with uncomplicated mild to moderate essential hypertension treated for up to 14 months.There were significant reductions in the systolic and diastolic pressures, from 167/102 to 146/91 mmHg at 2 months, and to 137/85 mmHg at the end of the study. Blood lipid concentrations did not change during the observation period (cholesterol 5.1 vs 5.3 mmol·l^–1, triglycerides 1.1 vs 1.0 mmol·l^–1, HDL-cholesterol 1.1 vs 1.2 mmol·l^–1).The results show that lacidipine did not affect lipid metabolism and suggest that calcium antagonists may be safely prescribed for a prolonged period to patients with combined hypertension and hyperlipidaemia.     

Protection by the calcium antagonist tiapamil, against cardiac lymphatic enzyme leakage and arrhythmias in canine hearts during reperfusion

We examined the effects of tiapamil, a Ca2+ antagonist, on infarct size, lymphatic enzyme release, and arrhythmias in reperfused, ischemic canine hearts. Three-hour reperfusion of the left anterior descending coronary artery, which had been ligated for 3 h, significantly increased cardiac lymphatic release of lactate dehydrogenase (LDH), cathepsin D and creatine phosphokinase (CPK), and the incidence of ventricular premature contractions (VPCs), the increases being markedly higher than those in ligation period. Tiapamil, at the i.v. dose of 3 mg/kg/h for 6 h during the ligation and reperfusion periods markedly reduced these increases in lymphatic levels of LDH and cathepsin D and in VPCs, and significantly decreased infarct size. Tiapamil treatment only during the ligation period had similar preserving effects, but tiapamil treatment only during reperfusion did not. These results suggest that blockade of the Ca2+ channel must be achieved during the early phase of an ischemic episode in order to prevent myocardial deterioration during reperfusion.     

Cardiac action of KB-944, a new calcium antagonist

A comparative study was made between the cardiac action of diethyl 4-(benzothiazol-2-yl)benzylphosphonate (KB-944) and those of nifedipine, diltiazem and verapamil in anesthetized dogs and isolated right atria of guinea pigs. In anesthetized dogs, KB-944 caused a dose-dependent fall in mean blood pressure and dose-dependent increase in coronary sinus outflow. Coronary sinus outflow oxygen pressure was increased with increasing coronary sinus outflow; and consequently, the coronary arterio-venous oxygen difference was decreased. The cardiac output was slightly increased, while the myocardial oxygen consumption and myocardial work were reduced. In the isolated right atria of guinea pigs, KB-944 produced a decrease in spontaneous atria rate, and at the concentration of 10(-6) g/ml atrial standstill was seen in few preparations. The contractile force was decreased by KB-944. Especially, KB-944 exerted the weakest effect on contractile force among the tested drugs. These actions of KB-944 are very similar to those of nifedipine, diltiazem and verapamil.     

Vasodilator action of KB-944, a new calcium antagonist

Vasodilator action of diethyl 4-(benzothiazol-2-yl)benzylphosphonate (KB-944) was mainly examined in comparison with papaverine in isolated perfused heart and anesthetized or conscious dogs. In isolated perfused heart, KB-944 (1-30 micrograms/heart i.a.) and diltiazem (1-30 micrograms/heart i.a.) produced a dose-dependent increase in coronary flow, and dose-dependent decrease in the heart rate and the myocardial contractile force. On the other hand, papaverine (3-100 micrograms/heart i.a.) produced a dose-dependent increase in coronary flow and heart rate, and did not practically affect the myocardial contractile force. KB-944 was about 3 times as active as papaverine and diltiazem on the percent increase of coronary flow. In anesthetized dogs, KB-944 (0.03-0.3 mg/kg i.v. or 10 mg/kg i.d.), diltiazem (0.03-0.3 mg/kg i.v. or 10 mg/kg i.d.) and papaverine (0.1-1 mg/kg i.v.) significantly increased the coronary blood flow with hypotension. Simultaneously, KB-944 and diltiazem decreased the heart rate, whereas papaverine increased it. Furthermore, KB-944 and diltiazem selectively increased the coronary blood flow more than the carotid blood flow, though papaverine increased the carotid blood flow more than the coronary blood flow. In case of i.v. route, KB-944 and diltiazem were about 5 times as active as papaverine on the percent increase of coronary blood flow. In case of i.d. route, the effect on coronary blood flow and heart rate induced by KB-944 was quantitatively similar to that induced by diltiazem, although the decrease in blood pressure induced by diltiazem was lesser than that produced by KB-944. In conscious dogs, KB-944 (0.03-0.3 mg/kg i.v. or 10-100 mg/kg p.o.) produced a dose-dependent increase in coronary blood flow and heart rate. In case of i.v. route, this vasodilator activity of KB-944 was 10 times as potent as that of papaverine. Thus, KB-944 is a more potent coronary vasodilator. Furthermore, KB-944 is well absorbed from the intestinal tract, and produces a long-acting increase in the coronary blood flow.     

Antihypertensive effects of amlodipine, a new calcium antagonist]

The antihypertensive effects of oral administration of amlodipine (AML), a new calcium antagonist, were investigated in hypertensive animals. AML (1-10 mg/kg) produced a dose-dependent reduction of blood pressure (BP) in spontaneously hypertensive rats (SHR). The effect of AML reached a maximum at 4-6 hr and was sustained even at 10 hr post-dose, in contrast to the case of nifedipine that produced a maximum effect at 1 hr with a rapid recovery. Heart rate (HR) was increased slowly and slightly by AML (10mg/kg), but increased rapidly and markedly by nifedipine (3, 10 mg/kg). The dose (ED 30) of AML required to decrease BP by 30 mmHg was 2.3 mg/kg and similar to the case of nifedipine. AML also produced long-lasting reduction of BP in renal and DOCA hypertensive rats. The ED30 values were 2.4 and 2.2 mg/kg and similar to the respective values of nifedipine (ED 30:2.4,2.1 mg/kg). In renal hypertensive dogs (RHD), the effect of AML (0.1,0.3,1.0 mg/kg) was maximum at 4-6 hr and long-lasting, producing similar reductions of both systolic and diastolic BP (ED30: 0.3-0.4 mg/kg respectively). In SHR (1 or 3 mg/kg/day, for 15 days) and RHD (0.2 mg/kg/day for 20 days) chronically receiving AML, there was an enhancement of the antihypertensive effect of AML within a few days after starting chronic dosing, and thereafter a significant reduction of BP at 24 hr after dosing and constant effects of AML during subsequent treatment. BP after cessation of the chronic dosing gradually recovered to the level before the start of the experiments. No significant changes in HR were observed throughout the experiments. These results indicate that AML produces the antihypertensive effect with a similar potency to nifedipine but with a profile of slow onset and long duration, and there was no development of tolerance to the antihypertensive effects and changes of HR during long-term treatment.     

Long-term effect of tiapamil in essential hypertension

To evaluate the long-term effect of tiapamil, a new calcium antagonist, in hypertension, 20 adult patients suffering from mild to moderate hypertension were entered into a 58-week open study. In 10 patients, blood pressure returned to normal within 1-6 weeks with a daily dose of 600-900 mg tiapamil. In the remaining 10 patients, the blood pressure became normal after 8-28 weeks with a daily dose of 900-1,200 mg tiapamil. The more severe the hypertension, the higher the dose needed and the longer the time required for the blood pressure to return to normal. The overall results at the end of the 58-week treatment showed a significant decrease of the blood pressure to 142 (+/- 9)/88 (+/- 4) mmHg from a before treatment average of 166 (+/- 16)/105 (+/- 7) (p less than 0.001). There was no marked difference in the blood pressure between supine and sitting positions before or after treatment. Side effects were mild and self-limiting, with no patient being dropped from the study. Electrocardiogram (ECG) and laboratory values were not affected during the treatment with the exception of a moderate decrease in the blood glucose. Neither plasma renin activity, nor aldosterone concentration, nor serum cholesterol or triglyceride levels were altered during tiapamil administration. Tiapamil appears to be an effective and well-tolerated drug for use in mild to moderately severe hypertension.     

Effects of tiapamil, a new calcium channel blocker, on ambulatory intraarterial blood pressure and exercise-induced changes in blood pressure

The duration and magnitude of effect of a new calcium-channel blocker, tiapamil, given twice daily, was studied in 17 hypertensive patients using ambulatory intraarterial blood pressure recording. The drug produced moderate reductions of blood pressure throughout the 24-h cycle with slight reduction of effect before each dose. Ten patients reported side effects, and one withdrew as a result of these. Tiapamil attenuated the blood pressure rise during dynamic cycle ergometry but had no effect on the increase during isometric hand grip. We conclude that tiapamil is similar to existing calcium-channel blocking agents in lowering the blood pressure, but it does not appear to influence the response to isometric exercise in this dose.     

Interaction potential of lercanidipine, a new vasoselective dihydropyridine calcium antagonist

Using some calcium channel blockers of the dihydropyridine-type (amlodipine (CAS 88150-42-9, felodipine (CAS 72508-76-3), lercanidipine (CAS 100472-26-7), nifedipine (CAS 21829-25-4), nitrendipine (CAS 39562-70-4)) as example the interaction potential of these substances will be compared in terms of affecting metabolism and transport of drugs. The cytochrome P450 (CYP) isoform CYP3A4 and the P-glycoprotein (P-gp), respectively, will have a high impact for both pharmacokinetic processes, as all 5 calcium channel blockers are substrates of CYP3A4 and in addition nifedipine, nitrendipine and felodipine represent inhibitors of P-gp, which can cause an increase in the plasma levels of digoxin (model substrate of P-gp). If inducers (e.g. rifampicin, anticonvulsants, St John's wort) or inhibitors (ketoconazole, itraconazole, erythromycin, clarithromycin, nefazodone, fluvoxamine, fluoxetine, sertraline, ritonavir, indinavir, amprenavir, saquinavir or grapefruit juice) of CYP3A4 are concomitantly administered pharmacokinetic interactions could be expected to a variable extent. Some alternative drugs are mentioned which will not affect CYP3A4. In addition to these putative pharmacokinetic interactions also pharmacodynamic interactions with other cardiovascular active substances might be considered and some caution should be exercised if vasodilators are given as comedication.     

Antihypertensive effects of a new dihydropyridine calcium antagonist

Methyl 2,6-dimethyl-4-(2-nitrophenyl)-5-(2-oxo-1,3,2-dioxaphosphorinan-2 -yl)-1,4-dihydropyridine-3-carboxylate (DHP-218) is a new vasodilatory calcium antagonist with pronounced and long-lasting antihypertensive effects. It produced a significant decrease in blood pressure at doses more than 1 mg/kg in normotensive rats, 0.1 mg/kg in spontaneously hypertensive rats (SHR) and desoxycorticosterone acetate (DOCA)-salt hypertensive rats and 0.3 mg/kg in renal hypertensive rats. In SHR, the antihypertensive effect of DHP-218 was approximately 7 times more potent than nifedipine. The antihypertensive effect of DHP-218 appeared very slowly and persisted even after it was injected i.v. No tolerance to the antihypertensive effects of DHP-218 was observed for 5 weeks at daily doses of 0.3 and 1 mg/kg. The antihypertensive effects of DHP-218 in cats and dogs with normal blood pressure was more than 10 and 30 times more potent than those of nifedipine, respectively. At an equivalent antihypertensive dose, the effect of DHP-218 persisted longer than that of nifedipine in all the animal species used.     

Cardiovascular effects of a new dihydropyridine calcium antagonist

The effects of methyl 2,6-dimethyl-4-(2-nitrophenyl)-5-(2-oxo- 1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydropyridine-3-carboxylate (DHP-218), a 1,4-dihydropyridine derivative, on the cardiovascular system and myocardial oxygen consumption were investigated. Effects on cardiovascular system: In urethane-alpha-chloralose anesthetized dogs, DHP-218 at a dose of 0.01 mg/kg i.v. decreased blood pressure (BP), and at 0.03 mg/kg i.v., long-lasting BP decrease was accompanied by an increase in heart rate (HR), and an increase in blood flow of the coronary, vertebral and internal carotid arteries. No significant changes in myocardial contractile force (MCF) and blood flow of the common carotid and renal arteries were observed. The duration of action was different for various effects. At doses more than 0.05 mg/kg i.d., blood pressure decreased and HR, MCF and the blood flow of coronary and vertebral arteries increased. The effects of nifedipine on the cardiac and regional blood flow were observed at doses more than 0.001 mg/kg i.v. and 1 mg/kg i.d., but the duration of its action was very short compared to those of DHP-218. Effects on cardiohemodynamics: In urethane-alpha-chloralose anesthetized dogs, DHP-218 at a dose of 0.01 mg/kg i.v. produced a decrease in BP and total peripheral resistance (TPR) and an increase in cardiac output (CO). At a dose of 0.03 mg/kg, a decrease in BP and TPR and increases in HR and CO were observed. The duration of action was different for various parameters. No significant changes in dp/dtmax, stroke volume and cardiac work were observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

First-step treatment of mild to moderate uncomplicated essential hypertension by a new calcium antagonist: nicardipine

Nicardipine, a new calcium antagonist, was tested in a 14-week double-blind trial including 15 outpatients with uncomplicated essential hypertension. They were randomly assigned to nicardipine (20-30 mg three times daily) or placebo as first-step treatment. When necessary but always after a minimum of 4 weeks, pindolol (15 mg/day) was combined with nicardipine or placebo. At the end of step 1 (85 +/- 6 days with nicardipine vs. 58 +/- 6 days with placebo, p less than 0.01), nicardipine induced larger drops in supine systolic and diastolic blood pressure (SBP and DBP) than the placebo (21 +/- 2.5 vs 1.4 +/- 3 mm Hg, p less than 0.001, and 13 +/- 2 vs. 3.5 +/- 1.5 mm Hg, p less than 0.001, respectively). In the nicardipine group (n = 57), 53% of patients had controlled blood pressure (SBP less than 160 mm Hg and DBP less than 95 mm Hg) versus 17% in the placebo group (n = 47), p less than 0.001. There was no significant correlation between the decrease in blood pressure and the age of patients. The most common side effects in the nicardipine group were flushes (12%), headache (8%), ankle edema (5%), and asthenia (4%). When blood pressure was not brought under control and pindolol was prescribed as the second-step treatment, the nicardipine group (n = 52) displayed larger drops in SBP and DBP than the placebo group (n = 40) (27 +/- 5 vs. 15 +/- 3 mm Hg, p less than 0.01, and 18 +/- 1 vs. 9 +/- 2 mm Hg, p less than 0.001, respectively). These results show that a calcium antagonist is useful for first-step treatment of hypertension.     

Metabolism of nilvadipine, a new dihydropyridine calcium antagonist, in rats and dogs

1. The metabolic profiles of nilvadipine in the excreta of male rats and dogs were studied after i.v. and oral dosing. Six types of metabolites were isolated and identified from the urine of male rats and dogs or bile of rats. 2. Several metabolites were detected in the urine (12) and bile (17) of rats by two-dimensional t.l.c., after dosing with 14C-nilvadipine. The metabolic profiles in the excreta of rats and dogs were qualitatively similar but quantitative differences were observed. 3. The main metabolites were products of (i) oxidation of the 1,4-dihydropyridine ring to the corresponding pyridine, (ii) hydrolysis of the 5-isopropyl ester or 3-methyl ester group to carboxylic acid, and/or (iii) hydroxylation of the 6-methyl group or methyl group of the isopropyl ester chain. 4. Minor metabolites were products of hydrolysis from the 5-isopropyl ester to the carboxylic acid having a dihydropyridine ring, or reduction of the 3-nitro group of the phenyl moiety having a pyridine ring.