Cardiovascular and renal effects of single administration of three different doses of isradipine in hypertensive patients. Dose-response curves of the different effects.

The antihypertensive, humoral, and renal effects of acute single oral administration of placebo and isradipine, a new dihydropyridine calcium antagonist, at doses of 2.5 mg, 5.0 mg, and 7.5 mg once daily were investigated in 11 patients with mild-to-moderate uncomplicated essential hypertension. The patients maintained a constant daily intake of 100 mmol of sodium and 40 mmol of potassium. Placebo and isradipine were randomly administered to each patient, according to a Latin-square design, at intervals of at least 48 hours. The antihypertensive effect was dose-dependent and peaked at two hours after oral administration; changes at the lowest dose were already statistically significant (p less than 0.01). Increases in heart rate were mild and similar with all isradipine doses. Glomerular filtration rate and renal plasma flow showed a trend towards a dose-dependent rise; plasma renin activity was statistically increased (p less than 0.05) following the highest isradipine dose, whereas plasma aldosterone was unmodified. Isradipine resulted in a statistically significant rise (p less than 0.05) in sodium excretion and urine volume, which was similar with all active doses. In conclusion, the antihypertensive efficacy of isradipine is dose-dependent, whereas the natriuretic and diuretic effects are already at maximum following 2.5 mg per day, the lowest dose in this study.

Acute hypotensive and renin-stimulating actions of captopril before and during treatment with a beta-blocking drug.

There is no general agreement on the relation between the hypotensive effect of captopril and the pretreatment plasma renin levels of hypertensive patients. To determine whether the hypotensive effect of captopril was directly related to plasma renin, the angiotensin-converting enzyme inhibitor was administered acutely to 10 essential hypertensive patients with normal or suppressed plasma renin activity before and after inhibition of renin secretion with propranolol. Captopril was equally effective in reducing blood pressure both when administered alone (25 mg: -29/-17; 50 mg: -37/-23 mm Hg) and after chronic treatment with propranolol (25 mg: -33/-20; 50 mg: -30/-20 mm Hg). The increase in renin induced by captopril was not decreased by propranolol therapy. The persistence of the hypotensive effect of captopril after renin suppression by propranolol suggests that this drug has some blood pressure decreasing properties independent of plasma renin.

Renal effects of felodipine in hypertension.

The results of 2 recent studies on the renal effects of felodipine in hypertensive patients are described. Antihypertensive doses of felodipine (10mg bid) displayed a clear natriuretic and diuretic effect associated with a constant glomerular filtration rate and an increase in renal plasma flow. With higher doses of felodipine (up to 50mg tid), the natriuretic effect was reversed to an antinatriuretic effect, accompanied by a reduction in glomerular filtration rate. The natriuretic effect of felodipine 10mg bid was evident during the first 2 days of administration, but a negative sodium balance was still present at the end of the seventh day. The mechanisms of the renal effects of calcium antagonists are discussed as well as the relevance of the natriuretic effect for the antihypertensive action of these compounds.

Antihypertensive and water and sodium balance effects of felodipine, a new vasodilating calcium antagonist, in hypertensive patients.

Felodipine, a new dihydropyridine derivative with a selective action on vascular smooth muscle, was investigated in 2 short term studies in hypertensive patients. In the first study, oral administration of felodipine 12.5 mg three times daily in a preliminary tablet formulation for 3 days significantly reduced supine and upright blood pressure with only a slight increase in heart rate and no clinically relevant signs of sodium and water retention. By increasing each dose to 25 and 50 mg three times daily, there was a further, but quite moderate, decrease in blood pressure; however, this was accompanied by an increase in heart rate and a tendency towards a reduction of creatinine clearance and urinary sodium output. In the second study, a new oral formulation containing 10 mg felodipine, administered twice daily for 7 days, was effective in lowering blood pressure without a clinically relevant tachycardia. Following the first dose of felodipine, urinary sodium excretion was slightly increased while potassium excretion showed only minor changes. The new calcium antagonist, felodipine, lowers blood pressure without the clinically relevant adverse reactions commonly related to other direct vasodilator antihypertensive drugs.

Omeprazole vs. ranitidine in the short-term treatment of duodenal ulcer: an Italian multicenter study.

A double-blind, double-dummy, randomized Italian multicenter trial was carried out to compare the efficacy and safety of omeprazole 20 mg in the morning and ranitidine 150 mg b.i.d. in short-term treatment of acute duodenal ulcer. One hundred and twenty-one patients (61 in the omeprazole and 60 in the ranitidine group) with endoscopically proven active duodenal ulcer, completed the study. The healing rates after 2, 4 and 6 weeks were 66, 97 and 100%, respectively, with omeprazole and 53, 85 and 92%, respectively, with ranitidine. The difference was statistically significant (p less than 0.05) at weeks 4 and 6. Night and day pain were markedly reduced during both treatments, as also antacid consumption. Both drugs were well tolerated, and the adverse events were infrequent and moderate. In our experience, omeprazole 20 mg once daily seems to be superior to ranitidine 150 mg b.i.d. in the short-term treatment of duodenal ulcer.

Pharmacokinetics of cadralazine in hypertensive patients.

Pharmacokinetics of cadralazine, urinary recovery of its putative active metabolite 3-hydrazino-6-aminopiridazine derivative (ISF 2405) and clinical effects were assessed in a placebo-controlled trial in 8 hypertensive in-patients, after acute oral administration of cadralazine. After a 2-week placebo-washout period, the protocol envisaged two consecutive days of monitoring of blood pressure and heart rate. On the first day a placebo tablet was given (9 am), while on the second day patients received a 30 mg cadralazine tablet in single-blind conditions. Blood and urine samples were obtained during the active drug day until 12 h after administration. Concentration of cadralazine in plasma and urine was detected by a specific HPLC method, while the metabolite ISF 2405 was detected in urine by a GC-MS method. Cadralazine caused gradual and long-lasting pressure decrease, statistically significant in comparison to placebo between 3 and 12 hours from drug intake, accompanied by a significant increase in heart rate. Cadralazine by oral route was promptly absorbed with a mean peak time of 1.3 h. Thereafter it followed a monoexponential decay curve, with a plasma half life of 3.1 h. The relative different bioavailability of oral cadralazine among patients was not correlated with cardiovascular changes. Urine recovery of unchanged drug after 12 h was high, reaching 67.3%, while concentration of metabolite ISF 2405 was about 1/1000 of parent compound.

Effects of a low-sodium diet on antihypertensive and natriuretic responses to acute administration of nifedipine.

This study was designed to determine (1) whether different sodium intakes influence the acute antihypertensive effect of a single dose of nifedipine, (2) whether the combination of nifedipine and a low-sodium diet lowers blood pressure to a greater extent than administration of nifedipine alone and (3) whether a reduction in sodium intake can dissociate the antihypertensive from the natriuretic response to nifedipine. We studied 11 hypertensive patients in order to investigate the antihypertensive and natriuretic effects of a single oral dose of 10 mg nifedipine during sodium repletion (100 mmol/day sodium intake) and depletion (20 mmol/day sodium intake), with a constant potassium intake (40 mmol/day). Nifedipine significantly (P less than 0.01) lowered supine blood pressure, from 178 +/- 14/107 +/- 7 to 161 +/- 12/100 +/- 7 mmHg during sodium repletion and from 152 +/- 12/95 +/- 9 to 142 +/- 11/90 +/- 8 mmHg with sodium depletion. The natriuretic and diuretic actions of nifedipine were marked and statistically significant during sodium repletion and almost absent during sodium depletion. We conclude that (1) the acute antihypertensive effect of a single dose of nifedipine is present both in the sodium-replete and in the sodium-depleted states, although during sodium depletion the nifedipine effect is somewhat reduced in extent and duration; (2) the blood pressure reached after administration of nifedipine in the sodium-depleted state is significantly lower than the values reached after nifedipine treatment in the sodium-replete state; (3) the natriuretic action of calcium antagonists is not essential to the acute antihypertensive action of these compounds.

Does beta 1-selective agonistic activity interfere with the antihypertensive efficacy of beta 1-selective blocking agents?

In order to investigate whether addition of beta 1-selective agonism can interfere with the antihypertensive efficacy of beta 1-selective adrenoceptor blockers, two separate studies were carried out to evaluate the effects on blood pressure and heart rate of three beta 1-selective blockers with or without varying degree of beta 1-selective agonism. In hypertensive patients at rest, the greatest blood pressure reduction and bradycardia were found with atenolol, a beta 1-selective blocker without any agonistic activity; a consistently smaller effect on blood pressure and heart rate was observed with Visacor (ICI 141 292), a beta 1-selective blocker with moderate beta 1-selective agonism, whereas no clinically relevant decrease in blood pressure occurred with Corwin (ICI 118 587), the beta 1-selective blocker with high beta 1-selective agonism. In contrast, during exercise-induced sympathetic activation, all three compounds reduced systolic blood pressure and heart rate to a similar degree.

Renal and antihypertensive effects of felodipine in hypertensive patients.

The effects of small doses of felodipine (10 mg twice daily) on blood pressure, renal function and sodium and water balance were studied in 11 patients with arterial hypertension. Felodipine significantly reduced systolic and diastolic blood pressure: most of the antihypertensive effect was already evident on day 1 of administration (-18/-11 mmHg) and only slightly increased during the subsequent week. Heart rate rose moderately only during day 1 of felodipine administration (+7 beats/min). Sodium excretion was increased during days 1 and 2, and no signs of water and electrolyte retention was observed in the week during which the balance study could be performed (Na, -135 +/- 65 mmol/7 days). At relatively low doses felodipine appears to be an effective antihypertensive agent, initially exerting some diuretic and natriuretic action and subsequently being devoid of a water- and sodium-retaining action.

Nicorandil, a new vasodilator drug, in patients with essential hypertension.

In 12 mild to moderate hypertensive patients we investigated the acute antihypertensive efficacy of three different doses of nicorandil, a new vasodilating agent which probably acts by increasing the potassium efflux from smooth muscle cells and causing a cellular hyperpolarization. After a 3-day placebo period the patients were given, according to a double-blind Latin-square randomized design, 10, 20 and 30 mg nicorandil as a single acute dose every other day. Blood pressure and the heart rate were measured in both supine and upright positions at various times for 24 h after the dosing; fractional urine collections were obtained at the end of the placebo period and after each active dose. All doses of nicorandil similarly and significantly (P less than 0.01) reduced supine blood pressure, with a peak after 4-6 h (10 mg: -21/-8 mmHg; 20 mg: -20/-9 mmHg; 30 mg: -29/-17 mmHg), and the effect was still present, though reduced, after 24 h; no change in the heart rate was observed. The results from the upright position were similar. There were no significant changes in urine volume and electrolyte excretion during the nicorandil administration. The three different doses of nicorandil caused similar acute blood pressure reductions without change in the heart rate, nor in the urine volume and urinary sodium.

Electrophysiological effects of bisoprolol.

The aim of this study was the electrophysiological evaluation of bisoprolol, a new highly cardioselective beta blocker, void of intrinsic sympathomimetic activity and without significant membrane stabilizing action. 10 patients (4 males and 6 females, mean age 67.5 years) with cardiac arrhythmias or syncopes of undetermined origin underwent His bundle recording with incremental as well as programmed atrial and ventricular pacing in an electrophysiological study. Electrophysiological parameters were measured at basal conditions and at 15 and 30 minutes after the infusion of bisoprolol 5 mg (for patient 1 to 5) and 10 mg (for patient 6 to 10). All electrophysiological parameters were within normal range at basal evaluation. Bisoprolol prolongs significantly sinus cycle length, corrected sinus node recovery time, AH interval, cycle length inducing AV-node block, effective and functional refractory periods of the AV-node. All these parameters remained within normal limits and were modified to about the same extent by 5 and 10 mg of the drug. No drug-related changes of QT interval were observed. Bisoprolol have been confirmed to have strictly beta-blocking properties.

Felodipine, a new vasodilating drug: blood pressure, cardiac, renal, and humoral effects in hypertensive patients.

We studied the antihypertensive action of felodipine, a new dihydropyridine vasodilator interfering with intracellular calcium mechanisms, in 11 patients with essential hypertension whose supine blood pressure averaged 181/109 mm Hg after 5 days of placebo administration. Felodipine, 12.5 mg t.i.d., for 3 days, caused a marked reduction (-39/-19 mm Hg) of supine systolic and diastolic pressures. Doses of 25 and 50 mg t.i.d., for three consecutive days, caused only a slight further reduction of blood pressure. At the highest dose tested all patients had their supine blood pressure brought down to values below 150 mm Hg systolic and 90 mm Hg diastolic at all six daily measurements. The antihypertensive effect was of the same magnitude when the patients lay supine or stood upright. Lowering of blood pressure was accompanied by tachycardia, which was quite moderate after the 12.5 mg t.i.d. dose, but more conspicuous with the two higher doses. There was some increase in plasma renin activity and in plasma aldosterone. A significant decrease in renal sodium and water excretion occurred only during administration of the highest dose of 50 mg t.i.d., when reduction in blood pressure was pronounced and there were reflex increases in plasma renin activity and plasma aldosterone.

Effects of different sodium intakes on the antihypertensive and renal effects of single oral doses of nifedipine in hypertensive patients.

The aim of this study was to investigate whether the antihypertensive and renal effects of Ca2+ antagonists are related to the sodium state of the patients. For this purpose, in a group of 11 patients with essential hypertension we have compared the blood pressure lowering effects of a single oral dose of nifedipine before (100 mmol Na+/day and 40 mmol K+/day) and after sodium depletion (20 mmol Na+/day and 40 mmol K+/day: each period was of 6-8 day duration). During the normal sodium diet nifedipine significantly lowered supine blood pressure (from 185 +/- 13/107 +/- 7 to 161 +/- 13/100 +/- 7 mm Hg, p less than 0.001) and induced a significant rise in Na+ excretion (from 52 +/- 10 to 94 +/- 13 mmol/6 h) and in urine volume (from 520 +/- 80 to 947 +/- 120 ml/6 h; p less than 0.01). Sodium depletion significantly lowered supine blood pressure (152 +/- 12/95 +/- 9 mm Hg, p less than 0.001); nifedipine caused a further and significant blood pressure reduction (142 +/- 11/90 +/- 8 mm Hg, p less than 0.01), but only a minor and not significant increase in sodium excretion (from 10 +/- 2 to 22 +/- 5 mmol/6 h) and urine volume (from 338 +/- 76 to 463 +/- 94 ml/6 h). Our data suggest that the natriuretic action of calcium antagonists is not relevant to their antihypertensive effect.

Effects of single and repeated doses of the calcium antagonist felodipine on blood pressure, renal function, electrolytes and water balance, and renin-angiotensin-aldosterone system in hypertensive patients.

Doses of 10 mg b.i.d. of the new dihydropyridine calcium antagonist, felodipine, were tested for seven consecutive days in 11 hospitalized hypertensive patients. A significant reduction of both systolic and diastolic blood pressures, with patients in both the supine and upright positions, occurred immediately after the first dose and was maintained (daily average 15%) throughout the following days. An increase in heart rate was observed after the first dose (15 and 23 beats/min, in supine and upright postures), and subsequently declined to average values of 8 and 14 beats/min on the seventh day. There was a marked natriuretic response during the first and second day, during which an average negative sodium balance of 95 mmol developed; on the following days sodium output was not significantly different from control, but a negative balance averaging 135 mmol was still present on the seventh day of felodipine administration. A moderate negative potassium balance also progressively developed and reached -48 mmol on the seventh day. Glomerular filtration rate was unchanged, but renal plasma flow increased significantly during administration of felodipine. Plasma renin activity and plasma aldosterone were also increased very moderately by felodipine. Compared with previous observations by our group with higher doses of felodipine (12.5, 25, and 50 mg t.i.d.), 10 mg b.i.d. of this new calcium antagonist appear to exert a marked and prolonged blood pressure reduction, accompanied by a definite natriuretic instead of an antinatriuretic effect.

A double-blind comparison of bisoprolol and captopril for treatment of essential hypertension in the elderly.

The aim of the study was to compare the antihypertensive efficacy and safety of a new beta blocker with high beta 1 selectivity, bisoprolol, with captopril in 28 elderly patients, aged over 65 years, with mild-to-moderate essential hypertension (WHO classes I and II). After a placebo run-in period of 4 weeks, the patients were randomly allocated to receive bisoprolol (5 mg od) or captopril (25 mg bid) (double-dummy technique) for 6 weeks, according to a crossover double-blind design, with a 4-week washout period between the two active treatments. The doses were doubled after 2 weeks if the supine blood pressure was greater than 160/95 mmHg. In basal conditions and after 2, 4, and 6 weeks of each treatment, the blood pressure and heart rate were assessed both in the supine and erect positions. At the same time, the side effects and quality of life were investigated by a checklist and a self-assessment questionnaire. Standard laboratory tests and a resting ECG tracing were performed before and after each active treatment. The data from 24 patients (4 dropouts) showed a significant antihypertensive effect of both treatments (p less than 0.01) with a reduction of diastolic blood pressure to values less than or equal to 95 mmHg in 75% (18/24) of the patients treated with bisoprolol and in 83.3% (20/24) of those treated with captopril, without significant differences between the two drugs. Bisoprolol also produces a marked but symptom-free reduction of heart rate compared with captopril (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of bisoprolol and diazepam in the treatment of cardiac neurosis.

In order to compare the beta blockers bisoprolol and diazepam in the treatment of cardiac neurosis, 40 patients (16 males and 24 females, mean age: 39 +/- 11 years) were examined in a double-blind, crossover study. Following a 4-week placebo period, patients were randomized to receive either bisoprolol 10 mg daily or diazepam 5 mg twice daily for 4 weeks. After a second 4-week washout period on placebo, patients were switched to the alternative regimen for a further 4 weeks. At the end of the placebo periods and during each phase of treatment, the following parameters were evaluated: somatic symptoms by self-assessment questionnaire, anxiety state by Hamilton rating scale, reaction time to both acoustic and visual stimuli, blood pressure, and heart rate. Both treatments were effective in reducing somatic symptoms of cardiac neurosis, but bisoprolol was significantly more effective than diazepam (p less than 0.01). On the contrary, diazepam was superior to bisoprolol in improving the Hamilton scale related to psychic symptoms. Only diazepam prolonged reaction times. Both treatments were well tolerated; however, 12 patients complained of drowsiness and nine of sedation under diazepam. In conclusion, bisoprolol appeared to be as effective as diazepam in the treatment of cardiac neurosis, but with better effects on somatic symptoms and without affecting patients' psychomotor performance.

Bisoprolol in the treatment of angina pectoris: a double blind comparison with verapamil.

In order to verify the anti-ischaemic effect of a new beta-blocking agent, bisoprolol, a double blind parallel groups trial was carried out in comparison with verapamil. 26 patients with a history of spontaneous and/or effort angina were studied. After a two-week treatment with placebo, they were randomized in two groups. One group was treated for 4 weeks with bisoprolol 10 mg o.d. and for the following 4 weeks with bisoprolol 20 mg o.d. The other group received verapamil 80 mg t.i.d. for the first 4 weeks and 120 mg t.i.d. for the remaining 4 weeks. Throughout the study isosorbide dinitrate 20 mg b.i.d. was administered and sublingual nitroglycerin was allowed when necessary. 21 patients completed the study. Both bisoprolol and verapamil significantly reduced the number of angina episodes and nitroglycerin tablets consumption, as well as ischaemic episodes recorded on Holter ECG. The total number and severity of ectopic ventricular beats were reduced too. On multistage treadmill exercise test, both drugs increased effort time and time to ST depression = 1 mm, and reduced ST depression and double-product. The effect of bisoprolol on double product was greater than that of verapamil because of the better control of heart rate. The relationship ST/double product suggested that beta-blockers act essentially through the reduction of myocardial oxygen consumption and verapamil possibly with an additive effect on coronary circulation. Radionuclide ventriculography showed no deterioration of rest ventricular function with both drugs. In conclusion, bisoprolol and verapamil showed a satisfactory anti-ischaemic effect, with good tolerability.