Antiarrhythmic effects of intravenous timolol in supraventricular arrhythmias.

The antiarrhythmic effect of timolol was investigated in 160 subjects with supraventricular arrhythmias. In our double-blind, randomized, parallel, multiclinic study, subjects received timolol, 1 mg iv, or matching placebo as a starting dose, followed by a second and third dose of 1 mg each (or matching placebo) at 20-min intervals if the arrhythmia did not convert to sinus rhythm. Subjects in whom the sinus rhythm returned or the ventricular rate decreased to less than 100 bpm were transferred to a dosing regimen of timolol in 10-mg tablets twice a day by mouth, 1 hr after the last intravenous dose. Data indicated that the mean decrease in heart rate was 44 bpm after timolol and 7 bpm after placebo. The overall proportion of responders (either conversion to sinus rhythm or a decrease in ventricular rate to less than 100 bpm) was 68% after timolol and 7% after placebo. The proportions of responders after timolol were significantly higher than the proportions after placebo for paroxysmal supraventricular tachycardia (26 of 32 subjects and two of 38 subjects), atrial fibrillation (17 of 29 subjects and three of 32 subjects), and atrial flutter (seven of 11 subjects and one of nine subjects). The most common adverse effects were bradycardia and hypotension.

Efficacy and safety of lisinopril in older patients with essential hypertension.

Angiotensin-converting enzyme inhibitor therapy has been thought to be more effective in hypertensive patients with normal or elevated levels of renin in the plasma. However, several studies have challenged this concept by demonstrating the efficacy of angiotensin-converting enzyme inhibitors (captopril and enalapril) in older patients, among whom a low level of renin activity in the plasma is common, and in other patients with low-renin essential hypertension. Lisinopril, a new long-acting angiotensin-converting enzyme inhibitor, also has been shown to be an effective antihypertensive agent in older patients. This report examines data from 97 older and 710 younger hypertensive patients enrolled in four multicenter trials of eight to 12 weeks' duration. In these trials, the dose of lisinopril was titrated until a diastolic pressure of less than 90 mm Hg was reached, or to a maximal dose of 80 mg per day. In general, the antihypertensive effect achieved in older patients with lisinopril was equal to or greater than that achieved in younger patients. The drug was generally well tolerated. Lisinopril can be expected to be used frequently in older patients.

Enalapril worldwide experience.

Overall, the worldwide experience on enalapril to date is very encouraging. The drug produces good to excellent responses in 54 to 66 percent of patients with essential hypertension and is at least as effective as either diuretics or beta blockers. The effects of enalapril compared with those of diuretics confirm that patients more dependent upon the renin-angiotensin system respond better. When hydrochlorothiazide is administered concomitantly with enalapril, almost all patients respond, with good long-term maintenance. In patients with severe hypertension, Blocadren or Aldomet may be added in addition to hydrochlorothiazide and will produce additional benefit. Enalapril attenuates the adverse metabolic effects of hydrochlorothiazide, particularly hypokalemia. Overall, although the efficacy of enalapril and that of captopril are similar, enalapril is better tolerated and does not appear to be associated with any significant occurrence of captopril-type side effects, particularly the skin rash and loss of taste. As expected, enalapril and other converting inhibitors may be associated with azotemia in patients with bilateral renovascular hypertension.

Enalapril in hypertension and congestive heart failure. Overall review of efficacy and safety.

Multiclinic controlled studies have shown that enalapril alone 10 to 40 mg/day orally is effective in lowering blood pressure in patients with essential hypertension. Enalapril has been compared with thiazides and beta-blockers (propranolol, metoprolol and atenolol). The effect on systolic blood pressure has been greater with enalapril than with beta-blockers. The proportion of patients who respond to enalapril alone with a decrease in diastolic blood pressure (greater than or equal to 10mm Hg) is around 70%. When a thiazide is added to the treatment, the proportion is above 90%. Enalapril improves the signs and symptoms associated with congestive heart failure. Patients increased their exercise tolerance by an average of 148 sec and improved in their NYHA cardiac status and prognosis classification. The overall incidence of side effects is similar to that seen in the placebo control groups. Side effects such as agranulocytosis, taste loss, rash, proteinuria were not characteristic of enalapril. This supports the hypothesis that the improved safety profile of enalapril is the result of being a nonsulphydryl angiotensin-converting enzyme (ACE) inhibitor. The most common side effects reported were dizziness, headache and asthenia. Abnormalities in electrolytes, uric acid, glucose or in lipids have generally not been associated with enalapril.

Multiclinic evaluation of the antihypertensive effect of a methyldopa, hydrochlorothiazine, and amiloride combination.

A multiclinic, double-blind, randomized study in 361 patients with essential hypertension compared Aldoretic, (Merck & Co., Inc., New Jersey), a combination of methyldopa, hydrochlorothiazide, and amiloride with the combination of hydrochlorothiazide and amiloride and with methyldopa alone. At the end of week 12, the proportion of patients who were classified as normotensive (diastolic less than or equal to 90 mm Hg) was 61% in the group treated with Aldoretic, which was statistically significantly greater than the 48% in the hydrochlorothiazide/amiloride group and the 35% in the methyldopa group.

[Worldwide experience with enalapril]. / L'énalapril dans les expériences mondiales.

Up to now, the experiments carried out throughout the world with enalapril have been most encouraging. The drug gives good, even excellent responses in 54 to 66 % of patients with essential hypertension, and it is at least as effective as diuretics and beta-blockers. Compared with those of diuretics, the effects of enalapril confirm that the best responders are those patients who are most dependent on the renin-angiotensin system. When a diuretic is administered concomitantly with enalapril, almost all patients respond and the therapeutic effect is well maintained in long term. Blocadren or alpha-methyldopa can be added to hydrochlorothiazide, thus providing additional benefits to patients with severe hypertension. Enalapril reduces the undesirable metabolic effects of hydrochlorothiazide, particularly hypokalaemia. Altogether, enalapril and captopril have similar effectiveness, but enalapril is better tolerated and does not seem to produce the side-effects encountered with captopril, notably skin rashes and ageusia. As expected, enalapril and other angiotensin-converting enzyme inhibitors may be associated with azotaemia in patients with bilateral renovascular hypertension.

Overall tolerance and safety of enalapril.

To date, more than 5000 patients have had experience with enalapril. Over 1000 subjects have been exposed to the drug for more than one year and approximately 600 for over two years. In controlled trials, 2249 subjects, who included normal volunteers and patients with hypertension and congestive heart failure, have received enalapril alone or concomitantly with hydrochlorothiazide or other antihypertensive agents. There have been no deaths attributed to enalapril. The incidence of serious adverse experiences in controlled trials was similar to placebo, and was not higher in the elderly. The incidence of adverse experiences was not dose-related. Drug discontinuation due to adverse experiences was 3.5%, similar to placebo, and approximately half that of control drugs. Serious laboratory adverse experiences were rare. Enalapril attenuated the adverse metabolic effects of hydrochlorothiazide, particularly hypokalaemia. Skin rash occurred in approximately 1.0% of patients. One case of transient taste loss occurred on enalapril, and one on enalapril in combination with hydrochlorothiazide. Neutropenia and agranulocytosis were not encountered. Mean white blood cell counts did not change overall. Most patients (approximately equal to 80%) show no change or an improvement in renal function on enalapril. Discontinuation of concomitant hydrochlorothiazide usually normalized renal function. Enalapril is well tolerated in renal insufficiency. Azotaemia may occur in bilateral renovascular hypertension. Proteinuria was rarely seen and often improved on enalapril. Compassionate use protocols have been available to patients either resistant or intolerant to captopril. Of 68 patients admitted for captopril-related skin rashes, only five recurred on enalapril.(ABSTRACT TRUNCATED AT 250 WORDS)

The clinical pharmacology of lisinopril.

Lisinopril is an orally active, nonsulfhydryl angiotensin-converting-enzyme (ACE) inhibitor that is not metabolized or bound to protein. Peak serum concentrations occur 6-8 h after oral dosing. Lisinopril bioavailability (approximately 25%) is not significantly affected by food, age, or coadministration of hydrochlorothiazide (HCTZ), propranolol, digoxin, and glibenclamide. Lisinopril is excreted unchanged in the urine. Steady state is achieved in 2-3 days with little accumulation. Significant accumulation occurs in patients with severe renal impairment (creatinine clearance less than or equal to 30 ml/min). Lisinopril inhibits ACE activity, thereby reducing plasma angiotensin II and aldosterone and increasing plasma renin activity. Lisinopril produces a smooth, gradual blood pressure (BP) reduction in hypertensive patients without affecting heart rate or cardiovascular reflexes. The antihypertensive effect begins within 2 h, peaks around 6 h, and lasts for at least 24 h. Lisinopril produces greater systolic and diastolic BP reductions than HCTZ. Lisinopril is similar to atenolol and metoprolol in reducing diastolic BP, but superior in systolic BP reduction. Lisinopril and nifedipine produce comparable reductions in systolic and diastolic BP. When lisinopril is given once daily as monotherapy, the range of BP reductions is 11-15% in systolic and 13-17% in diastolic. HCTZ addition enhances its antihypertensive effect. Lisinopril does not produce hypokalemia, hyperglycemia, hyperuricemia, or hypercholesterolemia. Lisinopril has natriuretic properties; renal blood flow remains stable or increases. Lisinopril increases cardiac output, and decreases pulmonary capillary wedge pressure and mean arterial pressure in patients with congestive heart failure refractory to conventional treatment with digitalis and diuretics. Human experience to date (2,800 patients/subjects) indicates that lisinopril is well tolerated and has a good safety profile.

Tolerance and safety of enalapril.

Enalapril is the result of a targeted research programme to develop a non-mercapto converting enzyme inhibitor with a long duration of action and an improved safety profile for use in the therapy of hypertension and congestive heart failure. Over 3500 patients world-wide have received enalapril or enalaprilat. Long-term experience at present includes over 2500 patients. While enalapril and captopril produce similar efficacy, enalapril is better tolerated and appears not to be associated with occurrence of captopril-type side-effects, particularly the skin rash, taste loss, leukopenia and proteinuria. Enalapril and other converting enzyme inhibitors may be associated with renal insufficiency when given to patients with bilateral renovascular hypertension.