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J N Lessem

Publications and source records attributed to J N Lessem.

10 recordsLinked to original sources
PubMed1993

Development of a multiaction beta blocker. Scientific challenges and regulatory needs.

The search for the ideal antihypertensive drug is ongoing. Since hypertension initially is a relatively symptom-free disease, it is important that any agent developed be not only efficacious but also safe, with minimal side effects. Additionally such a drug should ideally possess both primary and secondary cardiovascular preventive properties. This review discusses the most commonly used antihypertensive drugs in the light of these goals, and highlights the development of multiaction drugs. Carvedilol, which is a nonselective beta-blocking and alpha 1-blocking drug, with additional Ca(2+)-antagonistic properties, is being developed as an antihypertensive, antianginal drug and as an adjunct therapy in congestive heart failure. The development challenges for this single-entity drug are discussed and evidence for its antihypertensive efficacy, as well as its antianginal efficacy, is presented. The cardioprotective potential of carvedilol based on preclinical experiments is addressed. Finally, the regulatory questions regarding the development of a multiaction drug are highlighted.

Adrenergic beta-Antagonists↗
PubMed1993

Antihypertensive treatment with a dual-acting beta-blocker in the elderly.

Risk factors in elderly hypertensives: Recent large-scale clinical trials have shown that antihypertensive treatment in the elderly produces meaningful reductions in strokes and other cardiovascular events. However, the treatment of hypertension in older patients is often complicated by the presence of concomitant disorders. Clinical and silent myocardial ischemia, as well as left ventricular hypertrophy and both systolic and diastolic left ventricular dysfunction, frequently coexist with hypertension. Additional clinical considerations in elderly hypertensives include a high prevalence of abnormal lipid and glucose metabolism and a tendency toward decreased renal function. Effects of different antihypertensive drugs: Although diuretics and conventional beta-blockers have been used as first-line drugs in the major clinical trials, some of their effects on metabolic parameters and on the myocardium can make them inappropriate in some patients. Newer drug classes, including angiotensin converting enzyme (ACE) inhibitors, calcium-channel blockers and, more recently, alpha 1-adrenergic blockers are effective alternatives. Dual-acting beta-blockers offer an important new approach for treating hypertension in elderly patients. Effects of carvedilol: Carvedilol possesses both beta- and alpha 1-blocking activity and appears to exhibit calcium channel blocking activity in animals. The alpha 1-blocking properties of this drug help to produce a desirable hemodynamic profile and facilitate appropriate blood pressure and heart rate responses to exercise. Carvedilol does not appear to adversely affect left ventricular systolic function and, in selected patients with heart failure, has been shown to increase the ejection fraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1989

Calcium channel antagonism and beta blockade in combination--a therapeutic alternative in cardiovascular disorders. A review.

Calcium-channel antagonists and beta-adrenergic blocking agents have become important modalities in the cardiovascular therapeutic armamentarium. These drugs are often administered as monotherapy to a wide range of cardiological patients with angina pectoris, hypertension, arrhythmias, congestive heart failure, and other diseases. Since within each class these drugs exhibit pharmacologic differences, it follows that their effectiveness varies in different disease states and that they exhibit a wide variety of side effects. In an attempt to optimize therapy, the individual drugs from these two classes can be combined; and the efficaciousness and side-effect profile of various combinations between calcium-channel antagonists and beta blockers are discussed in this review. Recommendations as to which patients may benefit from a combination and as to which patients may be harmed by the combination therapy will be made. Very few studies have compared the safety and efficacy of a single agent with the combination and with placebo in a controlled randomized fashion. To determine which therapy is superior and to determine which combination one should recommend under what circumstances, such placebo-controlled, randomized trials are a necessity, and will hopefully be performed although the complexity is enormous.

Adrenergic beta-Antagonists↗
PubMed1989

Nicardipine and propranolol in the treatment of essential hypertension.

Two hundred thirty-four patients with supine diastolic blood pressure of between 95 and 114 mm Hg were enrolled into a double-blind, randomized, parallel, multicenter trial. The patients were randomized to either nicardipine 30 mg tid, propranolol 40 mg tid, or nicardipine 30 mg tid and propranolol 40 mg tid for six weeks. Two hundred six patients yielded data for analyses. Of the 28 not included, seven had missing data, whereas the remaining 21 were excluded because they either failed to meet inclusion criteria or were noncompliant at endpoint. Both nicardipine and propranolol as monotherapies and in combination achieved statistically significant, (P less than .01), supine diastolic blood pressure reduction relative to baseline. The combination of nicardipine and propranolol showed a greater reduction in supine diastolic and systolic measurements than either of the monotherapies. Nicardipine produced greater blood pressure reductions one hour after dosing, whereas the propranolol treatment tended to produce slightly greater blood pressure decreases eight hours after dose. The combination always resulted in the greatest blood pressure reduction, independent of time after dose. Adverse experiences were reported by 26% of patients in the nicardipine-treated group, most often transient vasodilatory effects, by 17% of the propranolol-treated patients, and by 18% of the combination-treated group. This study demonstrated at the doses studied that nicardipine alone produced equivalent blood pressure reductions to those obtained by propranolol alone, but that the combination of these two drugs produced greater reductions in blood pressures than either of the monotherapies.

Adult↗
PubMed1989

Monotherapy of stable angina with nicardipine hydrochloride: double-blind, placebo-controlled, randomized study.

The effect of nicardipine hydrochloride, a calcium-channel blocking agent, was studied in 46 patients with stable angina in a double-blind, placebo-controlled, randomized, repeated cross-over protocol, using a 30 or 40 mg dose of nicardipine or placebo three times a day. Mean resting heart rate and blood pressure did not change significantly with 30 mg nicardipine; heart rate increased from 81 +/- 10 to 88 +/- 13 beats min-1, systolic blood pressure decreased from 129 +/- 18 to 119 +/- 16 mmHg, and diastolic blood pressure from 81 +/- 12 to 74 +/- 11 mmHg (P less than 0.01 for all three variables) with a 40 mg dose. Using a treadmill exercise protocol, mean exercise duration increased from 5.4 +/- 1.8 to 6.0 +/- 1.8 min (P less than 0.01) with 30 mg nicardipine, and from 5.8 +/- 1.7 to 6.6 +/- 1.9 min (P less than 0.01) with 40 mg. Time to onset of angina increased from 4.6 +/- 1.9 to 5.2 +/- 1.7 min (P less than 0.05) with 30 mg and from 5.1 +/- 1.8 to 5.7 +/- 1.8 min (P = NS) with 40 mg. Mean anginal frequency and sublingual nitroglycerin consumption were low during the cross-over placebo period and did not change significantly during therapy with nicardipine. Non-cardiac side-effects were mild and required the withdrawal of only one patient from the study. However, during nicardipine therapy four patients had unstable angina and two developed a non-Q wave myocardial infarction. Of these patients, five were receiving a beta-adrenergic blocker that was discontinued prior to the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Multicenter trial of sotalol for suppression of frequent, complex ventricular arrhythmias: a double-blind, randomized, placebo-controlled evaluation of two doses.

Sotalol is a unique beta-adrenergic blocking agent with additional actions characteristic of Vaughn-Williams class III antiarrhythmic agents in experimental models. To test the efficacy of sotalol to suppress ventricular arrhythmias, a 6 week parallel, placebo-controlled out-patient study of two doses (320 and 640 mg/day, in two divided doses) was performed in four hospitals in 56 patients with chronic premature ventricular complexes at a frequency of 30/h or more (mean +/- SE, 528 +/- 60/h) on 48 hour ambulatory electrocardiographic recording. During a placebo week, no change occurred in arrhythmia frequency (532 +/- 76/h). Subsequent sotalol therapy significantly reduced median arrhythmia frequency in patients receiving both low (n = 19) and high (n = 18) doses compared with that in patients receiving placebo (by 77 and 83%, respectively, versus 6%; p less than 0.001). Twenty-two (59%) of 37 sotalol-treated patients, 11 in each group, reached the prospectively defined criterion of efficacy (greater than or equal to 75% arrhythmia reduction) versus 2 (11%) of 19 placebo control patients (p less than 0.001). Sotalol reduced the median frequency of couplets by 94% (p less than 0.0001) and that of runs by 89% (p less than 0.0007). The electrocardiographic effects of sotalol included reductions in heart rate (by 17 to 27%) and increases in the QTc (by 6 to 9%) and PR (by 6%) intervals. Ejection fraction was unchanged. The most common adverse side effect was fatigue, but drug discontinuation was required in only three patients taking 640 mg/day. No proarrhythmic events or biochemical abnormalities were observed. In summary, sotalol displays significant antiarrhythmic activity of moderately high degree with good tolerance in doses of both 320 and 640 mg/day. Its antiarrhythmic actions are distinguished from those reported for other beta-blockers by its effects on the QTc interval and its moderately high degree of antiarrhythmic activity.

Aged↗
PubMed1985

Long-term enalapril--a new converting enzyme inhibitor--in the treatment of mild to moderate essential hypertension, results of a worldwide multiclinic study. Comparing two ways of analyzing data.

The antihypertensive effect of enalapril maleate, a new converting enzyme inhibitor, was evaluated in a multiclinic, double-blind, randomized study in patients with mild to moderate essential hypertension. The analyses were done in two ways, with patients who violated the entry criteria of the protocol excluded, and according to the intention to treat principle. Enalapril in dosages of 10 to 40 mg daily administered alone or concomitantly with hydrochlorothiazide was compared to propranolol (80 to 240 mg daily) alone or concomitantly with the diuretic. The study showed that enalapril significantly lowered both systolic and diastolic blood pressure. At each timepoint measured in the course of 26 weeks of therapy, the patients in the enalapril group consistently had greater decreases in blood pressure than patients in the propranolol group although not always significantly. The enalapril treatment group had a decrease in the mean arterial blood pressure of 22.2 mmHg compared to the propranolol group of 17.9 mmHg at the end of the study. These results were similarly independent of the way the data were analyzed. Fewer patients in the enalapril group required the addition of hydrochlorothiazide to maintain optimal control of blood pressure. Enalapril was found to be safe and well tolerated over the long-term of 48 weeks. Side effects such as leukopenia and taste perversions believed to be sulfhydryl-related were not encountered. The occurrence of rash and proteinuria was rare. Thiazide-induced hypokalemia, hyperuricemia and hyperglycemia appeared to be attenuated by enalapril. The favorable efficacy and side-effect profile provide the basis for enalapril to be a drug of choice when initiating antihypertensive therapy.

Adult↗