Hillel S. Ribner

Treatment of Chronic Congestive Heart Failure with Captopril, an Oral Inhibitor of Angiotensin-Converting Enzyme

The renin-angiotensin system is thought to maintain elevated systemic vascular resistance in heart failure. The hemodynamic effects of captopril (SQ 14225), an oral inhibitor of angiotensin-converting enzyme, were measured in 10 patients with stable congestive heart failure poorly controlled by digitalis and diuretics. At single daily doses of 25 to 150 mg, the cardiac index rose from 1.75 +/- 0.18 to 2.27 +/- 0.39 (mean +/- S.D.) liters per minute per square meter (P less than 0.001), and pulmonary-wedge pressure fell from 26.5 +/- 7.5 to 17.3 +/- 6.1 mm Hg (P less than 0.01). Systemic vascular resistance decreased from 2006 +/- 300 to 1393 +/- 238 dyne seconds per centimeter (P less than 0.001), and mean arterial pressure fell from 83.7 +/- 7.0 to 70.3 +/- 9.9 mm Hg (P less than 0.001) (mean +/- S.D.). Heart rate did not change appreciably. Hemodynamic alterations peaked at 90 minutes and persisted for three to four hours. Control plasma renin activity ranged from 1.1 to 7.3 ng per milliliter per hour and did not correlate with changes in hemodynamic values. Three patients on long-term treatment maintained clinical improvement. Although its mechanism of action has not been completely elucidated, captopril may prove useful in the treatment of chronic congestive heart failure.

Sustained beneficial effects of oral amrinone on cardiac and renal function in patients with severe congestive heart failure

Although effectiveness of oral amrinone has been demonstrated in animals, amrinone has been shown in human subjects to improve cardiac performance in the failing heart only after acute intravenous administration. Therefore, we studied the hemodynamic and renal effects of orally administered amrinone (50 to 300 mg) in 10 patients with advanced congestive heart failure. Cardiac index increased from 1.56 ± 0.41 (mean ± standard deviation) to 2.20 ± 0.43 liters/min per m2 (p < 0.001); pulmonary wedge pressure decreased from 26.1 ± 5.7 to 17.0 ± 5.7 mm Hg (p < 0.001). Mean arterial pressure decreased from 86.0 ± 8.4 to 81.3 ± 7.7 mm Hg (p < 0.001) and systemic vascular resistance from 2,406 ± 603 to 1,693 ± 261 dynes sec cm−5 (p < 0.001). Heart rate was unchanged. The onset of action ranged from 30 to 120 minutes and the duration of action from 4 to 7 hours after a single oral administration. After 24 hours of continuous therapy, no tachyphylaxis to amrinone was observed. A correlation (r = 0.62, p < 0.001) was found between the oral dose of amrinone and the percent increase in cardiac index. Left ventricular ejection fraction, determined in five patients, increased from 14 ± 8 to 21 ± 8 percent (p < 0.01). Effective renal plasma flow, measured in six patients, increased from 186.0 ± 72.0 to 231.1 ± 88.8 ml/min (p < 0.05) and the glomerular filtration rate from 82.2 ± 14.9 to 110.0 ± 20.6 ml/min (p < 0.05). Thus, this study demonstrates the cardiotonic efficacy of orally administered amrinone in human subjects and recommends its further investigation as a therapeutic agent for the continued treatment of congestive heart failure.

Clinical pharmacology of the new beta-adrenergic blocking drugs. Part 5. Pindolol (LB-46) therapy for supraventricular arrhythmia: a viable alternative to propranolol in patients with bronchospasm.

Abstract Pindolol (LB-46) is a new beta-adrenoceptor blocking agent with intrinsic sympathomimetic activity. In order to evaluate the efficacy of pindolol in the treatment of patients with supraventricular arrhythmias and propranolol-induced bronchospasm, 18 patients with paroxysmal supraventricular tachycardia, atrial fibrillation, atrial flutter, multifocal atrial tachycardia or junctional tachycardia, were treated with placebo followed by pindolol in intravenous and then oral form. Following a no-response placebo period (in all patients), intravenous pindolol converted six out of seven patients with paroxysmal supraventricular tachycardia to normal sinus rhythm. In six patients with atrial fibrillation, three reverted to normal sinus rhythm, and three remained in atrial fibrillation but with a slower ventricular response (less than 100 beats/minute). Of two patients with atrial flutter, one converted to normal sinus rhythm, while the other patient failed to respond. Both patients with junctional tachycardia and one with multifocal atrial tachycardia converted to normal sinus rhythm. Long-term oral pindolol therapy sustained these responses in most patients, as documented by serial Holter ECG studies. There was no deterioration in indices of airway resistance ( FEV 1·0 VC ) in patients treated with pindolol (both intravenously and orally), in contrast to a marked deterioration in FEV 1·0 VC in the same patients treated with propranolol. Pindolol appears to be a reasonable substitute for propranolol in patients with bronchospastic illness who require beta-blockade for control of supraventricular arrhythmias.

Hemodynamic effects of captopril in patients with severe chronic heart failure.

The hemodynamic effects of captopril (SQ 14225), an oral inhibitor of angiotensin-converting enzyme, were measured in 10 patients with severe chronic heart failure poorly controlled by digitalis and diuretics. After administration of a 25 mg dose, the cardiac index increased from 1.82 +/- 0.14 to 2.28 +/- 0.30 liters/min/m2 (p less than 0.05) while pulmonary capillary wedge pressure decreased from 22.7 +/- 2.0 to 14.7 +/- 4.7 mm Hg (p less than 0.05). Mean blood pressure and systemic vascular resistance decreased from 85.7 +/- 6.7 to 71.2 +/- 12.0 mm Hg (p less than 0.001) and from 1,909 +/- 246 to 1,362 +/- 347 dynes-s-cm5 (p less than 0.001), respectively. Heart rate did not change significantly. There was an inverse relation between maximal augmentation in cardiac index and maximal reduction in pulmonary capillary wedge pressure (r = -0.82, p less than 0.01). While most patients demonstrated a constant hemodynamic benefit after repeated administration of captopril, some exhibited a triphasic response with attenuation of effects after the second dose and restoration of effects after the third dose. These hemodynamic benefits were observed in patients with stable chronic heart failure whose plasma renin activity was within normal range (1.1 to 7.3 ng/ml/hour).

Lidocaine prophylaxis against ventricular fibrillation in acute myocardial infarction

D ESPITE recent clinical progress concerning treatment of pump failure in acute myocardial infarction, the therapy of lifethreatening arrhythmia remains the area in which we are best able to reduce morbidity and mortality.’ The death rate of patients with acute myocardial infarction admitted to nonmonitored hospital beds is 30%-40%.‘-” This is in sharp contrast to the IO%-20% in-hospital rate for those in the coronary care unit,“-” a difference due to the ready detection, treatment, and prevention of electrical disturbances. Anti-arrhythmic drugs, especially the local anesthetic lidocaine (lignocaine), have played an important role in this therapeutic advance. This article will review the pharmacology and mode of action of lidocaine and the evidence that demonstrating: (1) that almost all patients in the early phase of acute myocardial infarction experience ventricular arrhythmias; (2) that one cannot predict with certainty which patients will develop life-threatening ventricular fibrillation, and (3) that routine prophylaxis with lidocaine is both a safe and efficacious method with which to prevent such events.

Improvement in exercise capacity despite cardiac deterioration: Noninvasive assessment of long-term therapy with amrinone in severe heart failure

Seven patients with severe congestive heart failure (CHF) were treated with oral amrinone for a mean duration of 39 weeks (range 16 to 72). During the first week of therapy, exercise capacity as assessed on a treadmill using the Naughton protocol, increased substantially from 7.6 +/- 4.2 to 12.1 +/- 4.4 minutes (p less than 0.01). At an early period of follow-up (8 to 12 weeks), a further significant increase in exercise capacity to 14.7 +/- 5.0 minutes (p less than 0.05) was demonstrated, while at a later follow-up exercise capacity had decreased to 11.4 +/- 6.8 minutes (p less than 0.05). This was still significantly greater than prior to amrinone therapy (p less than 0.01). Left ventricular ejection fraction was increased from 14 +/- 4 to 19 +/- 4% (p less than 0.05) during the first week of therapy, but was not significantly different from control at the early and late periods of follow-up. Left ventricular end-diastolic dimension index increased from control value of 43 +/- 5 to 47 +/- 7 mm/m2 (p less than 0.01) at the late period of follow-up. Thus long-term amrinone therapy resulted in a substantial improvement in exercise capacity despite a slow, but progressive decline in cardiac performance.

Effects of combined dopamine and nitroprusside therapy in patients with severe pump failure and hypotension complicating acute myocardial infarction.

In severe pump failure with hypotension complicating acute myocardial infarction, dopamine has been useful in raising arterial pressure by increasing myocardial performance and augmenting peripheral resistance. Once adequate blood pressure are obtained, vasodilators may be used to reduce peripheral resistance and thus enhance pump performance. Accordingly, the hemodynamic effects of dopamine and nitroprusside administration were monitored in eight patients who developed hypotension following an acute myocardial infarction. With dopamine therapy alone, mean arterial pressure averaged 84 +/- 3.6 mm Hg and mean left ventricular filling pressure 32 +/-7.9 mm Hg. The addition of nitroprusside, at doses ranging from 0.5 to 1.6 micrograms/kg/min, resulted in a decrease in arterial pressure to 75 +/- 2.4 mm Hg (p less than 0.01) and in left ventricular filling pressure to 23 +/- 7.2 mm Hg (p less than 0.001). Cardiac index increased modestly from 1.81 +/- 0.61 to 2.01 +/- 0.60 liters/min/m2 (p less than 0.05), while systemic vascular resistance fell from 1,967 +/- 707 to 1,586 +/- 634 dynes-sec-cm-5 (p less than 0.01). Heart rate did not change significantly. Seven of eight patients died in the hospital within 4 days of admission. It appears that despite a beneficial hemodynamic response effected by combined dopamine-nitroprusside administration, the prognosis of this group of patients may not be favorably altered because of the extensive destruction of myocardium.