Safety and efficacy of oral sotalol for sustained ventricular tachyarrhythmias refractory to other antiarrhythmic agents.

The safety and efficacy of oral sotalol were evaluated in 481 patients with drug-refractory sustained ventricular tachyarrhythmias (VT) in an open-label multicenter study. After drug-free baseline evaluations, therapy was initiated at 80 mg every 12 hours, with upward dose titrations of 160 mg/day being allowed at intervals of 72 hours to a maximum dose of 480 mg every 12 hours. Efficacy determinations were made by either programmed electrical stimulation (PES) or Holter monitoring responses. Of the 481 patients enrolled, 473 underwent acute-phase titration. Of the 269 patients assessable by PES, 94 (34.9%) exhibited complete response (suppression of inducible VT), with an additional 67 patients (24.9%) exhibiting partial response. Of the 109 patients assessable by Holter monitoring, 43 (39.4%) exhibited a complete response. There were no significant differences between responders and nonresponders with regard to left ventricular ejection fraction. Although response rates tended to improve as the sotalol dose was increased to 640 mg/day, efficacy was most commonly achieved at a sotalol dose of 320 mg/day. Sotalol was discontinued because of adverse effects in 42 (8.9%) of the acute-phase patients. The most common adverse effect was proarrhythmia, which was observed in 23 patients (4.9%). Proarrhythmia took the form of torsades de pointes in 12 patients and an increase in VT episodes in 11. In 3 acute-phase patients (0.6%), sotalol was discontinued because of the emergence of congestive heart failure. A total of 286 patients entered the long-term phase. Life-table estimates of the proportion of patients who remained free of recurrence of arrhythmia at 12, 18, and 27 months were 0.76, 0.72, and 0.66, respectively. There were no significant differences in time to recurrence of arrhythmia as related to PES response, Holter monitor response, baseline left ventricular ejection fraction, or history of congestive heart failure. Among the 70 patients (24.5%) in whom there was recurrence of arrhythmia, sudden death occurred in 17 and sustained VT in 41. Sotalol was discontinued owing to presumed adverse effects in 21 (7.3%) of the long-term patients, including 8 with proarrhythmia; proarrhythmia consisted of torsades de pointes in 3 patients and increased episodes of VT in 5. These findings suggest that sotalol is an effective drug for the long-term treatment of patients with drug-refractory sustained VT. Proarrhythmia was observed in only 6.4% of the study population and tended to occur during the acute titration phase. The need to discontinue therapy because of congestive heart failure was uncommon.(ABSTRACT TRUNCATED AT 400 WORDS)

Pemirolast, a new oral nonbronchodilator drug for chronic asthma.

Pemirolast is a new oral, nonbronchodilator antiallergy medication that is being evaluated for the therapy of asthma. In this multicenter, double-blind, randomized study, 96 patients with mild asthma received pemirolast, 50 mg (n = 34); pemirolast, 25 mg (n = 31); or placebo (n = 31) BID for 6 weeks. Patients were evaluated weekly at the research centers; they maintained daily symptom diaries and measured peak expiratory flow rates twice a day. Methacholine challenge was performed at the start and end of the study. Results with pemirolast, 50 mg BID, showed statistically significant decrease in nocturnal symptoms (P = .02), in composite symptom scores (P = .02) and in bronchodilator use (P = .05) when compared with placebo. There were no statistically significant differences between treatments in pulmonary function tests or in methacholine challenge sensitivity. Pemirolast, 25 mg BID, did not differ from placebo. There were no significant adverse effects. Pemirolast, 50 mg BID, demonstrated sufficient antiasthma activity to warrant further studies in patients with more severe asthma and with higher doses.

Clinical safety profile of sotalol in patients with arrhythmias.

Key safety parameters of sotalol were examined in 1,288 patients entered into recent controlled trials of ventricular (85% of patients) or supraventricular arrhythmias (15%). Most patients were middle-aged male Caucasians with significant heart disease. The most serious adverse event was proarrhythmia, occurring in 56 patients (4.3%). Of these, 27 had hemodynamic compromise due to malignant ventricular arrhythmias. Most had a history of sustained ventricular tachycardia, myocardial infarction, congestive heart failure (CHF) or cardiomyopathy, or a combination of these. The other 29 had nonsevere events; 38% continued taking sotalol. Proarrhythmia was manifested by torsades de pointes in 24 of the 56 patients. No universal causal relation was found with commonly associated factors such as bradycardia, hypokalemia and long QT interval. The mean QT and QTc at baseline within 1 week of a severe proarrhythmic event were greater than those of patients not having proarrhythmia. Nineteen patients (1%) discontinued therapy with sotalol because of drug-related CHF. Predisposing conditions included low initial baseline ejection fraction, history of CHF, cardiomyopathy or cardiomegaly, or both, male gender and age greater than 65 years. Heart failure usually occurred within 7 to 30 days of initiating therapy. The most common reason for premature discontinuation of the drug in patients treated for sustained ventricular tachycardia was ineffectiveness (39%), whereas adverse effects were the most common reasons among patients treated for complex ventricular ectopy (21%). Dyspnea and bradycardia were the most common cardiovascular effects, and fatigue, dizziness and asthenia the most common noncardiac, adverse effects. Although frequently reported, these adverse effects resulted in discontinuation of only 1 to 4% of the patients at risk.(ABSTRACT TRUNCATED AT 250 WORDS)

Safety and efficacy of sotalol in patients with drug-refractory sustained ventricular tachyarrhythmias.

The safety and efficacy of oral sotalol, an investigational beta-adrenergic blocker with class III antiarrhythmic drug properties, were examined in a multicenter study in 236 patients with sustained ventricular tachyarrhythmias. In 104 patients, the index arrhythmia was a cardiac arrest, and all patients had undergone at least 3 previous unsuccessful antiarrhythmic trials (mean = 5 per patient). In the 106 patients assessed by programmed electrical stimulation, sotalol completely suppressed induction of ventricular tachycardia (VT) in 33 (31%) and rendered VT slower (greater than 100 ms prolongation of cycle length) or more difficult to induce in 29 (27%). Using continuous 24-hour ambulatory monitoring methods, sotalol complete- and partial-response rates were 51 and 12%, respectively. Of the 236 acute-phase patients, 151 were discharged receiving long-term sotalol therapy. The median sotalol dose was 480 mg/day. At a mean follow-up of 346 +/- 92 days, 27 patients (18%) had recurrence of sustained arrhythmia; 9, sudden death; 11, sustained VT; 5, automatic defibrillator discharge; and 2, syncope. Adverse effects forced discontinuation of therapy in 10 patients (7%): 6 secondary to symptomatic bradyarrhythmia, 2 due to refractory heart failure, 1 due to torsades de pointes, and 1 from bronchospasm. Life-table analysis of sotalol's overall long-term efficacy at 6, 12 and 18 months were 80, 76 and 72%, respectively. Although mean follow-up was short (less than 1 year), neither acute-phase programmed stimulation nor 24-hour ambulatory monitoring responses were significantly predictive of subsequent arrhythmic outcome. Proarrhythmia was documented in 18 patients (7%), 17 during the acute phase and 1 during long-term follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative hemodynamic effects of intravenous dobutamine and MDL-17,043, a new cardioactive drug, in severe congestive heart failure.

In 14 patients with severe congestive heart failure (CHF) due to ischemic heart disease or idiopathic dilated cardiomyopathy, the hemodynamic response to intravenous infusion of dobutamine (D) was compared to that of a new non-catechol, non-glycoside, inotropic and vasodilator agent, MDL-17,043 (MDL) administered in incremental intravenous doses. D and MDL produced comparable increases in cardiac index (L/min/m2) (1.8 +/- 0.4 to 2.9 +/- 0.8 and 1.7 +/- 0.3 to 3.3 +/- 0.6, respectively; both p = 0.001) and stroke volume index (ml/beat/m2) (24 +/- 8 to 35 +/- 9 and 22 +/- 7 to 39 +/- 11, respectively; both p = 0.001). Both D and MDL reduced left ventricular filling pressure (29 +/- 5 to 24 +/- 5 and 29 +/- 6 to 17 +2- 6 mm Hg, respectively; both p less than 0.05), and mean right atrial pressure (11 +/- 4 to 8 +/- 4 and 13 +/- 5 to 6 +/- 4 mm Hg, respectively; both p = 0.001). The overall changes in heart rate and mean arterial pressure were small with both D and MDL. However, MDL in comparison to D resulted in a significantly lower left ventricular filling pressure (p = 0.001), mean pulmonary arterial pressure (p = 0.001), and mean arterial pressure (p less than 0.05). The salutary hemodynamic effects of MDL on cardiac index and left ventricular filling pressure were sustained for an average of 9.6 hours, whereas the effects of D dissipated within 30 minutes of stopping the infusion. No serious adverse effects were noted during acute administration with either drug. Therefore, intravenous MDL may be a useful substitute for D in the acute therapy of severe CHF.

Intravenous and oral MDL 17043 (a new inotrope-vasodilator agent) in congestive heart failure: hemodynamic and clinical evaluation in 38 patients.

To evaluate the potential benefit of MDL 17043, a new inotrope-vasodilator agent, in the short- and long-term management of severe heart failure, its hemodynamic effects were determined after both intravenous (cumulative average dose 3.7 mg/kg) and oral (average 18.4 mg/kg) administration in 38 patients with severe intractable heart failure. After both intravenous and oral therapy, cardiac index increased from a control value of 2.1 +/- 0.4 to 3.6 +/- 0.9 liters/min per m2, p less than 0.001 (intravenous) and from 2.2 +/- 0.5 to 3.4 +/- 0.6 liters/min per m2, p less than 0.001 (oral). Pulmonary capillary wedge pressure decreased from 26 +/- 6 to 14 +/- 7 mm Hg (p less than 0.001) and from 26 +/- 7 to 18 +/- 8 mm Hg (p less than 0.001) after intravenous and oral routes, respectively. Stroke volume index and stroke work index increased, and right atrial and pulmonary arterial pressures and systemic vascular resistance decreased by similar magnitude after both intravenous and oral MDL 17043 (all p less than 0.001). The hemodynamic effects persisted during 4 hours of observation. Thirty-seven patients were discharged while receiving MDL 17043 therapy and were followed up for a mean of 5.6 months (range 0.5 to 13). Thirty-three of the 37 patients had short-term improvement clinically by at least one New York Heart Association functional class. Undesirable effects, including nausea (35%), anorexia (27%), fluid retention (24%) and thrombocytopenia (less than 1%), necessitated discontinuation of therapy in 11 patients (30%) who were receiving multiple drug therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms of improved left ventricular function following intravenous MDL 17,043 in patients with severe chronic heart failure.

To evaluate the mechanisms for improved left ventricular function with MDL 17,043 in patients with severe chronic heart failure, 24 patients were evaluated by simultaneous determination of hemodynamics by right heart catheterization and ejection fraction by computerized nuclear probe before and following intravenous administration of MDL 17,043 (mean cumulative dose 3.6 mg/kg). Following MDL 17,043, there was an increase in cardiac index (+62%), stroke volume index (+42%), and stroke work index (+68%), together with a decrease in pulmonary capillary wedge pressure (-46%), indicating improved left ventricular pump function. There was a marked reduction in systemic vascular resistance (-40%) and a modest reduction in arterial pressure, indicating decreased left ventricular outflow resistance. The ratio of peak systolic blood pressure to calculated left ventricular end-systolic volume tended to increase, but the change was not statistically significant. Despite a marked increment in stroke volume index, left ventricular ejection time corrected for heart rate was shortened, suggesting enhanced contractility. In the group as a whole, the calculated left ventricular end-diastolic volume remained unchanged, but it increased in 14 patients. Since pulmonary capillary wedge pressure fell in each patient, this suggests improved overall left ventricular distensibility. Thus, decreased left ventricular outflow resistance, and possibly increased contractile function, and improved left ventricular diastolic compliance may all contribute to improved left ventricular pump function with MDL 17,043 in patients with severe heart failure.

Acute hemodynamic effect of oral MDL 17,043 in severe congestive heart failure.

MDL 17,043, when administered intravenously in humans, produces a significant and salutary hemodynamic response. To determine its acute effect when administered orally (3 mg/kg), 10 patients with severe congestive heart failure were studied by right-sided cardiac catheterization for 8 hours. At 4 hours after drug ingestion, there was significant improvement in several hemodynamic measurements. Cardiac index increased 38% over baseline (from 1.9 +/- 0.4 to 2.6 +/- 0.4 liters/min/m2, p less than 0.01), arteriovenous oxygen difference decreased by 30% (from 8.0 +/- 1.4 to 5.6 +/- 1.2 vol%, p less than 0.01), heart rate increased by 8% (from 85 +/- 16 to 92 +/- 16 beats/min, p less than 0.05), stroke volume index increased by 22% (from 23 +/- 5 to 28 +/- 4 ml/beat/m2, p less than 0.05), left ventricular stroke work increased by 24% (from 18 +/- 5 to 22 +/- 5 g-m/m2, p less than 0.01), mean arterial pressure decreased by 10% (from 79 +/- 6 to 71 +/- 9 mm Hg, p less than 0.01), mean right atrial pressure decreased by 40% (from 10 +/- 5 to 6 +/- 4 mm Hg, p less than 0.01), and mean pulmonary artery wedge pressure decreased by 36% (from 22 +/- 5 to 14 +/- 6 mm Hg, p less than 0.01). Cardiac index, arteriovenous oxygen difference, mean arterial pressure, right atrial pressure, and pulmonary artery wedge pressure remained significantly improved at 8 hours. These findings indicate that MDL 17,043 is active when administered orally and produces beneficial hemodynamic effects for as long as 8 hours.

The acute hemodynamic effects of a new agent, MDL 17,043, in the treatment of congestive heart failure.

MDL 17,043 administered intravenously or orally exerts positive inotropic and vasodilator actions in experimental animal preparations. We studied its acute hemodynamic effects in 15 patients with severe congestive heart failure by right-heart catheterization. Intravenous MDL 17,043 at 10 minutes increased cardiac index (3.4 +/- 0.8 vs 1.9 +/- 0.4 l/min/m2), narrowed arteriovenous oxygen content difference (4.6 +/- 0.8 vs 7.8 +/- 2.0 vol%), increased heart rate (98 +/- 14 vs 89 +/- 18 beats/min), and decreased systemic arterial (67 +/- 10 vs 83 +/- 11 mm Hg), pulmonary capillary wedge (12 +/- 5 vs 24 +/- 5 mm Hg) and right atrial (6 +/- 5 vs 12 +/- 7 mm Hg) mean pressures significantly (p less than 0.001). In 11 patients, hemodynamics were monitored hourly for 6 hours. Compared with baseline, the cardiac index and heart rate were higher and mean systemic arterial pressure was lower for 6 hours; pulmonary capillary and right atrial mean pressures were significantly lower for 5 hours. No serious arrhythmias or side effects occurred. These data suggest that MDL 17,043 may be useful for treating congestive heart failure.