Clinicopharmacological studies of a newly synthesized cardiotonic agent (TA-064) in patients with congestive heart failure

In animal experiments, a new inotropic agent, (-)-(R)-1-(p-hydroxyphenyl)-2-[(3,4-dimethoxyphenetyl)amino] ethanol, designated TA-064 was found to possess a more positive inotropic than chronotropic action. Its effectiveness and lack of significant toxicity make it beneficial for clinical use as a cardiotonic in human heart failure. The effects of TA-064 were investigated in patients with various types of heart disease (n = 29). Cardiac output increased, left ventricular end-systolic dimension decreased, and left ventricular fractional shortening increased for 15 minutes after a single intravenous dose (1 mg). The plasma level of TA-064 at the cessation of infusion was 61.1 +/- 49.6 ng/ml and thereafter declined biexponentially. After a single oral dose (10 mg), TA-064 appeared in the plasma at 30 minutes and reached its peak levels of 13.7 +/- 5.6 ng/ml at 60 minutes. Seven hours later, the plasma level was 5.9 +/- 3.1 ng/ml which was considered to be within the effective range according to the results after intravenous administration. In conclusion, minimal effective plasma levels of TA-064 are obtained by oral administration of 10 mg three times a day.     

Randomized double-blind study of intravenous tocainide versus lidocaine for suppression of ventricular arrhythmias after cardiac surgery

To compare the therapeutic efficacy and safety of intravenous tocainide with that of intravenous lidocaine in patients with ventricular arrhythmias after cardiac surgery, 25 patients were randomized to either agent in a double-blind manner. Tocainide was given in 16 patients as a 250 mg bolus followed by a loading infusion of 500 mg over 15 minutes and a maintenance infusion of 33.3 mg/min. Lidocaine was administered in 9 patients as a 100 mg bolus followed by a loading infusion of 60 mg over 15 minutes and a maintenance infusion of 1.4 mg/min. Therapy was continued for 24 hours in initially responding patients. With analysis of 24-h taped electrocardiograms it was found that single premature ventricular complexes (PVCs) were suppressed by tocainide by more than 80% in 94% of patients and by lidocaine in 75% of patients (p = NS). Couplets and ventricular tachycardia events were eliminated in all patients by either drug. Multiform PVCs were abolished in 94% of the patients after tocainide and in 75% after lidocaine (p = NS). Average overall success over the 24 hours with more than 80% suppression of single PVCs and simultaneous elimination of higher forms of arrhythmia was 71% with tocainide and 59% with lidocaine (p = NS). Adverse effects were negligible, with only one patient in the lidocaine group developing diaphoresis without necessitating termination of therapy. Treatment rapidly produced and then maintained blood levels of 4-10 mg/l for tocainide and 1-4 mg/l for lidocaine. We conclude that intravenous tocainide is well tolerated and has comparable efficacy to lidocaine in the acute therapy of postcardiac surgery ventricular arrhythmias.     

Dosing recommendations for encainide

The onset of antiarrhythmic action of encainide in patients with ventricular arrhythmias occurred within 3 hours after a single dose of 25 or 50 mg. No significant antiarrhythmic activity was noted after only 10 mg. After 14 days of daily dosing, both the 25- and 50-mg dose levels of encainide administered 3 times/day abolished or decreased ventricular arrhythmias in patients tested over a 24-hour period, whereas the 10-mg dose was ineffective. In 5 well-controlled studies involving 331 patients, encainide produced a dose-related decrease in the absolute number of ventricular arrhythmias as well as an increase in the percentage of responders (greater than 75% decrease in ventricular arrhythmias). Doses of 75 mg/day were required to obtain at least a 50% reduction in ventricular arrhythmias or 50% of patients responding or both. Three-times-a-day dosing was as effective as 4-times-a-day dosing. Further, doses greater than 200 mg/day gave little or no increase in incidence of efficacy. Important side effects were very low using doses of less than or equal to 150 mg/day and increased significantly at greater than or equal to 150 mg/day. It is recommended that encainide be initiated at 25 mg 3 times/day for 4 to 7 days, then carefully titrated upward, as needed, to 35 and 50 mg 3 times/day, respectively, every 4 to 7 days. If needed, 50 mg 4 times/day is an appropriate next dosage. Rapid dose escalation or doses greater than 200 mg are discouraged. Patients with severe life-threatening arrhythmias should receive encainide in a setting with cardiac monitoring and advanced life support systems.     

Amiodarone: intravenous loading for rapid suppression of complex ventricular arrhythmias

A major disadvantage of conventional amiodarone therapy is the long delay between initiation of therapy and arrhythmia suppression. In this study, the hypothesis was tested that complex ventricular arrhythmias would be suppressed rapidly by an intravenous amiodarone infusion designed to achieve and maintain a therapeutic serum concentration. Eleven patients were studied. Each underwent a single intravenous dose kinetic study, followed by a two stage infusion of amiodarone that achieved and maintained a serum concentration of 2 to 3 micrograms/ml. In seven patients, arrhythmias during hours 24 to 48 after the infusion were compared with arrhythmias without therapy. Amiodarone therapy reduced episodes of ventricular tachycardia by 85% (p less than 0.01), paired premature ventricular complexes by 74% (p less than 0.01) and premature ventricular complexes by 60% (p less than 0.05). Four patients could not tolerate a control period without therapy because of symptomatic arrhythmias. In three patients, symptomatic arrhythmias were abolished during the 24 hour evaluation period. Two of 11 patients, both with severe left ventricular dysfunction, developed significant hypotension during the loading phase of the infusion. It is concluded that the achievement and maintenance of a therapeutic serum concentration of intravenous amiodarone are effective in the rapid suppression of life-threatening ventricular arrhythmias. Caution should be employed when using large intravenous doses in patients with severely impaired left ventricular function.     

Pharmacokinetics of verapamil: Experience with a sustained intravenous infusion regimen

Disappearance kinetic characteristics of verapamil were determined in 9 patients after a single intravenous dose. From the pharmacokinetic variables determined, we designed an intravenous regimen to maintain a plasma verapamil concentration of 150 ng/ml consisting of (1) a loading bolus (10 mg over 2 minutes), followed by (2) a rapid loading infusion (0.375 mg/min) for 30 minutes, and finally (3) a maintenance infusion (0.125 mg/min). We tested this regimen in 7 patients for 2 to 12 hours, and found it to be safe and to produce stable prolongation of the P-R interval. Verapamil concentration was highest immediately after the bolus administration and was prevented from falling below 67 ng/ml by the rapid infusion. Maintenance concentration remained between 77 and 156 ng/ml for all patients, and averaged 122 ng/ml.Transient and slight decreases in brachial blood pressure and sinus cycle length occurred coincident with the maximum verapamil concentration. Maximum P-R prolongation lagged behind peak plasma concentration but was sustained for the duration of the infusion. Prolongation of the P-R interval was not significantly different at the end of the infusion from that 90 minutes after the start of the regimen. No patient demonstrated significant side effects, arrhythmia, or clinically important hypotension. Although the specified regimen produced a final concentration averaging 125 ng/ml, it is predicted that infusion regimens producing other plasma concentrations can be similarly devised by changing the bolus, rapid loading infusion, and maintenance infusion doses in proportion to the desired final plasma concentration.     

Suppression of arrhythmias within hours after a single oral dose of amiodarone and relation to plasma and myocardial concentrations

In 65 patients a single oral dose of amiodarone (30 mg/kg) produced an antiarrhythmic effect on supraventricular or ventricular arrhythmias within 3 to 8 hours and lasted for 17 to 19 hours. On the second day a 15-mg/kg dose reproduced this effect within 3 to 9 hours. Plasma concentration of amiodarone increased to a maximum (2.2 +/- 1.7 mg/liter) mean +/- standard deviation) at 6 +/- 3.5 hours and plasma levels of N-desethylamiodarone (NDA) rose to 0.2 +/- 0.08 mg/liter at 12 +/- 6.4 hours. Sixty-one other patients were given a single 30-mg/kg dose 7 hours to 4 days before open heart surgery. Biopsies of the right atrial and left ventricular walls were taken during surgery. Myocardial concentration of amiodarone was maximal in the atrium after 7 hours (13 +/- 8 mg/kg) and in the ventricle after 24 hours (17 +/- 11 mg/kg). NDA myocardial concentration increased progressively until 24 hours and then remained stable over 4 days (1.5 mg/kg). The amiodarone myocardial to plasma concentration ratio was similar in the atrium and in the ventricle and averaged 22 and 10 for amiodarone and NDA, respectively. A significant relation existed between amiodarone concentration and the effect on ventricular premature complexes (r = 0.74, p less than 0.001) and between amiodarone plasma concentration and the effect on the atrioventricular conduction (r = 0.58, p less than 0.001). The plasma concentration of amiodarone corresponding to a 60% decrease in arrhythmias averaged 1.5 to 2 mg/liter.(ABSTRACT TRUNCATED AT 250 WORDS)     

Single-bolus injection of recombinant tissue-type plasminogen activator in acute myocardial infarction

Recombinant tissue-type plasminogen activator (rt-PA) has hitherto been administered in acute myocardial infarction as an intravenous infusion with an initial bolus of about 10% of the total dose, both due to its short half-life and to avoid possible early reocclusions. A single-bolus dose would simplify the therapeutic regimen. Therefore, 20 patients with symptom duration of 125 +/- 58 minutes were given a single bolus of 50 mg of rt-PA over 2 minutes. Coronary angiography 60 minutes after the rt-PA bolus revealed a patent infarct-related artery in 15 of 20 patients (patency rate 75%, 95% confidence limits 51 to 91%). In the remaining patients, reperfusion was achieved by coronary angioplasty and intracoronary fibrinolysis; in 2 patients coronary artery bypass grafting was necessary. Control angiograms at 24 hours showed reocclusions in 4 of 18 patients. One woman died due to an intracranial hemorrhage 48 hours after the rt-PA bolus injection. Circulating fibrinogen decreased from 2.7 +/- 0.5 to 1.5 +/- 0.9 g/liter after 2 to 4 hours and reached the initial value within 24 hours. Pharmacokinetic parameters were obtained in 7 patients by measuring rt-PA antigen levels in multiple plasma samples. Mean peak rt-PA concentration was 9.8 +/- 3.6 micrograms/ml, total plasma clearance 476 +/- 148 ml/min and dominant half-life 4.8 +/- 1.0 minutes. Thus, rt-PA administered as a 50-mg single bolus appears to provide similar patency rates and shows similar kinetics in comparison with the conventional infusion regimen. Assessment of the incidence of bleeding complications requires further studies.     

Two-dimensional echocardiographic assessment of left ventricular papillary muscles in their long axes: A new cross-sectional approach

Although a single intravenous bolus of disopyramide is an effective antiarrhythmic, side effects occur in some patients. We tested the safety of multiple bolus loading for intravenous disopyramide in 10 patients with frequent premature ventricular beats. Concurrent with a 1.0 mg/kg/hr infusion, a bolus of 0.5 mg/kg of disopyramide was given over 5 minutes. Up to three additional boluses were given 5 minutes after the first bolus unless a 50% reduction in premature ventricular beats or side effects occurred. The infusion was continued for 3 hours and was then decreased to 0.4 mg/kg/hr for 15 hours. All patients had a 50% reduction in premature ventricular beats and attained therapeutic blood leveis. Three patients with a history of controlled congestive heart failure developed either hypotension or pulmonary edema. Hypotension and pulmonary edema following intravenous disopyramide is more related to the pharmacology of the drug than to the loading scheme employed.     

Flecainide compared with a combination of digoxin and disopyramide for acute atrial arrhythmias after cardiopulmonary bypass.

Fifty six adult patients were randomised to treatment with flecainide (group 1, n = 29) or a combination of digoxin and disopyramide (group 2, n = 27) for acute atrial fibrillation and flutter after cardiac surgery. Intravenous flecainide was given as a 2 mg/kg bolus over 20 minutes followed by an infusion (0.2 mg/kg per hour) for 12 hours. Group 2 were given digoxin (0.75 mg) intravenously followed two hours later by an intravenous bolus of disopyramide (2 mg/kg) and an infusion (0.4 mg/kg per hour) for 10 hours. Within 12 hours sinus rhythm was restored in 86% of the group 1 (25 patients) and 89% of the group 2 (24 patients). The median time to reversion was significantly shorter in group 1 (80 minutes, range 30-180 minutes) than group 2 (220 minutes, range 138-523 minutes). None of the patients in group 1 and four of the patients in group 2 had transient relapses into atrial fibrillation during the 12 hours of intravenous treatment. There were five late relapses in group 1 and seven in group 2 during subsequent oral treatment. Two group 1 patients and two group 2 patients showed adverse drug effects. Intractable ventricular arrhythmias occurred after five days of oral treatment in one patient (group 1) who had poor left ventricular function, hepatic impairment, and toxic concentrations of drugs at the time of death. Flecainide was as effective as the combination of digoxin and disopyramide and it acted significantly faster and was associated with fewer relapses. Monitoring of blood concentrations of flecainide is essential in patients with poor left ventricular function and hepatic impairment.     

Flecainide compared with a combination of digoxin and disopyramide for acute atrial arrhythmias after cardiopulmonary bypass

Fifty six adult patients were randomised to treatment with flecainide (group 1, n = 29) or a combination of digoxin and disopyramide (group 2, n = 27) for acute atrial fibrillation and flutter after cardiac surgery. Intravenous flecainide was given as a 2 mg/kg bolus over 20 minutes followed by an infusion (0.2 mg/kg per hour) for 12 hours. Group 2 were given digoxin (0.75 mg) intravenously followed two hours later by an intravenous bolus of disopyramide (2 mg/kg) and an infusion (0.4 mg/kg per hour) for 10 hours. Within 12 hours sinus rhythm was restored in 86% of the group 1 (25 patients) and 89% of the group 2 (24 patients). The median time to reversion was significantly shorter in group 1 (80 minutes, range 30-180 minutes) than group 2 (220 minutes, range 138-523 minutes). None of the patients in group 1 and four of the patients in group 2 had transient relapses into atrial fibrillation during the 12 hours of intravenous treatment. There were five late relapses in group 1 and seven in group 2 during subsequent oral treatment. Two group 1 patients and two group 2 patients showed adverse drug effects. Intractable ventricular arrhythmias occurred after five days of oral treatment in one patient (group 1) who had poor left ventricular function, hepatic impairment, and toxic concentrations of drugs at the time of death. Flecainide was as effective as the combination of digoxin and disopyramide and it acted significantly faster and was associated with fewer relapses. Monitoring of blood concentrations of flecainide is essential in patients with poor left ventricular function and hepatic impairment.     

Efficacy of flecainide acetate for atrial arrhythmias following coronary artery bypass grafting

The antiarrhythmic efficacy of intravenous flecainide and intravenous digoxin was assessed in 29 patients (26 men), aged 43 to 73 (63 +/- 7) years who developed atrial arrhythmias in the first 96 hours after coronary artery bypass grafting. Twenty-seven had atrial fibrillation and 2 had atrial flutter. Patients were entered into the study if the arrhythmia persisted for at least 15 minutes with a ventricular rate greater than 120 beats/min. Fifteen patients were randomized to flecainide (group 1) and 14 to digoxin (group 2). Flecainide was given as a bolus of 1 mg/kg over 10 minutes followed by an infusion of 1.5 mg/kg/hr for 1 hour and then 0.25 mg/kg/hr for the rest of the study period (24 hours). Digoxin was given as 3 bolus doses (0.5 mg followed after 6 and 12 hours by 0.25 mg). In both groups, 10 mg of verapamil was given intravenously after 45 minutes if the arrhythmia persisted with a mean ventricular rate greater than 100 beats/min. The antiarrhythmic efficacy was assessed by 24-hour Holter monitoring and frequent 15-second rhythm strips. Within 45 minutes control of arrhythmia, which was maintained for the rest of the study period, was achieved in 10 of 15 patients in group 1 and 2 of 14 in group 2 (p less than 0.01). Nine of 15 reverted to sinus rhythm in group 1 compared to 0 of 14 in group 2 and 1 of 15 remained in arrhythmia with a controlled ventricular rate in group 1 compared to 2 of 14 in group 2.(ABSTRACT TRUNCATED AT 250 WORDS)     

Efficacy and safety of oral cibenzoline for ventricular arrhythmias

This study evaluates acute and chronic therapy with cibenzoline, a new class I antiarrhythmic drug, in 49 patients with ventricular arrhythmias. Acute therapy with 260 to 330 mg/day of cibenzoline resulted in a significant reduction in the number of hourly ventricular premature complexes (VPCs) (from 377 +/- 60 to 116 +/- 33, p less than 0.001), total paired VPCs in 24 hours (from 531 +/- 196 to 101 +/- 66, p less than 0.02), and total episodes of ventricular tachycardia in 24 hours (from 31 +/- 10 to 4 +/- 3, p less than 0.01). Among this group, acute therapy resulted in more than 75% suppression of VPC frequency in 29 of 49 patients, more than 90% suppression of paired VPCs in 31 of 42 patients, and complete suppression of ventricular tachycardia in 21 of 27 patients. Radionuclide evaluation of ventricular function revealed no deleterious effect of cibenzoline on ventricular function. Significant suppression of VPC frequency was maintained during 6 months of therapy in 16 of 19 patients and during 12 months of therapy in 9 of 10 patients. Trough plasma cibenzoline levels were measured during the acute dosing period. These levels did not differ among the group of responders (326 +/- 140 ng/ml) compared with nonresponders (354 +/- 282 mg/ml). Cibenzoline therapy resulted in adverse effects 18 patients and necessitated discontinuing therapy in 12. No patient had a proarrhythmic effect. In conclusion, cibenzoline appears to be as efficacious as the available antiarrhythmic drugs in treating chronic complex ventricular arrhythmias. Drug-related adverse effects occur with a frequency similar to that of other antiarrhythmic drugs.     

Intravenous amiodarone in the treatment of refractory life-threatening cardiac arrhythmias in the critically ill patient

Eleven critically ill patients with life-threatening cardiac arrhythmias refractory to currently approved antiarrhythmic drugs were treated with intravenous amiodarone. Two patients had acute myocarditis, five had acute myocardial infarction, two had left ventricular failure secondary to ischemic heart disease, one had Wolff-Parkinson-White syndrome, and one manifested postoperative atrial fibrillation. Eight of the patients had severe cardiac failure and five had hypotension requiring intravenous dopamine. Five patients were treated for recurrent ventricular fibrillation, two for recurrent ventricular tachycardia, and four for recurrent atrial arrhythmlas. Six patients had repeated cardioversions. The arrhythmias had lasted a mean of 88.3 hours resistant to a mean of 2.7 different intravenous antiarrhythmic drugs. The ventricular arrhythmias did not recur after commencing intravenous amiodarone, but some minor atrial arrhymias occurred for 24 hours. One patient died of intractable left ventricular failure, chronic obstructive lung disease, and respiratory arrest during treatment. The dose of amiodarone was 150 mg over 5 minutes, followed by 600 mg/24 hr for 3 to 4 days; one patient on total parenteral nutrition required intravenous amiodarone for 20 days. Hypotension, cardiac failure, and bradyarrhythmias were not induced by this treatment. Intravenous amiodarone can be used safely in critically ill patients with impaired left ventricular function to control life-threatening refractory cardiac arrhythmias.     

Acute Hemodynamic Effects of Amlodipine 15 Days After a Myocardial Infarction in Normotensive Patients Treated with Atenolol

The acute hemodynamic effects of 20 mg iv amlodipine were evaluated in a placebo-controlled study in 16 normotensive patients 15 ± 1 days after an acute myocardial infarction by covariance analysis. Atenolol was given orally for at least 1 week before the study to maintain the heart rate between 50 and 60 beats/min. All patients were given two doses of 10 mg of amlodipine, or 10 ml of a placebo twice, in iv infusion lasting 2 minutes each. Hemodynamic data were collected during the control period and 15 minutes after each of the two amlodipine or placebo infusions. At the time of the last measurements, 15 minutes after the second amlodipine or placebo infusion, the plasma amlodipine level was 31 ± 16 g/l and the plasma atenolol level was 773 ± 564 /l in the amlodipine group versus 795 ± 916 g/l in the placebo group. There were no chronotropic, dromotropic, or inotropic effects. The main hemodynamic effect was a fall in systemic vascular resistance (1548 ± 591 dynes.sec.cm^-5to 1176 ± 526 dynes.sec.cm^-5, p = 0.045) with decreases in aortic pressure and in the left ventricular stroke work index. The left ventricular ejection fraction was 51 ± 12% in the placebo group and 56 ± 15% in the amlodipine group (ns) during the control period, and did not change after infusion of placebo or amlodipine. Left ventricular compliance seemed to be enhanced by amlodipine, because the end-diastolic left ventricular volume index rose from 82 ± 11 ml/m² to 87 ± 11 ml/m² (p = 0.026) 15 minutes after the beginning of the second infusion of 10 mg of amlodipine, without any change in end-diastolic left ventricular pressure. Intravenous infusion of 20 mg of amlodipine is well tolerated 15 days after acute myocardial infarction in normotensive patients without deeply depressed left ventricular systolic function and chronically treated with atenolol. The main hemodynamic effects observed are potentially useful for such patients.     

Efficacy of recainam, a new antiarrhythmic drug, for control of ventricular arrhythmias

The antiarrhythmic efficacy and safety of oral recainam hydrochloride, a newly synthesized compound, were assessed during a 2-part study of 12 patients with frequent (at least 30/hour) ventricular premature complexes (VPCs). During the initial dose-ranging phase, 11 patients with qualifying arrhythmias (median VPC frequency 575/hour, range 37 to 1,494) received incremental oral doses of 100, 300 and 500 mg of recainam given every 8 hours, each for 3 days. Efficacy was assessed on the last day of each dose. The 300-mg/day dose of recainam was generally ineffective; the 900-mg/day dose was partially effective (58% median VPC reduction, p = 0.03); and the 1,500-mg/day dose was very effective (79% reduction, p less than 0.003). Median reductions in repetitive beats (beats in couplets and runs) for the 3 doses were 18% (difference not significant), 94% (p less than 0.01), and 98% (p less than 0.004), respectively. Recainam provided individual efficacy (at least 70% VPCs or at least 90% repetitive beat suppression, or both) in 7 (64%) of the patients taking 900 mg/day and in 8 (73%) taking 1,500 mg/day. Minimum steady-state plasma concentrations were higher in responders (1.8 +/- 0.5 microgram/ml) than in nonresponders (1.0 +/- 0.5 microgram/ml) (p less than 0.05). The electrocardiographic response to recainam (1,500 mg/day) included increases in PR (by 22%, p less than 0.003) and QRS (by 14%, p less than 0.002) intervals and a small decrease in JTc duration (by 9%, p less than 0.04). Radionuclide ejection fraction did not change. Noncardiac adverse reactions were minimal.(ABSTRACT TRUNCATED AT 250 WORDS)     

A dose-response study of intravenous enoximone in congestive heart failure

Previous clinical studies with intravenous enoximone have used cumulative dosing to quantify enoximone's hemodynamic effects. The magnitude and duration of the hemodynamic effects of single intravenous doses of enoximone were evaluated in patients with congestive heart failure. Sixty patients, who were in New York Heart Association functional classes III and IV, received single intravenous doses of enoximone, either 0.25 (12 patients), 0.5 (13 patients), 1 (14 patients), 1.5 (10 patients) or 2 mg/kg (11 patients). Cardiac index was increased by 20% with the 0.25 mg/kg dose and by 48% and 42% with the 1.5 and 2 mg/kg doses, respectively. These increases were statistically significant (Student's paired t test with Bonferroni's correction, p less than 0.007) for 1 hour after 0.25 and 0.5 mg/kg, for 2 hours after 1 mg/kg and for 4 hours after 1.5 and 2 mg/kg. Enoximone also reduced pulmonary artery diastolic pressure by 19% with 0.25 mg/kg and by 29% with 2 mg/kg. The duration of effect varied from 1 hour with 0.25 mg/kg to 4 hours with 2 mg/kg. Enoximone produced no consistent or dose-related effects on heart rate or blood pressure. Eighteen adverse reactions were reported by 15 patients, of which 11 were minor and transient (vein pain, flushes, nausea). In 5 patients ventricular or supraventricular arrhythmias were observed, including nonsustained ventricular tachycardia and extrasystoles; 3 of these patients had evidence of arrhythmias before enoximone. Laboratory studies before and after treatment showed no drug-related effects. Dose-related effects on the magnitude and duration of hemodynamic responses to intravenous enoximone were evident within the dose range of 0.25 to 2 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of intravenous mexiletine and lidocaine for the treatment of ventricular arrhythmias

The efficacy and safety of intravenous loading of mexiletine was compared to lidocaine in patients with ventricular premature depolarizations (VPDs). Seventeen men and five women, average age 63 years, completed this randomized parallel study. Twelve patients received mexiletine intravenously at (5 to 10 mg/min) until greater than or equal to 95% VPD suppression was achieved or a total of 450 mg of drug was given. The average loading dose of mexiletine was 4.4 mg/kg, at an infusion rate of 0.1 mg/kg/min. Ten patients received lidocaine (1 mg/kg) given over 3 minutes, with a second similar bolus given if after 10 minutes greater than or equal to 95% VPD suppression was not achieved. Total VPDs were determined for the 60 minutes before drug administration, during drug infusion, and 60 minutes thereafter. Eleven of 12 (92%) patients receiving mexiletine were full responders (greater than or equal to 95% suppression) and one was a partial responder (greater than or equal to 75% greater than or equal to 95% suppression). Five of 10 lidocaine patients (50%) were full responders, three (30%) were partial responders, and two failed to respond. At peak suppression, mexiletine reduced mean VPD from 37 +/- 33/5 minutes (mean +/- S.D.) to 0.8 +/- 0.9/5 minutes (p less than 0.01) and lidocaine decreased mean VPDs from 28 +/- 47/5 minutes to 4.7 +/- 2.2/5 minutes (p less than 0.01). Mexiletine resulted in greater suppression of VPDs than lidocaine in terms of mean percent reduction (96% vs 68%, p less than 0.01). All lidocaine patients had therapeutic plasma levels (range 1.6 to 3.5 micrograms/ml).(ABSTRACT TRUNCATED AT 250 WORDS)     

Rapid suppression of complex ventricular arrhythmias with high-dose oral amiodarone

Although amiodarone is effective for the suppression of complex ventricular arrhythmias, a major problem with its use is the long delay between the initiation of therapy and the onset of effective suppression of arrhythmia. To test the hypothesis that rapid loading with oral amiodarone to a target serum concentration can overcome much of this delay, eight patients with refractory, sustained, hemodynamically compromising ventricular arrhythmias and 10 patients with potentially life-threatening ventricular arrhythmias were treated with a flexible, very high dose, oral loading protocol (800 to 2000 mg two to three times a day). Dosage was adjusted on the basis of amiodarone serum concentrations to maintain the trough serum concentrations between 2.0 and 3.0 micrograms/ml. Comparison of 24 hr Holter electrocardiograms obtained before and during therapy revealed statistically significant reductions in premature ventricular complexes (PVCs) and paired PVCs beginning the first day of therapy and a reduction in ventricular tachycardia (VT) beginning the second day. By day 2, four of eight patients with sustained VT and six of 10 patients with nonsustained VT showed no VT. Pulmonary arterial catheterization during the first 24 hr (mean amiodarone dose 3933 mg) revealed no significant hemodynamic alterations. Minor side effects were common (10 patients) but major side effects were rare (one patient). High-dose oral loading with amiodarone utilizing serum concentration guidelines is a safe and effective method of rapidly controlling life-threatening arrhythmias in selected patients.     

Antiarrhythmic actions of tocainide in canine models of previous myocardial infarction.

The antiarrhythmic and antifibrillatory efficacies of the class IB antiarrhythmic agent tocainide were characterized in conscious dogs in the early subacute phase of anterior myocardial infarction (48 hours after infarction) and in anesthetized dogs with ventricular tachyarrhythmias that were inducible by programmed stimulation more chronically (10.8 +/- 1.0 days) after anterior myocardial infarction. The frequency of spontaneous premature ventricular complexes in the early subacute postinfarction phase was reduced significantly from 48.4% +/- 10.5% to 8.2% +/- 5.0% of total complexes (p less than 0.01) by the cumulative intravenous administration of 10 mg/kg tocainide. In the late postinfarction setting, the intravenous administration of tocainide (6 mg/kg intravenous loading dose + 100 micrograms/kg/min intravenous maintenance infusion) suppressed the initiation of ventricular tachyarrhythmias by programmed stimulation in 5 of 12 animals that were tested and slowed the rate of tachycardia in 3 additional animals. However, the incidence of ventricular fibrillation and of the total number of arrhythmia-related deaths that resulted from the occurrence of a secondary ischemic insult in the presence of previous infarction did not differ significantly between tocainide (75% [9 of 12] incidence of both ventricular fibrillation and of total number of arrhythmia-related deaths) and saline-vehicle control groups (80% [12 of 15] incidence of ventricular fibrillation; 93.3% [14 of 15] incidence of total number of arrhythmia-related deaths). These findings suggest that although class I agents such as tocainide may be efficacious in the suppression of spontaneous premature ventricular complexes and ventricular arrhythmias immediately after myocardial infarction, they may be of limited value in the prevention of malignant ischemic arrhythmias that occur later after myocardial infarction.     

Early interruption of antiarrhythmia treatment in the acute phase of infarction complicated by ventricular arrhythmia

18 patients with myocardial infarction complicated by severe ventricular arrhythmias (polymorphic VEBs or bigeminy = 5; VT = 11; VF = 2) were treated with antiarrhythmics which were stopped after 24 hours (intravenous infusion of mexiletine 0.5 mg/kg/hr after a loading dose). This treatment resulted in one failure (recurrent VF) and 17 successes, after increasing the dose in 3 cases of VT. After stopping treatment, 72% of patients had no further arrhythmia. 5 cases had recurrent VT within 72 hours, which was controlled by oral mexiletine in 4 cases. The ejection fraction was significantly decreased in the group with recurrent VT. Plasma assays were of little help. Stopping the antiarrhythmic treatment after 24 hours does not therefore present any particular risks and can be proposed even in cases with severe arrhythmias.