Effects of a high dose intravenous bolus amiodarone in patients with atrial fibrillation and a rapid ventricular rate

BACKGROUND: Amiodarone, given as intravenous bolus has not yet been studied in patients with atrial fibrillation and a high ventricular rate. METHODS: One hundred consecutive patients with atrial fibrillation and a ventricular rate above 135 bpm were randomized to receive either 450 mg amiodarone or 0.6 mg digoxin given as a single bolus through a peripheral venous access. If the ventricular rate exceeded 100 bpm after 30 min, another 300 mg amiodarone or 0.4 mg digoxin were added. Primary endpoints of the study were the ventricular rate and the occurrence of sinus rhythm after 30 and 60 min. Secondary endpoints were blood pressure during the first hour after drug administration, and safety regarding drug induced hypotension, and phlebitis at the infusion site. RESULTS: Baseline heart rate was 144+/-19 in the amiodarone group and 145+/-15 in the digoxin group (p=0.72). Following amiodarone, heart rate was 104+/-25 after 30 min compared to 116+/-23 in the digoxin group (p=0.02) and 94+/-22 versus 105+/-22 after 60 min (p=0.03). After 30 min, sinus rhythm was documented in 14 (28%) patients following amiodarone compared to 3 (6%) patients in the digoxin group (p=0.003), and after 60 min in 21 (42%) versus 9 (18%) patients (p=0.012). Asymptomatic hypotension was observed in 4 amiodarone treated patients, and superficial phlebitis in 1 patient. CONCLUSIONS: Amiodarone, given as an intravenous bolus is relatively safe and more effective than digoxin for heart rate control and conversion to sinus rhythm in patients with atrial fibrillation and a rapid ventricular rate.     

Heart rate control with nebivolol in patients with tachysystolic atrial fibrillation

AIM: To find out whether selective beta-adrenoblocker nebivolol can be used for heart rate (HR) control in patients with chronic tachysystolic atrial fibrillation. MATERIAL: Patients (n=20, 7 men, 13 women, age 47-79 years) with ischemic heart disease and permanent atrial fibrillation (duration 2.5 months - 11 years) admitted to a specialized clinic for diagnosis and treatment of cardiac arrhythmias. All patients had tachycardia throughout 24 hours despite therapy. METHODS: Dosing of nebivolol: week 1 - 2.5 mg/day, week 2 7 5 mg/day. If after 2 weeks HR was considered inadequate the dose was increased up to 7.5 mg/day. Holter ECG was registered at baseline and in the end of weeks 1 and 2 of treatment. RESULTS: After 1 week of nebivolol (2.5 mg/day) HR decreased: day-time average - from 116.3+/-13.4 to 97.2+/-14.5, day-time minimal - from 78.1+/-13,5 to 71.4+/-8.2, day-time maximal - from 154.4+/-18.1 to 142.1+/-15.5; night-time average - from 83.6+/-7.1 to 76.3+/-7.14, night-time minimal - from 61.2+/-6.7 to 56.6+/-5.1, night-time maximal - from 93.5+/-10.5 to 88.2+/-10.8 bpm. After week 2 when patients received 5 mg/day of nebivolol their HR was: day-time average - 79.6+/-9,8, day-time minimal -65.2+/-7.7, day-time maximal - 128.7+/-12,2, night-time average - 69.9+/-7.6, night-time minimal - 53.1+/-4,7, night-time maximal - 80.8+/-10.1 bpm. In 2 patients (10%), interruption of nebivolol was required because of atrioventricular block in evening and nocturnal periods. CONCLUSION: Nebivolol effectively controlled HR in hospitalized patients with chronic atrial fibrillation due to ischemic heart disease. In most patients 5 mg /day was sufficient for attainment of acceptable HR.     

Effect of treatment with amiodarone on sinus node function

Treatment with amiodarone is often associated with sinus bradycardia. We studied 477 patients (mean age 48.7 +/- 0.7 years) with various cardiac rhythm disturbances. Most patients had ischemic heart disease. Average saturation dose of amiodarone was 809.4 +/- 13.4 mg/day, average maintenance dose - 263.2 +/- 5.4 mg/day, average duration of follow-up - 20.85 +/- 1.2 months. Regular Holter ECG monitoring was used for detection of sinus bradycardia (heart rate less than 60/min). Sinus bradycardia was registered in 32 and 11.2% of patients during saturation with amiodarone and maintenance treatment, respectively. Bradycardia usually improved after lowering of amiodarone dose. Heart rate slowing was not pronounced and required neither cessation of amiodarone administration nor electrical cardiac pacing.     

Amiodarone-digoxin interaction: clinical significance, time course of development, potential pharmacokinetic mechanisms and therapeutic implications

Administration of amiodarone (600 to 1,600 mg/day) to 28 patients during long-term digoxin therapy (0.25 +/- 0.05 mg/day) increased serum digoxin level from 0.97 +/- 0.45 to 1.98 +/- 0.84 ng/ml (p less than 0.001). Gastrointestinal side effects occurred in nine patients, central nervous system reactions occurred in five and cardiovascular reactions occurred in four. Pharmacokinetic studies in six patients with a 1 mg intravenous digoxin dose before and during amiodarone therapy increased serum digoxin level at 30 minutes from 8.59 +/- 1.68 to 10.07 +/- 1.70 ng/ml (p less than 0.05). Amiodarone caused a 31% prolongation of digoxin elimination half-life from 49.5 +/- 8.8 to 65.0 +/- 28.8 hours, but the increase in half-life was not statistically significant. Total body clearance was reduced significantly (29%, p less than 0.05) from 2.05 +/- 0.76 to 1.46 +/- 0.64 ml/min per kg. Nonrenal clearance also showed a significant decrease (33%, p less than 0.05) from 1.20 +/- 0.46 to 0.80 +/- 0.30 ml/min per kg. The renal clearance decreased by 22% and the volume of distribution decreased by 11% after amiodarone therapy, but these changes were not significant. The data show that the mechanism of digoxin-amiodarone interaction is multifactorial and emphasize the need for close monitoring of serum digoxin levels and clinical features during concurrent digoxin-amiodarone therapy.     

Pharmacokinetic evaluation of the digoxin-amiodarone interaction

Amiodarone is known to raise serum digoxin levels. This study was designed to evaluate the pharmacokinetic basis of this interaction in 10 normal subjects. The pharmacokinetic variables for digoxin were determined after a 1.0 mg intravenous dose of digoxin in each subject, before and after oral amiodarone, 400 mg daily for 3 weeks. During amiodarone administration, systemic clearance of digoxin was reduced from 234 +/- 72 ml/min (mean +/- standard deviation) to 172 +/- 33 ml/min (p less than 0.01). This was due to reductions in both renal clearance (from 105 +/- 39 to 84 +/- 15 ml/min) (p less than 0.05) and nonrenal clearance (from 130 +/- 38 to 88 +/- 20 ml/min) (p less than 0.01). Digoxin half-life of elimination was prolonged from 34 +/- 13 to 40 +/- 16 hours (p less than 0.05). Digoxin volume of distribution was not significantly changed. Amiodarone caused a three- to fivefold increase in serum reverse triiodothyronine levels, but changes in thyroid function were not quantitatively related to the changes in digoxin pharmacokinetics. These alterations in digoxin pharmacokinetics produced by amiodarone explain the increase in serum digoxin level that has been observed when this drug combination has been used clinically.     

Correction of rate and structure of ventricular rhythm in permanent atrial fibrillation: a novel pathogenetic approach

AIM: To analyze action of digoxin and some non-digitalis drugs (beta-blockers, verapamil, amiodarone, d,l-sotalol) and their combinations on electrical activity of atria, frequency and structure of ventricular rhythm in patients with permanent atrial fibrillation. MATERIAL AND METHODS: One hundred patients with permanent atrial fibrillation and heart rate at rest above 80 bpm were divided into 9 treatment groups. High-resolution orthogonal Frank lead ECG was recorded before and after allocated treatment. Analysis included construction of ff-waves periodograms, histograms of RR interval, cardiointervalograms and application of autocorrelation function. RESULTS: It was demonstrated that frequency and form (structure) of ventricular rhythm was determined not only by the state of AV conduction but also by value of basic period of ff-waves. The mechanisms of ventricular rate deceleration by investigated drugs were not identical. beta-blockers and verapamil directly slowed AV conduction without changing parameters of ff-waves and differed from each other only in action on parameters of concealed conduction in AV node. Action of digoxin in patients with ff-waves period equal to or exceeding 0,15 s was biphasic. During phase I shortening of ff-wave period (by 0.025+/-0.012 s) occurred. This was associated with increase of their concealed conduction through AV node. The latter phenomenon represented independent mechanism of ventricular rhythm deceleration. During phase II of digoxin action direct inhibition of AV conduction took place. Amiodarone and d,l-sotalol increased basic ff-waves period. This facilitated their conduction through AV node. Greater heart rate slowing effect of d,l-sotalol was attributed to its ability to augment concealed conduction. Due to their antiarrhythmic qualities amiodarone and d,l-sotalol slowed heart rate in patients with peak RR duration in the region of 0.28-0.46 s. These patients often had bi- and tri-modal structure of interval RR histogram. Changes of ventricular rhythm structure during use of various drugs were different. Action of digoxin was most whilst that of beta-blockers least favorable. CONCLUSION: Choice of a drug for treatment of permanent atrial fibrillation should be conducted with consideration of ff-waves periodicity, parameters of RR interval histogram, and characteristics of ventricular rhythm structure.     

Dynamic electrocardiogram in chronic atrial fibrillation treated with digitalis

To assess heart rate variability in chronic atrial fibrillation, 60 patients (20 men, 40 women: mean age 63 +/- 8 years: NYHA 2.0 +/- 0.5) with various cardiac conditions were investigated with 24-hour Holter monitoring during daily life. Twenty-five healthy subjects (5 men, 20 women: mean age 55 +/- 9) were considered as the control group. All patients had "controlled" heart rate (50-90 bpm) on basal ECG, normal hematological and thyroid hormone values, and took digoxin alone (mean dosage 0.22 +/- 0.05 mg). Mean digoxin plasma levels were 0.88 +/- 0.48 ng/ml. Maximum, minimum and average heart rate were quite good during the night but too high during the daytime and far higher than those observed in healthy subjects. In fact, up to 82% of patients (at 9 a.m.) had a maximum heart rate higher than 115 bpm. Pauses between 2.0 and 3.0 sec occurred in 40 out of 60 patients (66%). No patients had pauses longer than 4.0 sec. In our experience, patients in chronic atrial fibrillation "controlled" with digoxin alone showed a daytime heart rate which was often too high. We suggest 24-hour Holter monitoring to detect subgroups that may be treated successfully with digoxin associated with calcium-antagonists or beta-blockers.     

Low-dose amiodarone for patients with advanced heart failure who are intolerant of beta-blockers.

The tolerability and effectiveness of amiodarone in patients with advanced heart failure (HF) who are intolerant of beta-blockers was investigated in 22 patients (13 with and 9 without 180+/-26 mg/day of amiodarone). Heart rate (HR), blood pressure (BP), left ventricular diastolic dimension and fractional shortening (FS) using echocardiography, plasma atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and norepinephrine concentrations were determined at baseline and after 1 and 3 months of therapy. Although 9 patients tolerated amiodarone without any signs of HF, it was exacerbated in 4 patients. In 10 patients taking amiodarone who could be followed medically for 3 months, HR decreased after 1 month and remained unchanged until after 3 months (81+/-12 vs 65+/-7 vs 65+/-7beats/min), accompanied by decreased concentration of BNP (688+/-485 vs 392+/-203 vs 261+/-192pg/ml). FS increased significantly only after 3 months (0.12+/-0.05 vs 0.14+/-0.05 vs 0.16+/-0.04). Amiodarone may be used in patients with advanced HF who are intolerant of beta-blockers.     

Effect of oral L-type calcium channel blocker on repetitive paroxysmal atrial fibrillation: spectral analysis of fibrillation waves in the Holter monitoring.

AIMS: The electrical remodelling is considered to play a role in promoting arrhythmogenic substrate of atrial fibrillation (AF), and intracellular calcium overload may play a key role, especially in its early phase. The effect of oral verapamil on repetitive paroxysmal AF (PAF) was evaluated in clinical cases. METHODS AND RESULTS: Thirty-five patients with repetitive PAF (total PAF duration >2/24 h) were divided into two groups with and without verapamil administration (240 mg/day) and they were followed-up for 12 months. Before and after the follow-up period, 24 h Holter ECG was recorded. In each Holter recording, total PAF duration and the longest PAF duration was evaluated and spectral analysis was performed for fibrillation waves in PAF episodes to evaluate the fibrillatory frequency. Total PAF duration was prolonged by 45 +/- 79 min in the control group (n = 18) whereas shortened by 25 +/- 55 min in the verapamil group (n = 17, P = 0.005). The fibrillatory frequency was increased from 5.66 +/- 1.05 to 6.73 +/- 1.02 Hz in the control group and was unchanged in the verapamil group. There was inverse relationship between Deltatotal PAF duration and Deltafibrillatory frequency (P = 0.0002). CONCLUSION: Verapamil prevented the increase in fibrillatory frequency in PAF patients in relatively long-term observation. Verapamil might be effective for prevention of the electrophysiological change and increase in PAF episodes at least in specific type of PAF cases.     

Diltiazem and digoxin interaction. Development of digoxin plasma levels and electrocardiographic parameters in healthy subjects

In order to determine the interaction between diltiazem and digoxin, plasma digoxin concentrations and the principal ECG parameters (24 hour Holter monitoring) were measured in 10 healthy volunteers under basal conditions (P0), with 0.375 mg/day of digoxin (P1 = 17 days), during association with 240 mg/day of diltiazem (P2 = 17 days) and then again on digoxin alone (P3 = 10 days). The addition of diltiazem was associated with a 20.4% rise in plasma digoxin concentrations (0.59 ng/ml vs 0.49 ng.ml). There was no significant variation of plasma digoxin after withdrawal of diltiazem; in some cases it remained unchanged, in others it fell or continued to rise. During the administration of digoxin and diltiazem, the mean RR period and the duration of the maximal pauses increased (p less than 0.05); the RR interval also increased (p less than 0.01) but the mean QRS duration and the QTc interval did not change significantly with respect to their values on digoxin alone. After withdrawal of diltiazem, the PR interval was the only parameter to decrease significantly (p less than 0.05). These results suggest that patients receiving this drug association should be followed up carefully.     

Differential effects of a long-acting angiotensin converting enzyme inhibitor (temocapril) and a long-acting calcium antagonist (amlodipine) on ventricular ectopic beats in older hypertensive patients.

We studied differences in the effects of a long-acting angiotensin-converting enzyme (ACE) inhibitor (temocapril) and a long-acting calcium channel blocker (amlodipine) on ventricular ectopic beats (VEB) in relation to sympathetic nerve activity in 46 patients with essential hypertension. We performed 24-h Holter electrocardiography and ambulatory blood pressure (BP) monitoring simultaneously, and examined blood samples during the baseline, temocapril and amlodipine treatment periods. The ambulatory BP was lower in the amlodipine period than in the temocapril period. However, the number of VEB was significantly increased in the amlodipine period compared to that in the baseline period (11.9 vs. 7.4/day, p<0.05). In the temocapril period, the number of VEB was not significantly increased compared to that in the baseline period (8.6 vs. 7.4/day, p=0.30). Ambulatory heart rate (HR) was significantly increased in the amlodipine period compared to that in the baseline period (24-h HR: 70 vs. 66 bpm, p<0.001; daytime HR: 75 vs. 71 bpm, p<0.001; nocturnal HR: 60 vs. 58 bpm, p<0.05). Plasma norepinephrine (NE) also was significantly increased in the amlodipine period compared to that in the baseline period (457 vs. 369 pg/ml, p<0.001). However, when patients receiving amlodipine were divided into a high dose group (8.6 +/- 1.2 mg/day) and a low dose group (4.6 +/- 1.2 mg/day), increases in HR and plasma NE levels were found only in the high dose group. These results indicate that amlodipine is effective at lowering BP in older hypertensives, although it may increase VEB, especially when given at a high dose.     

Effects of amiodarone on serum T3 and T4 concentrations in hyperthyroid patients treated with propylthiouracil.

Amiodarone (Cordarone) has been proven to be useful in the management of atrial fibrillation. However, because of a large iodine content, this drug is not used in this complication of thyrotoxicosis. We previously have observed a greater fall in serum T3 and T4 concentrations in hyperthyroid patients treated with amiodarone and methimazole than with methimazole alone. In the present study, we determined whether the addition of amiodarone to propylthiouracil (PTU) could improve the levels of circulating thyroid hormones in hyperthyroid patients, and we assessed the release of iodide from amiodarone by measuring the 24 h urinary iodine excretion. Twelve hyperthyroid patients were treated either with PTU, 600 mg daily for 10 days (group PTU), or with amiodarone (A), 1200 mg daily for 3 days in addition to PTU (group A-PTU). Basal serum T4, T3, and rT3 concentrations (mean +/- SEM) were respectively 206 +/- 13 nmol/L, 5.13 +/- 0.8 nmol/L, and 81 +/- 7 ng/dL for group PTU and 238 +/- 39 nmol/L, 4.73 +/- 1.06 nmol/L, and 84 +/- 12 ng/dL for group A-PTU (NS). In group A-PTU, plasma amiodarone peaked on day 3 (mean +/- SEM: 0.48 +/- 0.11 mg/L), and urinary iodine reached 5.27 +/- 1.28 mg/day on day 5. The fall in serum T3 and the increase in serum rT3 concentrations were significantly greater in group A-PTU than in group PTU (ANOVA, p less than 0.05). In group A-PTU, the minimal serum T3 concentration was observed on day 5 of treatment (28 +/- 6% of the pretreatment values).(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative study of the efficacy of propafenone and amiodarone in the treatment of chronic ventricular extrasystole

30 patients (mean age 56 +/- 18 years) suffering from multiple ventricular extrasystoles (VES) of various origin, like ischemic, hypertensive, valvular and congenital cardiopathy, and arrhythmogenic ventricular dysplasia, were treated during 12 days by a daily dose of 900 mg of propafenone (15 cases) or 600 mg of amiodarone (15 cases). The study was randomized and a portable ECG was used for 24 h. At the time of entering into the study (H0) the patients were without any therapy. The mean total number of VES was 16,878 +/- 9,212 in the propafenone group (2,062 +/- 2,342 of them being repetitive) and 19,497 +/- 7,930 in the amiodarone group (2,907 +/- 3,615 of them being repetitive). The difference between the two groups was not statistically significant, even with the use of Holter (H1) ECG monitoring one week later. After 12 days of treatment (H2) a significant decrease in the number of total VES was noted: by 78% with propafenone (76% isolated and 89% repetitive VES) and by 77% with amiodarone (74% isolated and 91% repetitive VES). The difference between the effect of the two drugs was not significative. After 12 days of wash-out (H3) the number of VES returned to initial values with propafenone but not with amiodarone where the values were still decreased after 82 days of wash-out (H4). Both drugs produced significant bradycardia which was more apparent and more spread out during the nyctohemeral with amiodarone. Propafenone affected rather the maximal and diurnal frequencies. No correlation was found between the bradycardic and antiarrhythmic effect. Amiodarone was well tolerated and propafenone produced minor digestive and neurosensory troubles in about half the cases, only in one patient a more pronounced arrhythmogenic effect was observed. In conclusion, the efficacy and the good hemodynamic tolerance of the two drugs was found to be similar in the short-term treatment of chronic, isolated or repetitive VES, irrespective of their etiology.     

Value of electrophysiologic studies in hypertrophic cardiomyopathy treated with amiodarone

The relation of electrophysiologic effects of amiodarone to long-term outcome was studied in 35 patients with hypertrophic cardiomyopathy (HC). Indications for electrophysiologic studies were: cardiac arrest (n = 3), syncope/presyncope (n = 27) and asymptomatic ventricular tachycardia (VT) (n = 5). Twenty-eight patients (80%) had VT, 3 (9%) atrial tachycardia and 3 (9%) paroxysmal atrial fibrillation during 24-hour Holter monitoring. The studies were repeated after a total amiodarone dose of 58 +/- 122 g and during a maintenance median daily dose of 400 mg. Amiodarone abolished paroxysmal atrial arrhythmias in all 6 patients. However, it caused marked atrioventricular nodal conduction abnormality in 3 patients and heart block or marked HV interval prolongation (to greater than or equal to 100 ms) in 4 patients. Sustained VT was induced in 26 patients (74%) at baseline study and in 23 patients (66%) taking amiodarone therapy. With amiodarone, VT was no longer inducible or was more difficult to induce in 11 patients (31%), and the drug abolished VT during Holter monitoring in all patients. However, VT was easier to induce with amiodarone or was induced only with amiodarone in 18 (51%) patients. Amiodarone significantly slowed the rate of induced VT (from 248 +/- 29 to 214 +/- 37 beats/min, p less than 0.001). This was associated with a change in its morphology from polymorphic to monomorphic VT in 7 patients. During a follow up of 18 +/- 14 months (range 2 to 56), amiodarone was discontinued because of adverse effects in 8 patients (23%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Decreased TSH response to TRH induced by amiodarone

In order to test the reactivity of TSH to TRH during amiodarone treatment we investigated 7 hypothyroid subjects treated with 50 micrograms T3/day. A TRH test (200 micrograms iv) was performed before and after 6 weeks of treatment with 400 mg amiodarone/day. Amiodarone treatment induced a significant increase in serum total and free T3 (from 2.17 +/- 0.13 to 3.55 +/- 0.58 nmol/l and from 5.6 +/- 0.61 to 9.46 +/- 1.41 pmol/l). Basal TSH levels were significantly decreased and the maximal stimulation of TSH 20 min after TRH injection was only 20.0 +/- 3.3 mU/l during amiodarone treatment compared with 61.4 +/- 10.4 mU/l before treatment. These results indicate that in hypothyroid patients treated with amiodarone, the TSH response to TRH is blunted and that this is likely to be related to the higher total and free T3 levels or to a direct effect of amiodarone at the pituitary level.     

Propranolol treatment of congestive heart failure in infants with congenital heart disease: The CHF-PRO-INFANT Trial. Congestive heart failure in infants treated with propanol.

AIM: Infants with congenital heart disease and left-to-right shunts may develop significant clinical symptoms of congestive heart failure in spite of therapy with digoxin and diuretics. We investigated the effects of beta-blockade in infants with severe heart failure. METHODS AND RESULTS: We performed a prospective, randomized, open monocenter trial in infants treated with digoxin and diuretics (n=10) in comparison to 10 infants receiving additional beta-blocker therapy. After 17 days on average beta-blocker treated infants (propranolol:1,6 mg/kg/day) improved significantly with respect to Ross heart failure score (3.3+/-2.3 vs. 8.3+/-1.9, P=0.002), lower renin levels (338+/-236 vs. 704+/-490 microU/l, P=0.008) and lower mean heart rates in Holter ECG (118+/-10 vs. 142+/-11 beats/min, P<0.001). While digoxin and diuretic treated infants had unchanged mean heart rate (149+/-8 vs. 148+/-10 beats/min), less decrease of symptoms (Ross Score: 8.5+/-1.7 vs. 6.8+/-2.3, P=0.02) but a significant increase of renin levels (139+/-102 vs. 938+/-607 microU/l, P=0.001). CONCLUSION: Additional propranolol treatment but not digoxin and diuretics alone can effectively reduce clinical symptoms of heart failure in infants with congenital heart disease, who suffer from increased neurohormonal activation.     

Comparison of programmed stimulation and Holter monitoring for predicting long-term efficacy and inefficacy of amiodarone used alone or in combination with a class 1A antiarrhythmic agent in patients with ventricular tachyarrhythmia

The values of two Holter ambulatory electrocardiographic monitoring criteria and one programmed stimulation efficacy criterion reported to be predictive of the efficacy of amiodarone were compared in 70 patients taking amiodarone for sustained ventricular tachyarrhythmias. At baseline, all patients had ventricular tachycardia inducible by programmed stimulation. After amiodarone loading (935 +/- 271 mg for 16 +/- 7 days), efficacy was determined by a programmed stimulation criterion (ventricular tachycardia no longer inducible or less than or equal to 15 beats) and two Holter monitoring criteria (Holter I = greater than or equal to 85% reduction of ventricular premature complexes and abolition of couplets and triplets in 64 patients who had greater than or equal to 10 ventricular premature complexes/h or couplets or triplets or both before therapy; Holter II = abolition of triplets in 41 patients who had triplets before therapy). Amiodarone was effective in 12 of 70 patients by the programmed stimulation criterion, in 49 of 64 patients by Holter criterion I and in 37 of 41 patients by Holter criterion II. In assessing efficacy of amiodarone, programmed stimulation and Holter criteria were discordant in 69% of patients or more (p less than 0.001). There were 16 recurrences or sudden deaths during the entire follow-up period (19 +/- 19 months). Arrhythmia-free survival rates at 24 months of patients with efficacy and inefficacy by each criterion, respectively, were 90 and 78% by programmed stimulation, 84 and 62% by Holter criterion I (p less than 0.05) and 73 and 50% by Holter criterion II (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Steady-state interaction between amiodarone and phenytoin in normal subjects

Amiodarone has been reported to increase phenytoin levels. This study was designed to evaluate the pharmacokinetic basis of this interaction at steady-state. Pharmacokinetic parameters for phenytoin were determined after 14 days of oral phenytoin, 2 to 4 mg/kg/day, before and after oral amiodarone, 200 mg daily for 6 weeks in 7 healthy male subjects. During amiodarone therapy, area under the serum concentration time curve for phenytoin was increased from 208 +/- 82.8 (mean +/- standard deviation) to 292 +/- 108 mg.hr/liter (p = 0.015). Both the maximum and 24-hour phenytoin concentrations were increased from 10.75 +/- 3.75 and 6.67 +/- 3.51 micrograms/ml to 14.26 +/- 3.97 (p = 0.016) and 10.27 +/- 4.67 micrograms/ml (p = 0.012), respectively, during concomitant amiodarone treatment. Amiodarone caused a decrease in the oral clearance of phenytoin from 1.29 +/- 0.30 to 0.93 +/- 0.25 liters/hr (p = 0.002). These results were due to a reduction in phenytoin metabolism by amiodarone as evidenced by a decrease in the urinary excretion of the principal metabolite of phenytoin, 5-(p-hydroxyphenyl)-5-phenylhydantoin, 149 +/- 39.7 to 99.3 +/- 40.0 mg (p = 0.041) and no change in the unbound fraction of the total phenytoin concentration expressed as a percentage, 10.3 +/- 2.7 versus 10.7 +/- 2.1% (p = 0.28) during coadministration of amiodarone. The alterations in phenytoin pharmacokinetics suggest that steady-state doses of phenytoin of 2 to 4 mg/kg/day should be reduced at least 25% when amiodarone is concurrently administered. All dosage reductions should be guided by clinical and therapeutic drug monitoring.     

Combined amiodarone and silymarin treatment,but not amiodarone alone,prevents sustained atrial flutter in dogs

Amiodarone/Silymarin Treatment for Sustained Atrial Flutter. INTRODUCTION: Because amiodarone generates free radicals that may mediate amiodarone's toxicity, simultaneous therapy with an antioxidant might be beneficial if the antioxidant did not impair amiodarone's antiarrhythmic action. We tested whether simultaneous administration of a flavonoid antioxidant, silymarin, altered the electrophysiologic (EP) actions of amiodarone in 62 open chest dogs with electrically induced atrial flutter created by a Y-shaped right atrial incision. METHODS AND RESULTS: Fifteen dogs received oral amiodarone (600 mg/day); 15 dogs received amiodarone (600 mg/day) and silymarin (70 mg bid); and 8 dogs received silymarin (70 mg bid) alone. All dosing was for 8 weeks; 24 control dogs received no drugs prior to induction of atrial flutter. Atrial flutter was induced by rapid right atrial pacing, and EP measurements were made before (presurgical) and after (postsurgical) creation of a Y-shaped right atrial incision. There was no difference in the frequency of induction of atrial flutter lasting >30 minutes among amiodarone-treated (8/15 [53%]), silymarin-treated (4/6 [67%]), and control (15/21 [71%]) groups, whereas the frequency of induction in the amiodarone+silymarin dogs (2/15 [13%]) was significantly reduced (P = 0.008) compared with the other three groups. Both amiodarone and amiodarone+silymarin treatment prolonged the presurgical and postsurgical right atrial effective refractory period (P = 0.012) compared with control; however, there was no significant difference in either parameter between the amiodarone+silymarin-treated and amiodarone-treated groups. The increase in atrial flutter mean cycle length (postsurgical minus presurgical) was significantly (P = 0.005) less in the amiodarone+silymarin-treated and control dogs compared with the amiodarone-treated dogs (16 +/- 11 msec for amiodarone+silymarin; 24 +/- 8 msec for control; and 42 +/- 14 msec for amiodarone treatment). Amiodarone+silymarin treatment resulted in a longer postsurgical right atrial refractory period (155 +/- 13 msec) than atrial flutter mean cycle length (154 +/- 19 msec), consistent with reduction and/or elimination of the excitable gap. Silymarin alone did not exert significant EP or antiarrhythmic action. CONCLUSION: Amiodarone exerted no preventative antiarrhythmic action in this atrial flutter model, probably because it could not reduce the excitable gap of atrial flutter. However, an antioxidant, silymarin, without a direct antiarrhythmic action, when administered together with amiodarone, potentiated amiodarone's antiarrhythmic actions and prevented sustained atrial flutter by reduction and/or elimination of the excitable gap.