Nelson D. Mostow

Amiodarone pulmonary toxicity.

Of the side effects that complicate amiodarone therapy, pulmonary fibrosis is potentially the most serious. Therefore, the development of techniques to predict the onset of this troublesome reaction would be of great practical value. Reports of 39 patients who developed pulmonary toxicity with amiodarone were evaluated for clues to precipitating factors and information on the response to corticosteroid treatment. The majority of patients were being given maintenance doses greater than 400 mg/day. Patients appeared to improve after withdrawal of amiodarone, both with and without corticosteroid treatment. In addition, a case report is presented of a patient who developed pulmonary changes that disappeared when amiodarone was withdrawn and did not recur when amiodarone was reinstituted. Data from sequential pulmonary function tests and cumulative amiodarone dosage in 35 patients were also examined to determine their value in predicting pulmonary complications. Pulmonary function tests did not appear to be useful in predicting the likelihood of an individual patients developing pulmonary complications. Although none of the available information identifies the mechanism mediating amiodarone pulmonary toxicity, the frequency of the complication probably can be reduced by timely reductions in maintenance dosage.

A general overview of amiodarone toxicity: Its prevention, detection, and management

Although amiodarone is a highly effective antiarrhythmic agent, it has a high incidence of side effects, some of which can be serious or even lethal. With close monitoring, side effects can be found in essentially all patients, but fortunately most of these are mild and well tolerated. Furthermore, many will respond to dosage reduction in a relatively short period of time, ie, days to weeks, which is remarkable considering the long period of time amiodarone has been shown to persist in tissues. There is reasonable evidence that toxicity, particularly the early toxic manifestations with large loading dosages, can be favorably modified by reducing the dosage. Similarly, reducing the maintenance dosage will, in most instances, reduce or eliminate most toxic manifestations. The mechanisms of toxic effects are uncertain, but suggestive evidence exists for and against both an immunologic reaction and an intracellular lysosomal lipoidosis. Principles of use of amiodarone should include individualizing administration of dosages for each patient due to the unusual pharmacokinetic properties of this drug and continuous long-term attempts at using the lowest effective dosage. There are no definite tests that predict amiodarone efficacy or toxicity, but the serum level can be used as a rough guide of absorption and distribution in the attempt to minimize the maintenance dosage. No guidelines regarding screening tests for toxicity can be made at this time since great variability in these tests has been reported, and no evidence exists for their benefit in preventing adverse effects to amiodarone. However, follow-up testing at the intervals noted in the package insert are reasonable and important. The possibility of interactions with drugs already reported and with others not yet reported should always be kept in mind, and appropriate monitoring for clinical evidence of toxicity due to the concomitantly used drugs should be undertaken. Amiodarone can have a tremendous beneficial effect in the proper circumstances, but it is a drug that should command utmost respect because of its side effects and requires constant vigilance from any physician wishing to use it.

Cardiac Rupture in Takotsubo Cardiomyopathy: A Systematic Review

Takotsubo cardiomyopathy (TSC) and its complications, such as cardiac rupture (CR), are increasingly being reported in the literature. CR is associated with rapid clinical decline and is uniformly fatal if not surgically repaired. To identify patients who developed CR we performed an analysis of all available indexed cases in the literature and compared them with a control group of patients with TSC without rupture.

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.

Amiodarone: Correlation of serum concentration with suppression of complex ventricular ectopic activity

Although amiodarone has been used for the suppression of complex ventricular arrhythmias since the early 1970s, there is a paucity of information regarding the relation of serum concentration to arrhythmia suppression. To investigate this relation, 25 patients receiving chronic amiodarone therapy for complex ventricular arrhythmias were retrospectively studied. At each visit a blood sample for determination of trough serum amiodarone concentration and a 24-hour 2-channel ambulatory electrocardiogram (ECG) were obtained. Dosage was adjusted, based on the ambulatory ECG, to maintain arrhythmia suppression at the lowest possible amiodarone dose and, hence, because of the extremely long half-life of amiodarone, patients were rarely in a true steady state. Over 17 months, 218 ambulatory ECGs with corresponding serum samples were analyzed. Negative correlations between serum amiodarone concentration and the frequencies of premature ventricular complexes (PVCs), paired PVCs and ventricular tachycardia were found (p less than 0.005, p less than 0.005 and p less than 0.05, respectively). No correlations existed between amiodarone dose and these arrhythmias. Trough serum amiodarone concentrations greater than 2.0 micrograms/ml were associated with significant reductions in the frequencies of PVCs (p less than 0.01) and paired PVCs (p less than 0.02) when compared with serum concentrations below this level. A reduction in ventricular tachycardia was seen with serum concentrations greater than 1.5 micrograms/ml (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of amiodarone and its n-deethylated metabolite in serum by high-performance liquid chromatography

A high-performance liquid chromatographic (HPLC) method utilizing hexane extraction and a normal bonded phase column (NH2-alkylamine) was developed to measure serum concentrations of amiodarone and its N-deethylated metabolite. A single analysis requires 8 min. The one-step extraction efficiencies of amiodarone and the internal standard are greater than 90%. The method is linear between 0.05 and 20.0 micrograms/ml. The average relative standard deviation of the slope of the standard curve is 4% and the single day coefficient of variation is 3.2%. The use of hexane extraction for sample cleanup and a bonded phase column for chromatography result in a sensitive and reproducible system well suited to laboratories monitoring serum concentrations of multiple drugs by HPLC. A preliminary study has shown the assay to be useful for the investigation of the pharmacokinetics of this agent.

Rapid control of refractory atrial tachyarrhythmias with high-dose oral amiodarone

To shorten the delay in the onset of antiarrhythmic effect when using amiodarone for the conversion of refractory atrial tachyarrhythmias to sinus rhythm, 19 patients were given oral amiodarone according to a high-dose loading protocol. In 18 of 19 patients (95%), sinus rhythm was restored 36 hours (range, 0 to 96 hours) after starting amiodarone. The conversion occurred as a result of amiodarone therapy alone within 48 hours in 12 patients (63%), and by amiodarone therapy plus electrical cardioversion at 48 to 96 hours in six patients (32%). Minor side effects were noted in eight patients (42%). No major side effects were encountered. The length of hospital stay after initiating amiodarone therapy was 3.6 days (range, 2 to 5 days). High-dose oral amiodarone loading is a safe and effective method for the rapid conversion of atrial tachyarrhythmias to sinus rhythm.

Quick Resolution of Takotsubo Cardiomyopathy: A Brief Review

Takotsubo cardiomyopathy is characterized by transient mid‐ and apical ventricular dysfunction disguising as acute coronary syndrome but carries a good prognosis. Though spontaneous resolution is common, clinical manifestations may last weeks. We describe a case of quick resolution of left ventricular dysfunction and clinical symptom. We also reviewed the literature regarding timing and possible sources of variation in improvement in ventricular function.

Determination of α-tocopherol in rat liver by high-performance liquid chromatography utilizing ultraviolet detection

A rapid, sensitive analytical procedure was developed to quantitate alpha-tocopherol in rat liver. Liver is homogenized in acetone, fractionated by reversed-phase high-performance liquid chromatography and alpha-tocopherol quantitated by monitoring the column effluent at 280 nm. A single analysis requires 18 min. The method is linear from 1.0 to greater than 30.0 micrograms alpha-tocopherol per g of liver (wet weight). The average relative standard deviation of the slope of the standard curve is 2.3% and the single-day coefficient of variation is 6.3%. The use of an acetone extraction, reversed-phase column chromatography and quantitation of alpha-tocopherol at 280 nm results in a sensitive and reproducible system for the determination of alpha-tocopherol concentrations in rat liver. Preliminary studies have shown the assay to be useful for investigation of the effects of age and diet on hepatic alpha-tocopherol concentration.

Pathology findings mimicking acute myocardial infarction in a case of Takotsubo cardiomyopathy complicated by cardiac rupture.

To the Editor Takotsubo cardiomyopathy (TTC) is a transient condition characterized by left ventricular apical ballooning, electrocardiographic changes and mild cardiac enzyme release in nonobstructive coronary artery disease (CAD). Although prognosis is usually good, cardiogenic shock, life-threatening arrhythmias and cardiac rupture can occur. The definitive cause of TTC is still unknown and several mechanisms have been proposed, including multivessel epicardial spasm, myocardial dysfunction