Amiodarone is an iodinated benzofuran derivative with recognised antiarrhythmic activity in man. As yet, its pharmacokinetic behaviour has not been satisfactorily characterised. Specific and sensitive high-pressure liquid chromatographic methods have become available only recently and this partly explains the scarcity of pharmacokinetic data on the drug. Available evidence suggests that absorption of amiodarone following oral administration is erratic and unpredictable; oral bioavailability ranges from 22 to 86%. The drug is eliminated largely by metabolism; less than 1% of the dose is excreted unchanged in the urine. Biliary excretion may have a role in the overall elimination of the drug. Desethyl-amiodarone is the only metabolite positively identified in the plasma of patients receiving treatment with amiodarone; no data are available on its possible pharmacological activity. Since it is a highly lipophilic drug, amiodarone is extensively distributed into tissues. Adipose tissue and skeletal muscle accumulate large amounts of the drug during long term treatment. Myocardium/plasma ratios of amiodarone are high both in man and in animals; peak concentrations in the myocardium are reached within half an hour after administration of an intravenous bolus to dogs. Placental transfer of amiodarone has been demonstrated in humans, while its blood profile is not modified by dialysis treatment. In vitro protein binding of amiodarone has been reported to be 96.3 +/- 0.6%. The plasma half-life of amiodarone after single-dose administration has been reported to be in the range of 3.2 to 79.7 hours. However, after withdrawal of long term amiodarone treatment the half-life is as long as 100 days. Total body clearance ranges from 0.10 to 0.77 L/min after single-dose intravenous administration, and the apparent volume of distribution ranges between 0.9 and 148 L/kg. Amiodarone disposition kinetics in patients with cardiac arrhythmias are not different from those in healthy volunteers. However, the possible effects of liver and cardiac failure on the drug's kinetics have not been studied. Amiodarone potentiates the anticoagulant effect of warfarin, probably by inhibition of its metabolism. Increases of steady-state concentrations of digoxin, together with the appearance of signs of digitalis toxicity, have been reported when amiodarone was given to patients receiving long term treatment with digoxin. Amiodarone has also been shown to interact with other antiarrhythmic agents such as quinidine and procainamide. The time of onset of action of amiodarone after a single intravenous dose ranges between 1 and 30 minutes and its duration of effect between 1 and 3 hours.(ABSTRACT TRUNCATED AT 400 WORDS)

We determined the efficacy, pharmacokinetics, and plasma concentration-response relationships of propafenone, a promising new antiarrhythmic drug. Thirteen patients with frequent and complex ventricular premature beats were studied after receiving four increasing doses, during drug washout and during a randomized double-blind placebo-controlled trial, to evaluate the optimal dose in each patient. A nonlinear relationship was found between propafenone dose and steady-state mean concentration with a 10-fold increase in drug concentration as dose increased threefold from 300 to 900 mg/day. There was great intersubject variability in elimination half-life (mean 6 hr, range 2.4 to 11.8), steady-state mean concentration on 900 mg/day of propafenone (mean 1008 ng/ml, range 482 to 1812), and "therapeutic" plasma concentration (mean 588 ng/ml, range 64 to 1044). The interaction of these three parameters in individual patients determined the duration of the antiarrhythmic action of propafenone during washout (mean 11.5 hr, range 4 to 22). There was a greater than 90% reduction of ventricular premature beats in 10 subjects during dose ranging and in seven during double-blind crossover. Side effects requiring discontinuation of the drug occurred in three patients and included apparent worsening of arrhythmias in two. We conclude that propafenone effectively suppresses ventricular arrhythmias and that nonlinear drug accumulation and intersubject variability in elimination of half-life, steady-state mean plasma concentration, and therapeutic concentration indicate a need for individual therapy. Circulation 68, No. 3, 589-596, 1983. PROPAFENONE is a promising new antiarrhythmic drug. In microelectrode experiments with guinea pig atria and sheep Purkinje cells, the drug slows the rate of rise of the action potential and decreases the action potential duration.",2 Propafenone also has weak ,Bblocking and Ca+ + antagonist properties in isolated tissues.1 Initial placebo-controlled trials in humans show that propafenone is effective for suppressing ventricular ectopic activity.4' Previous studies suggest that propafenone has a short half-life of 3 to 4 hr but that the duration of its antiarrhythmic effects may last longer.6'7 Studies with limited data have yielded con flicting information on the ability to predict antiarrhythmic effect from propafenone concentration. between plasma concentration and antiarrhythmic effect. MethodsProtocol design. Patients with high-frequency ventricular premature beats (VPBs) were candidates for this study if they did not have disabling angina, heart failure, or unstable intercurrent illness. A complete history was obtained, physical and laboratory examinations were performed, and a baseline 48 hr ambulatory electrocardiogram (ECG) was taken to establish a minimum baseline VPB frequency of B 1440 VPBs/24 hr after antiarrhythmic drugs had been discontinued for at least five half-lives. Digoxin was continued in one patient with atrial fibrillation, and propranolol was continued in one pat...

Defining the source of HIV-1 RNA in cerebrospinal fluid (CSF) will facilitate studies of treatment efficacy in the brain. Four antiretroviral drug-naive adults underwent two 48-hr ultraintensive CSF sampling procedures, once at baseline and again beginning on day 4 after initiating three-drug therapy with stavudine, lamivudine, and nelfinavir. At baseline, constant CSF HIV-1 RNA concentrations were maintained by daily entry of at least 10(4) to 10(6) HIV-1 RNA copies into CSF. Change from baseline to day 5 ranged from -0.38 to -1.18 log(10) HIV-1 RNA copies/ml in CSF, and from -0.80 to -1.33 log(10) HIV-1 RNA copies/ml in plasma, with no correlation between CSF and plasma changes. There was no evidence of genotypic or phenotypic viral resistance in either CSF or plasma. With regard to pharmacokinetics, mean CSF-to-plasma area-under-the-curve (AUC) ratios were 38.9% for stavudine and 15.3% for lamivudine. Nelfinavir and its active M8 metabolite could not be accurately quantified in CSF, although plasma M8 peak level and AUC(0-8hr) correlated with CSF HIV-1 RNA decline. This study supports the utility of ultraintensive CSF sampling for studying HIV-1 pathogenesis and therapy in the CNS, and provides strong evidence that HIV-1 RNA in CSF arises, at least in part, from a source other than plasma.

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