Effect of low oral doses of disopyramide and amiodarone on ventricular and atrial arrhythmias of chagasic patients with advanced myocardial damage.

Low-dose (7 mg/kg per day) disopyramide administration to arrhythmic chagasic patients decreased the frequency of ventricular extrasystoles in 4 of 17 patients (24%) and suppressed most complex ventricular arrhythmias in 12 of 15 patients (80%). This assessment was made from 72-h continuous Holter monitoring recorded during the course of this double blind, placebo-controlled randomized crossover study. Seven patients (41%) complained of anticholinergic side effects, but no contractile or conduction system depression was seen. Amiodarone (200 mg) given on a single blind, placebo-controlled basis to 9 of these patients reduced the frequency of ventricular extrasystoles in 6 of 9 patients (67%) and suppressed complex ventricular ectopy in 6 of 7 patients (85%). One patient was unable to tolerate this drug (11%). Both drugs seemed less effective in controlling supraventricular arrhythmias, although disopyramide eliminated paroxysms of supraventricular tachycardia in 9 of 13 (69%) and amiodarone in all 6 patients with this arrhythmia. Amiodarone appears to be a better antiarrhythmic drug for chagasic patients, due to its greater effectiveness and lower incidence of side effects.

Dose-dependence of the apparent half-life of phenytoin in the rat.

The effect of dose on phenytoin pharmacokinetics was examined in the rat. In a randomized study on nine animals (not crossed over) it was observed that the apparent half-life ((t 1/2) of this drug increased four-fold as dose was increased from 10 to 50 mg/kg (6 1/2 - 64 +/- 42 min vs. 267 +/- 118 min, respectively; mean +/- S.D.). In a crossover study on three animals, an even larger dose-dependent increase in t 1/2 was observed (37.8 vs. 271 min). Finally, six animals received the 10 and 50 mg/kg doses in a randomized crossover fashion and urine was collected for 72 hours. A dose-dependent decrease in the fraction of the dose excreted as conjugates of 5-(p-hydroxyphenyl)-5-phenylhydantoin (59 +/- 20 vs. 39 +/- 12%) was found. It is concluded that phenytoin pharmacokinetics in the rat are non-linear but that a simple one compartment Michaelis-Menten model cannot account for the observed behavior.

Impaired theophylline clearance in patients with cor pulmonale.

1 The relationship between serum theophylline concentration and daily dose was studied in 45 patients receiving aminophylline orally and in 36 patients receiving it by constant intravenous infusion. 2 Patients were categorized as uncomplicated chronic obstructive pulmonary disease (COPD) or COPD with cor pulmonale (CP). 3 Serum theophylline concentration relative to daily theophylline dose was significantly higher in patients with COPD plus CP than in patients with COPD alone. 4 Total body clearance of theophylline estimated from data obtained during constant intravenous infusion was significantly lower in COPD plus CP than in patients with COPD alone. 5 We conclude that reduced maintenance doses of theophylline are indicated in patients with COPD when complicated with CP.

Dose-dependent pharmacokinetic behavior of lidocaine in the conscious dog.

The apparent steady state blood concentration of lidocaine in dogs depends on the animal's lidocaine treatment history. For example, an infusion of 50 microgram/Kg/min X 240 min followed immediately by an infusion of 125 microgram/Kg/min X 240 min yields steady state lidocaine levels which are consistent with a linear drug dispositional system. However, when the sequence of these infusions is reversed the apparent steady state level during the low infusion rate step is much greater than those predicted from the steady state level observed during the high infusion rate (assuming a linear dispositional model). These data suggest that high dose lidocaine infusion treatment alters the dog's ability to clear lidocaine during a subsequent low infusion rate treatment period.

Bupivacaine and other amide local anesthetics inhibit the hydrolysis of chloroprocaine by human serum.

The rate of hydrolysis of chloroprocaine by human serum was studied in the presence and absence of a number of aminde local anesthetics and their metabolites. Bupivacaine (2.4 microgram/ml) and etidocaine (2.3 microgram/ml) caused 38% and 21% inhibition respectively of the rate of chloroprocaine hydrolysis. Circulating concentrations of these drugs have been reported in this range by several investigators following epidural doses of 150 to 400 mg of either drug. Mepivacaine, lidocaine, and two lidocaine metabolites (glycine xylidide and monoethylglycine xylidide) were only inhibitory at levels much greater than those seen in blood following the usual local anesthetic doses of the parent compounds. Since serum is an important site of chloroprocaine metabolism in man, the probability of chloroprocaine intoxication may be increased when it is administered with local anesthetics such as bupivacaine and etidocaine.