No abstract

SUMMARY The possible existence of kinetic interactions between rifampicin and isoniazid and the effect of the concomitant presence of an impaired liver function were investigated in man.In a first study normal healthy subjects and patients with chronic liver disease received, on three different occasions, a single dose of 600 mg rifampicin or isoniazid and of rifampicin and isoniazid associated in randomized sequences. The results have shown that in both groups the serum levels, half-life values, and urinary excretion of each drug given alone are not significantly different from those observed when the other drug is associated. Serum levels and half-life of rifampicin and isoniazid were significantly higher in patients with chronically impaired liver.In a second study, rifampicin and isoniazid were given in combination at the same doses as in the first study over a period of one week. The results have shown a trend to decrease in the serum levels of rifampicin of the healthy subjects and a trend to increase in the patients with chronic liver disease on day 7 of treatment. In both groups a reduction in the half-life of rifampicin was also observed. No changes in serum isoniazid concentrations were observed between day 1 and day 7 in the healthy subjects, whereas a significant increase was observed in the patients. No significant changes in the half-life of isoniazid were observed.

In a selected group of 10 apparently healthy subjects and 22 patients with organic heart disease, all with frequent ventricular ectopic beats on Holter monitoring, we assessed the influence of sympathetic activation by comparing the arrhythmogenic effects of a symptom-limited bicycle exercise stress test and 90 degree head up tilt. Tilting reduced ventricular arrhythmias in the normal subjects (-48 +/- 18% from 9 +/- 2 beats min-1, P less than 0.05). Exercise stress testing caused small and insignificant changes in arrhythmias during the early (50-75 W) phases and an almost complete suppression of ventricular ectopic beats in the final stages (-99 +/- 1%, P less than 0.01). In six of the 10 subjects, ventricular arrhythmias reappeared in the early recovery phase. In the 22 patients with organic heart disease, tilting increased ventricular ectopic beats (43 +/- 17% from 9 +/- 3 beats min-1, P less than 0.05); augmented repetitive forms in 12 patients (179 +/- 88% from 1.4 +/- 0.6 per 3 min) and produced repetitive forms in six of the 10 remaining patients who did not show repetitive forms during control conditions. Exercise stress testing caused a marked increase in ectopic activity in the early phase (84 +/- 35%) while the response during the maximal phase of exercise as well as during recovery was related to the effort capabilities. Arrhythmias were increased in 12 patients with limited exercise duration and were reduced in 10 patients with good exercise tolerance. These data indicate that sympathetic activation has different effects on ventricular arrhythmias depending on the clinical setting and that tilting is a useful maneuver to evaluate the arrhythmogenic effects of increased sympathetic activity.

To determine whether enhanced sympathetic activity could alter a non-invasive index of cardiac instability, we analysed the effects of 90 degrees head-up tilt and submaximal exercise stress test on high amplification signal-averaged electrocardiogram in 64 patients after acute myocardial infarction. At rest, ventricular late potentials were detected in 25% of patients, characterized by a significant prolongation of filtered QRS complex (137 +/- 3 vs 115 +/- 2 ms) and of its components smaller than 40 microV (38 +/- 2 vs 16 +/- 1 ms), as well as by a reduced root mean square voltage calculated for the terminal 40 ms of QRS complex (RMS40 voltage) (19 +/- 1 vs 75 +/- 9 microV) in comparison to patients without micropotentials. Sympathetic activation induced by tilt caused a significant increase in heart rate (from 67 +/- 3 to 79 +/- 3 beats min-1) but did not modify either the incidence of ventricular late potentials or the values of any of the signal-averaged electrocardiogram parameters considered. In 19 patients, recordings were also obtained during a submaximal bicycle exercise stress test at a heart rate of 114 +/- 4 beats min-1 and with systolic arterial blood pressure at 153 +/- 6 mmHg. No effect on signal-averaged electrocardiogram parameters was detectable during this experimental intervention. These data indicate that after myocardial infarction, sympathetic activation does not seem to modify signal-averaged electrocardiogram parameters.