SUMMARY During periods of tachycardia induced by atrial pacing in eight patients, moderate increments in dP/dt(max) and (dP/dt)/CPIP (common produced intraventriciilar pressure) and moderate reductions in left ventricular ejection time (LVET) and Q-S2 were demonstrated. These changes varied between individuals, but reduction in systolic intervals was consistently less than that reported from populations showing a range of resting heart rates. Individual regression formulae relating each variable to paced heart rate were used to calculate rate-dependent and rate-independent changes induced by isoprenaline and ouabain. Despite technical difficulty in precise measurement of systolic intervals, there was an excellent inverse correlation between rate-independent changes in Q-S2 and in both dP/dt(max) and (dP/dt)/CPIP. Rate-independent change in Q-S2 appears to be a practical, moderately sensitive, and reasonably precise measure of the inotropic effect of a drug which does not radically alter left ventricular end-diastolic pressure or blood pressure; Day-to-day variation in systolic intervals may limit the use of the technique to studies of short duration.Determination of the inotropic activity of a drug essentially belongs to the animal laboratory, but confirmation of this activity, and particularly characterisation of its dose-response effects in man, is a necessary prelude to its rational clinical employment. Direct measurement of changes in contractile activity and pumping function of the left ventricle presently furnish the most accurate indication of alterations in inotropic activity.1-3 Cardiac catheterisation, however, is cumbersome, limited by ethical considerations, and often of such brevity as to preclude the measurement of duration of activity of a drug or its dose-response effects. Non-invasive methods have therefore been sought as a means of making repeated measurements of left ventricular activity; among such methods measurement of the duration of the various components of systole has been the most widely acclaimed.46 The utility of these methods, however, in evaluating changes in left ventricular activity induced by drugs has yet to be fully tested. It was the purpose of this study, therefore, to evaluate the precision by which measurements of non-invasive systolic time intervals reflect changes in intraventricular pressure before and after the administration of drugs known to increase motropic activity. Subjects and methodsFour normal subjects (aged 20 to 35 years), and six male and two female patients (aged 23 to 45 years) admitted for the investigation of chest pain were studied. All were in sinus rhythm. In the patients, radiographic cardiac silhouette was normal. Electrocardiograms at rest and during treadmill exercise up to heart rates of 160 beats per minute were normal in all. Left ventricular end-diastolic pressure during supine leg exercise did not exceed 25 mmHg. None was receiving drugs at the time of the study. Informed consent was obtained from all patients. DESIGN OF INVESTIGATIONThe fou...

In a group of8 volunteers, peak plasma digoxin concentrations and areas under 8o-hour plasma concentration curves were significantly greater after i mg digoxin in paediatric elixir

Digoxin absorption was studied in healthy volunteers by determination of peak plasma concentrations, areas under plasma concentration curves, and urinary excretion after single-dose administration. By comparison with an aqueous solution, increased rate and extent of absorption occurred from experimental soft gelatin formulations of digoxin in solution. Enhanced bioavailability of the capsules was not affected by altered volume of contained solvent. Digoxin was considerably better absorbed from capsules than from tablets of moderately high dissolution rate. Mean percentage intestinal absorption was 75% from tablet and 97% from capsules. Reduced between-subject variability accompanied the enhanced absorption from capsules.

I The tendency of a given oral dose of digoxin to induce cardiac dysrhythmia was determined indirectly at various times after its administration to eight conscious dogs by measurement of the intravenous dose of acetylstrophanthidin necessary to induce toxic changes in the ECG. Acetylstrophanthidin was used because its rapid elimination from the body permitted estimates to be made 45, 180 and 360 min after digoxin administration. 2 Each dog underwent four studies in which doses of 0.05, 0.1, 0.2 and 0.4 mg/kg digoxin were used in a randomized sequence allowing at least ten days between each dose. 3 Digoxin reduced the amount of acetylstrophanthidin required to cause toxic changes in the ECG; this increase in cardiac sensitivity was dose-dependent. 4 There was no correlation between plasma levels of digoxin and the tendency to dysrhythmia, since peak plasma concentrations of digoxin were reached at about 60 min after dosing whereas maximal sensitivity to acetylstrophanthidin was found 3 to 6 h after administration of digoxin. 5These results suggest that there is little or no increased risk of cardiotoxicity during periods of transient increase in plasma levels ofdigoxin.

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