The acute electrophysiological and haemodynamic effects of UK-52,046, a novel otl-adrenoceptor antagonist (0.5 ,ug kg-') were studied in 10 patients. Resting and paced conduction intervals, refractory periods, Wenckebach cycle length and sinus node recovery time were measured and compared with baseline values. Haemodynamic measurements including cardiac output were measured before and after drug administration. Changes in QRS interval (83 to 105 ms) and QRS duration during sinus rhythm (83 to 105 ms) or during constant atrial pacing (85 to 109 ms), were not significant (P > 0.05). Myocardial refractoriness and sinus node recovery time were not altered by the drug.Slight increases in mean heart rate (72.5 to 78.8 beats min-'), mean right atrial pressure (4.5 to 5.5 mm Hg) and mean cardiac output (5.4 1 min-1 to 5.7 1 min-'), were not significant (P > 0.05). Systolic and diastolic arterial pressure, cardiac work indices, and vascular resistance remained unchanged. These results demonstrate the safety of this drug given intravenously in a non-ischaemic setting, and warrant its further investigation as an antiarrhythmic agent in myocardial ischaemia.
One hundred and sixty-nine patients with a wide range of cardiac arrhythmias and who had been treated with chronic oral flecainide acetate were reviewed retrospectively. The most common arrhythmia was atrial fibrillation (32%), and 20% of the patient population had the Wolff-Parkinson-White syndrome. Five hundred and three treatment episodes were assessed, 254 with flecainide alone or in combination, mean duration 7.3 +/- 9.4 months, and 249 without flecainide, mean duration 9.5 +/- 12.3 months. The most common dose for flecainide was 200 mg/day (57% of episodes), and it was used alone in 82% of flecainide treatment episodes. Arrhythmia frequency was reduced or abolished in 73% of flecainide treatment episodes, with little difference between arrhythmia groups. Unwanted effects were seen in 14% of flecainide treatment episodes, and half of these cases were managed by dose adjustment. It is concluded that flecainide acetate is effective in a wide range of cardiac arrhythmias, and that long-term management problems are few.
Twenty one patients with NYHA class II-III congestive heart failure received single ascending doses of 0.5, 1.25 and 2.5 mg cilazapril daily followed by the minimum effective dose for six weeks. Fifteen patients completed the study, but the data from only 11 were sufficiently complete for kinetic evaluation. The pharmacokinetics of the metabolite, cilazaprilat, after a single dose of 0.5 mg cilazapril were similar to previous observations in healthy volunteers at identical dosage. Repeat administration, however, led to greater accumulation than previously observed in volunteers at the higher dosages of 1.25 or 5 mg given for 8 days. Seven patients experienced adverse events. Four were severe, leading to withdrawal of the patients from the study, but only one event was related to cilazapril. Of the other three, one suffered a myocardial infarction and subsequently died due to worsening congestive heart failure. One other patient was withdrawn with two adverse events probably related to cilazapril. No other deaths occurred amongst the study population, and there were no significant abnormalities in haematology or blood chemistry.
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