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Clinical evaluation of bidisomide, a new class I antiarrhythmic: Initial intravenous dose‐finding study
Author(s) -
Li Moreno Fidela,
Summers Kaye L.,
Menlove Ronald L.,
Claypool William D.,
Cox James R.,
Garthwaite Susan M.,
Karagounis Labros,
Anderson Jeffrey L.
Publication year - 1992
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430270304
Subject(s) - tolerability , body weight , medicine , anesthesia , zoology , chemistry , adverse effect , biology
To assess effectiveness and tolerability of intravenous bidisomide, 16 patients (aged 57 ± 15 years) with ≥ 100 premature ventricular complexes (PVCs)/hr received a 10‐min infusion of bidisomide at 0.4 (n = 4), 0.75 (n = 4), 1.0 (n = 4), or 1.35 (n = 4) mg/kg body weight. Mean PVCs and repetitive beats per 3 and 15 min (± SD) from 2 hr pre‐ and 2 hr postdosing were determined and averaged after logarithmic transformation. Results: Group response assessed from 3‐min rhythm strips showed PVC reduction to be apparent at 15 min (48.2%, P = 0.06), significant at 30 min (57.2%, P = 0.02), maximal at 45 min (59.3%, P = 0.005), and declining at 60 min (48.8%, P = 0.06). Individual PVC reduction (> 70%) was observed in 0/4 (0%) at 0.4 mg/kg, 3/4 (75%) at 0.75 mg/kg, 3/4 (75%) at 1.0 mg/kg, and 3/4 (75%) at 1.35 mg/kg. Comparison of the log (PVCs per 3 min) showed a significant difference between lowest dose (0.4 mg/kg) and the higher doses (0.75 to 1.35 mg/kg) ( P = 0.04). Individual reduction assessed on a 48‐hr Holter monitor was observed in 0/4 (0%) at 0.4 mg/kg, 2/4 (50%) at 0.75 mg/kg, 1/4 (25%) at 1.0 mg/kg, and 3/4 (75%) at 1.35 mg/kg. Comparison of the log (PVCs per 15 min) at various time points also showed a significant difference between the lowest dose (0.4 mg/kg) and the higher doses ( P = 0.05). Analysis of log (PVCs/hr) in the succeeding 3 to 48 hr postdosing did not show a significant difference in PVC frequency compared to baseline. PR and QRS intervals increased significantly at 15 min ( + 5.4% for PR, + 6.8% for QRS, P < 0.05), and at 30 min ( + 5.3% for PR, + 4.8% for QRS, P < 0.05), returning to baseline by 90 min. RR and QT intervals did not change. Vital signs were stable and no evidence of any adverse hemodynamic effect was noted. No significant side effects occurred. Peak plasma bidisomide levels showed a dose response (1.7 ± 0.7, 2.8 ± 1.3, 5.4 2 0.3, 5.7 ± 1.7 μg/ml, doses 1 to 4 respectively, P = 0.0007). Similar results were obtained when the area under the curve (AUC) values were analyzed. Thus, bidisomide was well tolerated and effective in reduction of PVCs in single IV doses ≥ 0.75 mg/kg, associated with small increases in PR and QRS intervals. © 1992 Wiley‐Liss, Inc.