benzofurans and butoprozine

All detectable biliary butoprozine metabolites can be separated with a specially developed analytical approach based on gradient-elution reversed-phase h.p.l.c. without extraction steps. The high reproducibility of the h.p.l.c. systems allows preliminary intra- and inter-species comparisons based on retention times with single wavelength u.v. detection. Diode array u.v. spectrometry, radioactivity and mass-spectrometric measurements wee used to confirm the metabolic character of peaks in an individual chromatogram, and to obtain more evidence for the structure of metabolites with the same retention time in chromatograms of different bile fractions. Large inter-species differences in the biliary metabolic profiles are seen, indicating that great care must be exercised when trying to extrapolate preclinical drug safety evaluations from animals to man.

Topics: Aged; Amiodarone; Animals; Anti-Arrhythmia Agents; Benzofurans; Bile; Chromatography, High Pressure Liquid; Dogs; Female; Humans; Male; Mass Spectrometry; Middle Aged; Papio; Rats; Rats, Inbred Strains; Species Specificity

The purity analysis of butoprozine is described. Both gas chromatography-mass spectrometry (GC-MS) and high pressure liquid chromatography (HPLC) with UV-vis detection (conventional and multichannel) were used. In the butoprozine example disadvantages for both techniques became apparent: incorrect conclusions with regard to the purity of the drug would have been drawn if only one of these chromatographic techniques had been used. GC-MS allowed the identification of an impurity not found by HPLC.

Topics: Amiodarone; Benzofurans; Chromatography, High Pressure Liquid; Drug Contamination; Gas Chromatography-Mass Spectrometry; Spectrophotometry, Ultraviolet

Electrophysiological effects of butoprozine (L 9394 Labaz) were investigated on the anaesthetized dog by programmed electrical stimulation of the heart and simultaneous recording of the His bundle electrogram and monophasic action potentials from the auricular and ventricular endocardial wall. Butoprozine injected intravenously depressed sino-atrial node function, lengthened A-V nodal conduction time and the A-V nodal refractory period, and prolonged the atrial refractory period. Thus butoprozine acted preferentially on parts of the myocardial tissue where the slow inward current seems to be particularly involved. In this respect, butoprozine was more active than amiodarone, but in contrast to this drug, butoprozine did neither prolong the ventricular monophasic action potential duration nor the ventricular refractory period. In the anaesthetized dog both drugs have practically analogous actions except at the ventricular level, which suggests that their effect on ionic currents at this level may be different.

Topics: Amiodarone; Anesthesia; Animals; Atrioventricular Node; Benzofurans; Blood Pressure; Dogs; Electrophysiology; Female; Heart; Male; Purkinje Fibers; Time Factors

The effects of butoprozine on cardiac membrane currents of frog atrial and ferret ventricular fibres were investigated in voltage clamp conditions by means of the double sucrose gap technique. Comparison was made with amiodarone and verapamil. Butoprozine was found to decrease the fast sodium and slow calcium inward currents and the delayed outward current in a dose-dependent manner. The reactivation kinetics of both inward currents were reduced by butoprozine. Amiodarone principally decreased the delayed outward current but high concentrations also depressed the inward currents. In the same way, small concentrations of verapamil inhibited the slow inward calcium current while high concentrations also affected the delayed outward and the fast inward sodium currents. The reactivation kinetics of both inward currents were reduced by amiodarone. These of the fast inward current remained unaffected by verapamil while these of the slow inward current were reduced or sometimes not appreciably changed. The effects of butoprozine on the ionic currents accounted for the modifications observed on the action potential and automaticity and this study allowed the understanding of the mechanisms by which the drug can exert its antiarrhythmic action. Some of them are common to amiodarone and verapamil.

Topics: Amiodarone; Animals; Anti-Arrhythmia Agents; Benzofurans; Ferrets; Heart; In Vitro Techniques; Ion Channels; Membrane Potentials; Rana esculenta; Verapamil

The electrophysiological effects of butoprozine, a relatively new antiarrhythmic agent, were investigated in sheep cardiac Purkinje fibres using a microelectrode technique and in frog atrial and ferret ventricular fibres using a double sucrose gap technique. Comparison was made with amiodarone and verapamil. Butoprozine increased the action potential duration like amiodarone, depressed the plateau phase like verapamil and decreased the amplitude and the maximum rate of depolarization. Pacemaker activity in Purkinje fibres and repetitive activity in frog atrium were inhibited by the three drugs. The inhibition of automaticity was related to a reduction of the slope of diastolic depolarization in both tissues by butoprozine and amiodarone. The results confirm that butoprozine possesses a potent antiarrhythmic activity. It acts by mechanisms common to amiodarone and verapamil.

Topics: Action Potentials; Amiodarone; Animals; Anti-Arrhythmia Agents; Benzofurans; Ferrets; In Vitro Techniques; Membrane Potentials; Purkinje Fibers; Rana esculenta; Sheep; Verapamil

Topics: Amiodarone; Animals; Anti-Arrhythmia Agents; Benzofurans; Bile; Chromatography, High Pressure Liquid; Dogs; Spectrophotometry

Topics: Amiodarone; Animals; Benzofurans; Calcium; Guinea Pigs; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth, Vascular; Myocardial Contraction; Myocardium; Rats

A systematic approach to the investigation of metabolic degradation of drugs is presented. Extraction of the biological sample is avoided by direct injection of bile or urine in a reversed-phase high-performance liquid chromatography system. Good separation of the various metabolites is obtained by changing the composition of the mobile phase so that all components become separated from the solvent front and are eluted from the column. The metabolites can be detected by measuring the amount of radioactivity in the column effluent, which also serves as a check on the overall recovery. Simultaneous registration of the UV absorbance permits certain conclusions to be drawn with regard to the nature of the metabolites. This approach is illustrated in the screening for metabolites of Butoprozine, a new anti-anginal drug, in rat bile. Essentially, all metabolites could be followed by suitable adaptations of the mobile phase, thus providing a metabolid profile with a recovery of 95% of the radioactivity.

Topics: Amiodarone; Animals; Benzofurans; Bile; Cardiovascular Agents; Chromatography, High Pressure Liquid; Male; Rats

The effects of L 9394, a new compound closely related to amiodarone, were investigated in 44 patients by electrophysiological studies. Thirty two patients were given an intravenous injection of one of the following doses: 0.5, 1, 1.5 or 2 mg/kg. Conduction times of the A-V node (A-H interval) and of the His-Purkinje system (H-V interval) were measured by recording the His bundle potential. Refractory periods were determined by the extrastimulus technique. In the remaining 12 subjects, the action of L 9394 on sinus node was assessed. Sinus node recovery time was measured by rapid atrial stimulation and estimated atrial-sinoatrial conduction time deduced from the effects of atrial premature stimulation on sinus node activity. Results were as follows: (1) A-V nodal conduction was depressed after L9394. The A-H interval increased in direct proportion to the dose. Similarly, the effective and functional refractory periods of the A-V node were prolonged, more markedly after higher doses. (2) No change was shown in the His-Purkinje system. The H-V interval was unaltered. (3) L 9394 had no significant effects on the atrial or ventricular muscle. (4) Sinus cycle length as well as sinus node recovery time did not change significantly. In 7/12 patients, results of premature atrial stimulation suggested the formation of a sinoatrial block.

Topics: Adult; Aged; Amiodarone; Anti-Arrhythmia Agents; Atrioventricular Node; Benzofurans; Dose-Response Relationship, Drug; Female; Heart Conduction System; Humans; Male; Middle Aged; Refractory Period, Electrophysiological; Sinoatrial Node; Time Factors