Studies on the Possible Mechanisms of Lidoflazine Arrhythmogenicity

742 lACC Vol 4, No 4 October 1984 742- 7 Studies on the Possible Mechanisms of Lidoflazine Arrhythmogenicity GAD KEREN, MD, DAVID TEPPER, BA, BRENDA BUTLER, BA, WILLIAM MAGUIRE, MD, PHD, HOWARD WILLENS, MD, DENNIS MIURA, MD, PHD , JOHN C. SaMBERG, MD Bronx. New York Lidoftazine is a calcium channel blocking agent that is Dogsalso underwent programmed electrical stimulation effective and safe in the treatment of angina pectoris, while not receiving medications and then after incre but has been reported to be associated with sudden death mental doses of lidoftazine administered intravenously. when administered for the treatment of supraventricular Lidoflazinedid not cause spontaneous ventricular tachy arrhythmias. Studies were performed in dogs to deter cardia and did not lower the threshold of ventricular mine if lidoflazine caused a rise in serum digoxin con tachycardia induction. Combined administration of Ii centration that could cause arrhythmias or if it was di doflazine and digoxin did not facilitate arrhythmia in rectly arrhythmogenic. Dogsreceived chronic injections duction. These studies do not support a digoxin-lido of digoxin and then digoxin in combination with lido f1azine interaction or a direct arrhythmogenic action of ftazine. No increase in digoxin concentration was found. Iidoflazine. Several clinical studies (1-3) have shown the effectiveness Thus. we undertook studies in dogs to test if a digoxin and safety of lidoflazine in the control of angina pectoris. lidoflazine interaction exists and causes a rise in serum di However, in patients with atrial fibril1ation receiving digi goxin levels . Another series of studies used programmed talis therapy and being treated with Iidoflazine to convert electrical stimulation techniques to determine whether suc the supraventricular arrhythmia. an increased frequency of cessively greater doses of lidoflazine would lower the myo ventricular premature complexes and an enhanced propens cardial threshold for the induction of ventricular tachy ity for the development of serious ventricular arrhythmias cardia . This was undertaken as a means of assessing the have been reported (4,5). Also , other investigators (6) have proarrhythmic action of the drug. reported an antiarrhythmic action of lidoflazine. Lidoflazine has been shown to have an action similar to that of quinidine in the treatment of supraventricular arrhythmias and is also Methods known to possess some ofthe calcium entry blocking effects on supraventricular arrhythmias (7.8) . In view of recent Digoxin-Iidoflazine interaction. Eight mongrel dogs of studies demonstrating a digoxin-quinidine interaction (9-10 either sex, weighing between 25 and 35 kg, were housed and a digoxin-verapamil interaction (12-14), it is reasonable in the animal facilities for 7 days before drug administration. to postulate that lidoflazine may cause a rise in serum di All dogs were fed a standard diet. Dogs I to 5 (group I) goxin levels. These considerations suggest that concomitant received digoxin , 0.02 mg/kg daily , for 9 days. On days 8 administration of lidoflazine and digitalis may be the cause and 9, steady state digoxin levels were obtained. Concom of the enhanced arrhythmogenicity. However . lidoflazine itant adminstration of digoxin and lidoflazine was started itself may have arrhythmogenic activity and be the actual thereafter. Lidoflazine was injected for 14 days at 0.5 mgJkg cause of the enhanced myocardial vulnerability. daily. Serum digoxin levels were obtained in these dogs throughout the injection period of lidoflazine and digoxin From the Cardiology Division. Departments of Med icine and Phar on days 6, 8, 10 and 13. Then Iidoflazine administration macol ogy . Albert Einstein College of Medicine . Bronx. New York , Dr. was continued for an additional 6 days at double the dose Keren was supported in part by the MacRamer Found ation , New York , (1.0 rng/kg) , and serum digoxin levels were obtained on the New York. Dr. Somberg is an Estabh shed Investigator of the American Heart ASSOCIation. Dallas, Te xas, Tht s study was suppotted by a grant third day and last day of this injection period. Lidoflazine from Janssen R&D. lnc., New Brun swick. New Jersey. Manuscript re was then injected at 2.0 rng/kg for 7 to 10 days, and digoxin ceived February 14, 1984; revised manuscript received April 30, 1984, levels were monitored on days 4, 7 and 10. Dog 2 did not accepted May II, 1984. Addre ss for reprints: John C. Somberg. MD . Albett Einstein College survive the entire experiment and died because of pneu of Med icine, 1300 Morris ParkAvenue, F-208. Bronx, New York 10461. monia (determined at autopsy). © 1984 by the American Collegeof Cardiology 0735-1097/84/$300 lACC VI I 4. No 4 KEREN ET AL 743 October "84:742-7 IS LlDOFLAZINE ARRHYTHMOGENIC' DONS 6, 7 and 8 (group II) were given digoxin for 11 employed while placing Sz at 10 ms beyond the ventricular days hefore administration of lidoflazine. Digoxin levels refractory period. If S3 did not induce ventricular tachy were monitored on days 9 and 11. After this determination, cardia, then S4 and then S, were introduced sequentially. lidoflazine was administered at 1.0 mg/kg for 6 days, and All dogs underwent two control runs before administra digoxin levels were measured on days 3 and 6. Lidoflazine tion of lidoflazine. Lidoflazine was then administered in was then injected at 2.0 mg/kg for 7 days, and digoxin incremental doses of 0.5, 1, 2, 5 and 10 mg/kg at 30 minute levels were monitored on days 4 and 7. intervals. Programmed electrical stimulation was performed Lidoflazine and digoxin sample analysis. Samples of 30 minutes after administration of lidoflazine and before blood obtained from the dogs receiving digoxin were ob administration of the next dose. Blood was withdrawn to tained. centrifuged and the serum analyzed in duplicate. determine lidoflazine levels at each dose. If ventricular Standards consisting of serum from dogs not receiving drug, tachycardia or ventricular fibrillation was induced, the ar to which was added a known concentration of lidoflazine, rhythmia was terminated using burst pacing or defibrillation. demonstrated that levels of digoxin (0.09 ng/ml) were read Electrolytes were monitored during the experiment and were ily and reliably detectable using a radioimmunoassay kit found to be within normal limits. (Travenol Labs) with radiolabeled (iodine-l25) digoxin. The Lidoflazine anddigoxincombination. Additional elec assay was sensitive to 0.2 ng/ml digoxin. Control serum trophysiologic studies were performed on six dogs that re samples in each dog did not reveal detectable amounts of ceived digoxin, 0.02 mg/kg intravenously, for 4 days. On digoxin or other immunologically reacting substances. Li day 5, a digoxin serum sample was obtained and pro doflazine samples were determined by Janssen (Bersa. Bel grammed electrical stimulation was performed as just de gium I using high pressure liquid chromatographic analysis scribed. After initial programmed electrical stimulation sensitive to 25 ng/rnl. studies, lidoflazine was administered intravenously in in Effectoflidoflazine on arrhythmogenicity. Nine dogs cremental doses of 2, 4 and 10 mg/kg, and programmed of either sex, weighing 25 to 35 kg, were studied. The electrical stimulation was repeated 30 minutes after each animals were anesthetized with 10 mg/kg sodium pento dose. barbital administered intravenously. Animals were intubated Statistical analysis. The data obtained were analyzed with a cuffed endotracheal tube and ventilated with room for the presence or absence of ventricular tachycardia and air. Body temperature was maintained at 37°C using radiant to determine if these arrhythmias were abolished, reduced heat A large bore catheter was inserted into the left femoral or augmented by the drugs. Data are reported as mean values artery to monitor systemic blood pressure using a Statham ± standard error of the mean. Differences between means P23Db transducer. Depth and rate of respiration were ad were determined using Students t test. A two-tailed test was justed to maintain a partial pressure of oxygen (Po 2) greater employed to determine the level of significance. than 80 and pH between 7.35 and 7.45. A catheter was placed in the left femoral vein for administration of addi tional fluid and medications. A 7 French hexapolar electrode Results catheter was introduced through the right femoral vein into Long-term administration of digoxin and then digoxin in the apex of the right ventricle. combination with lidoflazine was performed to determine if Programmed stimulation protocol. The distal pair of lidoflazine caused a rise in serum digoxin concentration. electrodes of the hexapolar catheter was used for right ven All dogs achieved a steady state digoxin level before li tricular stimulation and the middle or proximal pair for doflazine administration. The mean serum digoxin levels intracardiac recording. All intracardiac electrograms were were monitored on days 8 and 9. In Dogs 1 to 5, at the end filtered at 40 to 500 Hz and displayed on a multichannel of 8 and 9 days of digoxin administration, mean serum oscilloscope along with electrocardiographic leads I and digoxin concentration was 2.2 ± 0.5 and 2.1 ± 0.5 ng/ml, aVL; arterial blood pressure was recorded simultaneously. respectively. Fifteen days of lidoflazine injection (0.5 mg/kg) Intracardiac electrical stimulation was performed utilizing did not produce a significant change in mean serum digoxin a Bloom stimulator generating square wave stimuli 2.0 ms level (1.6 ± 0.8 ng/ml). Additional injections of lidoflazine in duration with a stimulation intensity of 2.5 mAo Six beat (2.0 mg/kg) for the next 10 days caused no change in serum ventricular pacing (SIS,) with 8 second pauses between digoxin concentration. The mean digoxin concentrations for trains was introduced at a basic cycle 20 to 30 ms shorter all dogs at the incremental doses of lidoflazine are reported than the dogs' own intrinsic cycle length.

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