John K. Gibson

Comparative assessment of ibutilide, D-sotalol, clofilium, E-4031, and UK-68,798 in a rabbit model of proarrhythmia.

Summary Class III agents have been associated with development of a polymorphic ventricular tachycardia (PVT) known as torsades de pointes. We compared the class III agent ibutilide, which prolongs repolarizatipn through enhancement of an inward sodium current, with the potassium channel blockers E-4031, UK-68,798, clofilium, and D-sotalol for proarrhythmic effects in an anesthetized rabbit model. In these animals, prolongation of repolarization during a, stimulation with methoxamine produces early afterdepolarizations (EADs) and a pause-dependent torsades de pointes-like PVT. Agents were compared over dosage ranges that produced maximal increases in QTc interval and monophasic action potential duration (MAPD). PVT typically developed after atrioventricular (A-V) conduction block and slowing of heart rate (HR), and was preceded by development of repolarization arrhythmias characterized by EADs and triggered activity producing extrasystolic beats. Ibutilide administration resulted in significantly lower EAD amplitudes and a lower incidence of repolarization arrhythmias and PVT as compared with administration of other class HI agents. The percentage of rabbits developing PVT for each agent was ibutilide 12%, D-sotalol 70%, E-4031 56%, UK-68,798 69%, and clofilium 80%. Rabbits receiving saline vehicle instead of a class HI agent never developed conduction or repolarization abnormalities or PVT. Under the conditions of this study at doses that generate maximal class HI effects, ibutilide produces lesser increases in QTc interval and MAPD, and EADs of lower amplitude, resulting in a lower incidence of repolarization arrhythmias and PVT as compared with other class III agents.

Electrophysiology and Pharmacology of Ibutilide

Ibutilide fumarate is a new class III intravenous antiarrhythmic agent indicated for the acute termination of atrial fibrillation and flutter. Ibutilide prolongs repolarization in the atria and ventricle by enhancing the inward depolarizing, slow sodium current, a unique mechanism of action for a class III agent. Atrial refractoriness is prolonged with no evidence of reverse use dependence. Ibutilide may also block the delayed rectifier current, but this does not appear to be clinically relevant. In vitro and at high doses, ibutilide may shorten action potential duration, although this effect has not been noted clinically. Ibutilide can cause torsades de pointes in a rabbit model of proarrhythmia dependent on the formation of early afterdepolarizations. However, it causes less proarrhythmia than sotalol, dofetilide, or sematilide in this model. The pharmacokinetics of ibutilide are linear, its extravascular distribution is rapid and extensive, while its systemic clearance is high (elimination half-life 3-6 hours). Eight metabolites are formed by the liver, only one of which is slightly active. QT prolongation is dose dependent, is maximal at the end of the infusion, and returns to baseline within 2-4 hours following infusion. The pharmacokinetic and electrophysiologic characteristics of ibutilide are complementary in that any risk of proarrhythmia is made manageable by a short half-life. Almost all reported cases of drug-induced torsades de pointes ventricular tachycardia associated with ibutilide have occurred within 40 minutes of starting the infusion. Nevertheless, clinicians using ibutilide can further reduce the chance of torsades de pointes by being very familiar with the criteria for patient selection, and by being prepared to treat it should it occur. When used with full knowledge of its potential risks, ibutilide is a very effective intravenous agent for the acute termination of atrial fibrillation and flutter and is likely to become a significant treatment option for these arrhythmias.

Efficacy of Linezolid in Treatment of Experimental Endocarditis Caused by Methicillin-Resistant Staphylococcus aureus

ABSTRACT The efficacies of orally (p.o.) dosed linezolid and intravenously (i.v.) dosed vancomycin against methicillin-resistantStaphylococcus aureus (MRSA) in rabbits with experimental aortic-valve endocarditis were investigated. After endocarditis was established with a recent clinical MRSA isolate, rabbits were dosed for 5 days with linezolid (p.o., three times a day) at either 25, 50, or 75 mg/kg of body weight or vancomycin (i.v., twice a day) at 25 mg/kg. The 25-mg/kg linezolid group had a high mortality rate and bacterial counts in the valve vegetations that were not different from those of the controls. Linezolid dosed p.o. at 50 and 75 mg/kg and i.v. vancomycin produced statistically significant reductions in bacterial counts compared to those of the untreated controls. The reduced bacterial counts and culture-negative valve rates for the animals treated with linezolid at 75 mg/kg were similar to those for the vancomycin-treated animals. Concentrations of linezolid in plasma were determined at several points in the dosing regimen. These results suggest that the efficacy of linezolid in this infection model is related to trough levels in plasma that remain above the MIC for this microorganism. At the ineffective dose of linezolid (25 mg/kg) the concentration at sacrifice was 0.045 times the MIC, whereas the concentrations of linezolid in plasma in the 50- and 75-mg/kg groups were 2 and 5 times the MIC at sacrifice, respectively. The results from this experimental model suggest that the oxazolidinone linezolid may be effective for the treatment of serious staphylococcal infections when resistance to other antimicrobials is present.

Efficacy of Linezolid plus Rifampin in an Experimental Model of Methicillin-Susceptible Staphylococcus aureus Endocarditis

ABSTRACT The efficacy of linezolid, alone or in combination with rifampin, against methicillin-susceptible Staphylococcus aureus in rabbits with experimental endocarditis was investigated. Linezolid (50 or 75 mg/kg of body weight), rifampin, and linezolid (25, 50, or 75 mg/kg) plus rifampin produced statistically significant reductions in bacterial counts compared with those in untreated controls. Plasma or valvular vegetation levels of linezolid in the groups treated with the linezolid-rifampin combination were similar to those in the respective linezolid-only treatment groups. At therapeutic levels of linezolid, rifampin resistance was not observed. The results from this experimental model of endocarditis suggest that while rifampin did not provide synergy to the linezolid dosing, it did not antagonize the efficacy of linezolid.

Antiarrhythmic and electrophysiologic effects of ibutilide in a chronic canine model of atrial flutter.

We studied the effects of orally administered ibutilide, a class III antiarrhythmic agent, in a model of reentrant atrial flutter in conscious dogs. After baseline determination of atrial effective refractory period (AERP) and demonstration of reproducible induction of atrial flutter by rapid atrial pacing, 8 dogs received either placebo or one of six doses of ibutilide ranging from 0.1 to 5 mg/ kg. Refractory periods and the ability to induce atrial flutter were then assessed at periodic intervals for 8 hours. Ibutilide produced dose-related increases in AERP which were well correlated with prevention of initiation of atrial flutter after doses ≥ 0.25 mg/kg. Placebo and 0.1 mg/kg ibutilide had no effect on AERP or the ability to induce atrial flutter. Doses of 0.25 to 1.0 mg/kg ibutilide significantly increased AERP and prevented induction of atrial flutter for 4–6 h. After treatment with 2.5 or 5 mg/kg ibutilide, significant increases in AERP and prevention of induction of atrial flutter persisted throughout the 8-h study period. The cycle length of inducible atrial flutter was significantly increased after administration of 5 mg/ kg ibutilide. The results demonstrate oral efficacy of ibutilide with rapid onset of action (in 30–60 min), resulting in increased AERP and prevention of induced atrial flutter in this model.

Effects of ibutilide on spontaneous and induced ventricular arrhythmias in 24-hour canine myocardial infarction: a comparative study with sotalol and encainide.

Summary The electrophysiologic and antiarrhythmic effects of ibutilide, sotalol, and encainide were compared in dogs 24 h after myocardial infarction. Ibutilide (0.03 to 0.3 mg/kg i.v.) prevented the induction of ventricular arrhythmias in 100% of the dogs that had demonstrated inducible ventricular arrhythmias prior to treatment. This antiarrhythmic action was associated with significant increases in ventricular refractoriness and monophasic action potential duration. Sotalol (1.0 to 10.0 mg/kg i.v.) increased the ventricular refractory period and monophasic action potential duration and prevented the induction of ventricular arrhythmias in 75% of the dogs that demonstrated inducible ventricular tachyarrhythmias at baseline. Although 10 mg/kg of sotalol was required to prevent the initiation of ventricular tachycardia, this dose produced marked cardiovascular depression and hypotension in 50% of the dogs tested. Neither ibutilide nor sotalol significantly decreased the incidence of spontaneous ventricular arrhythmias. The class IC agent encainide (0.3 to 3.0 mg/kg i.v.) was successful in preventing the induction of ventricular arrhythmias in only 20% of the dogs tested. However, in contrast to ibutilide and sotalol, encainide significantly reduced spontaneous arrhythmias. Atrial and ventricular refractoriness were significantly increased only after the highest dose of encainide tested (3.0 mg/kg). Over the dose ranges studied, the relative efficacy for prevention of pacing-induced ventricular arrhythmias was ibutilide > sotalol ± encainide. For suppression of spontaneous ventricular arrhythmias, the relative efficacy was encainide ± ibutilide = sotalol. These results are consistent with the concept that spontaneous and pacing-induced ventricular arrhythmias result from different mechanisms and that class III agents are more effective in suppressing induced ventricular tachycardia due to reentry than spontaneous arrhythmias that may be due to nonre-entrant mechanisms.

Effects of U74006F, a novel inhibitor of lipid peroxidation, in stunned reperfused canine myocardium

U74006F, a novel 21-amino steroid is a potent inhibitor of iron-mediated lipid peroxidation and has been shown to be of therapeutic benefit in central nervous system ischemia. As oxygen radicals have been implicated in the development of postischemic myocardial dysfunction, we examined the efficacy of U74006F to enhance the recovery of function in a canine model of stunned, reperfused myocardium. Twenty-six dogs were randomized to either a vehicle (n = 11), U74006F (n = 10), or U74006F-paced group (n = 5). U74006F (6 mg/kg i.v.) was administered 15 min prior to coronary artery occlusion. Myocardial blood flows were measured by the microsphere technique, and function data were obtained by sonomicrometry. Both U74006F-treated groups demonstrated a significant increase in posterior wall thickening as compared to the vehicle treatment (U74006F-paced, 27.0 12.8%; U74006F, 22.4 ± 11%; vehicle, −13.5 ± 9.9%, p < 0.001 following 3 h of reperfusion). Enhanced function recovery was accompanied by lower heart rates in the U74006F-treated group following reperfusion (treated versus vehicle, 109 ± 6.7 versus 131 ± 8.8 beats/min, p = 0.004). The U74006F-paced group was maintained at the same rate as the vehicle group, with no diminution in function recovery compared to the unpaced group. No effects in systemic hemodynamics or nutrient blood flow were evident as a function of drug treatment. We conclude that pretreatment with U74006F enhances the recovery of function in stunned canine myocardium via the inhibition of oxygen radicals and lipid peroxidation products. This activity suggests that this compound represents a new therapeutic adjunct in reperfusion and recanalization therapies.

Electrophysiologic Actions of Lidocaine in a Canine Model of Chronic Myocardial Ischemic Damage—arrhythmogenic Actions of Lidocaine

Lidocaine facilitated the induction of ventricular arrhythmias by programmed electrical stimulation in 16 dogs, 5 to 14 days after a temporary (90-min) occlusion of the left anterior descending coronary artery. In these 16 animals, programmed stimulation failed to produce ventricular tachyar-rhythmias in any animal before lidocaine administration (3 mg/kg), while after lidocaine administration, programmed stimulation produced nonsustained ventricular tachycardia in four animals (25%), sustained ventricular tachycardia in nine animals (56%), and ventricular fibrillation in one animal (6%). Delayed electrical activity in ischemically injured ventricular myocardium produced by premature ventricular stimuli (X ± SD = 179 ± 34 ms) was delayed further by the administration of lidocaine (237 ± 42 ms, p < 0.01), resulting in continuous local electrical activity between the final premature ventricular stimulus and the initial beat of the resultant ventricular tachycardia. Lidocaine administration did not alter myocardial refractoriness in normal ventricular tissue, but it prolonged refractoriness in ischemically injured ventricular myocardium. These results show that lidocaine can have arrhythmogenic actions when administered in the presence of existing ischemic injury, possibly the result of increased delay in activation of ischemically injured ventricular myocardium with localized reentry of myocardial electrical activity.

Acute Intravenous Conversion of Canine Atrial Flutter: Comparison of Antiarrhythmic Agents

We studied the acute intravenous (i.v.) effects of the antiarrhythmic agents ibutilide, sematilide, lidocaine, and encainide in a canine Y-shaped right atrial incision model of atrial flutter. After baseline determination of atrial effective refractory period (AERP), sustained atrial flutter (AFL) was initiated by atrial pacing in 25 dogs. Each dog then received placebo, followed by sequential doses of a particular agent every 5 min until AFL was terminated or the highest dose was administered. Ibutilide increased AFL cycle length (CL: 26 +/- 6 ms) before termination of AFL in 8 of 8 dogs in 1 min after the effective dose (6 +/- 1 micrograms/kg). AERP determined immediately after termination of AFL was significantly increased (44 +/- 7 ms). AFL could not be reinitiated after termination with ibutilide. Sematilide increased AFL CL 12 +/- 6 ms, significantly increased AERP 25 +/- 6 ms, and terminated AFL in 4 of 8 dogs (0.6 +/- 0.2 mg/kg). After sematilide or pacing-induced termination, AFL was reinducible in only 1 dog. Lidocaine terminated AFL in 2 of 5 dogs (2.0 +/- 0.5 mg/kg). AERP was unchanged in both animals, and AFL CL increased by 37 +/- 3 ms. AFL was reinducible in all 5 lidocaine-treated dogs after AFL was terminated. Encainide terminated AFL in 3 of 4 dogs after a dose of 3.0 +/- 0.0 mg/kg. AERP was significantly increased 77 +/- 10 ms, and AFL CL was markedly increased by 226 +/- 11 ms. AFL could not be reinitiated after termination of AFL by encainide.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevention of chronic canine ventricular tachyarrhythmias with bretylium tosylate.

The ability of chronic bretylium tosylate treatment to prevent the induction of ventricular tachycardia was assessed in the conscious dog subjected to serial programmed ventricular stimulation on days 3-6 after acute myocardial infarction. In 34 untreated control dogs, programmed ventricular stimulation produced nonsustained ventricular tachycardia in 11 dogs (32%), sustained ventricular tachycardia in 10 (29%), and ventricular fibrillation in 10 (29%) on the third and fourth day after occlusion and reperfusion of the left anterior descending coronary artery. Bretylium tosylate, 5 mg/kg i.v., was given every 12 hours to a separate group of seven dogs after the induction of ischemic myocardial injury. Programmed ventricular stimulation on the third and fourth days after the induction of myocardial ischemic injury failed to elicit ventricular arrhythmias. Induction of arrhythmias by programmed electrical stimulation could be induced in each of the seven dogs; however, 36 hours after discontinuing bretylium tosylate, two dogs (29%) had non-sustained ventricular tachycardia and five (71%) had sustained ventricular tachycardia. When retested at 60 hours after withdrawal of bretylium tosylate, five (71%) had sustained ventricular tachycardia and two (28%) developed ventricular fibrillation. Readministration of bretylium tosylate (5 mg/kg, i.v.) to four of the five surviving dogs prevented the induction of ventricular arrhythmias in response to programmed ventricular stimulation. The results of these investigations suggest that bretylium tosylate may be effective in preventing the onset of reentrant ventricular rhythms after myocardial ischemic damage, and therefore may be of value in preventing sudden coronary death.