Gregory N. Beatch

The Mechanism of Atrial Antiarrhythmic Action of RSD1235

Introduction: RSD1235 is a novel drug recently shown to convert AF rapidly and safely in patients. 1 Its mechanism of action has been investigated in a rat model of ischemic arrhythmia, along with changes in action potential (AP) morphology in isolated rat ventricular myocytes and effects on cloned channels.

The effect of vernakalant (RSD1235), an investigational antiarrhythmic agent, on atrial electrophysiology in humans.

Objectives: To determine the acute effects of vernakalant (RSD1235) on electrophysiologic (EP) properties in humans. Background: Vernakalant is an investigational mixed ion channel blocker that can terminate acute atrial fibrillation (AF) in humans at 2 to 5 mg/kg and may be more “atrial-selective” than available agents. Methods: Patients (N = 19; 53% male; age, 48 ± 11 years) underwent EP study before and after 25 minutes of intravenous vernakalant administration: 2 mg/kg over 10 min + 0.5 mg/kg/hr for 35 min or 4 mg/kg over 10 min + 1 mg/kg/hr for 35 min. EP measurements, including atrial refractory period (AERP) and ventricular refractory period (VERP), were obtained. Results: The lower dose prolonged AERP at 600, but not at 400 or 300 msec paced cycle length. The higher dose significantly prolonged AERP from 203 ± 31 msec to 228 ± 24 msec at 600 msec, 182 ± 30 msec to 207 ± 27 msec at 400 msec, and 172 msec ± 24 to 193 ± 21 msec at 300 msec. There was no significant prolongation of VERP at either dose or at any cycle length. There was a small but significant prolongation of AV nodal refractoriness; Wenckebach cycle length prolonged by 18 ± 12 msec (from baseline 343 ± 54 msec) at the higher dose (P < 0.05). Sinus node recovery time also increased by 123 ± 158 msec (from baseline 928 ± 237 msec) at the higher dose (P < 0.05). There was a slight prolongation of QRS duration at the higher dose, during ventricular pacing at CL = 400 msec (15 ± 15 msec, P = 0.0547). QT and HV intervals were unchanged. Conclusions: At doses similar to those tested clinically, vernakalant dose-dependently prolonged atrial refractoriness, prolonged AV nodal conduction and refractoriness, and slightly prolonged QRS duration, but it had no effect on ventricular refractoriness.

RSD931, a novel anti-tussive agent acting on airway sensory nerves

The anti‐tussive effects, of the local anaesthetic, lidocaine and carcainium chloride (RSD931) have been investigated in guinea‐pigs and rabbits. Pre‐treatment of guinea‐pigs with aerosols of lidocaine or RSD931 at 0.1, 1.0 and 10 mg ml−1 reduced the number of citric acid‐induced coughs by 9.3, 32.6 and 40.9% (P>0.05) for lidocaine and by 25.3% (P>0.05), 40.4% (P>0.05) and 97.6% (P<0.01) for RSD931, respectively and increased the latency to onset of cough at 10.0 mg ml−1 only. In addition, RSD931 at 10 mg ml−1 reduced citric acid‐evoked cough responses in rabbits (with prior exposure to ozone at 3 p.p.m. for 1 h) from 22.1±5.1 to 2.7±0.9 coughs (P<0.01). Acute pre‐treatment of guinea‐pigs with aerosols of lidocaine or RSD931 at 10.0 and 30.0 mg ml−1 reduced the number of capsaicin‐evoked coughs by 42.2 and 10.3% (P>0.05) (lidocaine) and by 25% (P>0.05) and 76.9% (P<0.01) (RSD931), respectively. Lidocaine had little effect on the latency of cough onset at either 10.0 or 30.0 mg ml−1, however, RSD at 30.0 mg ml−1 significantly (P<0.05) prolonged the latency of cough onset. RSD931 (10.0 mg ml−1) significantly (P<0.05–<0.01) reduced the spontaneous and histamine‐evoked discharges in Aδ‐fibres originating from airway, rapidly adapting stretch receptors (RARs) without affecting histamine‐evoked bronchoconstriction. Lidocaine at 10.0 mg ml−1 also significantly (P<0.05) inhibited the spontaneous and histamine‐induced discharges of RARs without affecting histamine‐evoked bronchoconstriction. Aerosols of RSD931 (10.0 mg ml−1) caused a transient, but significant (P<0.05), activation of pulmonary C‐fibre endings 2.5 min after administration started. RSD931 had no significant (P>0.05) effects on discharges in bronchial C‐fibres originating from bronchial C‐fibre endings, capsaicin‐evoked discharges of either pulmonary or bronchial C‐fibre endings or on capsaicin‐evoked bronchoconstriction. In contrast, lidocaine (10.0 mg ml−1) significantly (P<0.05) inhibited spontaneous and capsaicin‐induced discharges in both pulmonary and bronchial C‐fibres respectively. Lidocaine also significantly (P<0.05) reduced capsaicin‐evoked bronchoconstriction. These studies suggest that the anti‐tussive actions of RSD931 are mediated via inhibition of discharges in Aδ‐fibres originating from airway RARs. The mechanism of action of RSD931 is distinct from that of the local anaesthetic lidocaine and RSD931 may represent a novel class of anti‐tussive agent.

Pharmacokinetics of Novel Atrial‐Selective Antiarrhythmic Agent Vernakalant Hydrochloride Injection (RSD1235): Influence of CYP2D6 Expression and Other Factors

Vernakalant hydrochloride injection (RSD1235) is a relatively atrial‐selective antiarrhythmic agent that converts atrial fibrillation rapidly to sinus rhythm. The pharmacokinetics of vernakalant were explored in healthy volunteers and in patients with atrial fibrillation or atrial flutter in 4 clinical studies. Key pharmacokinetic parameters analyzed were the maximum plasma concentration and the area under the plasma concentration—time curve. Vernakalant exhibited linear pharmacokinetics over the dose range of 0.1 mg/kg to 5.0 mg/kg in healthy subjects, and generally showed dose proportionality in patients with atrial fibrillation or atrial flutter who received 1 or 2 vernakalant infusions. Vernakalant was metabolized rapidly via 4‐O‐demethylation by cytochrome P450 (CYP)2D6 to its major metabolite RSD1385, which then circulated predominantly as an inactive glucuronide conjugate. In most patients, the maximum plasma concentration of RSD1385 glucuronide exceeded that of vernakalant. Unconjugated RSD1385 was found at low levels in all patients demonstrating either a cytochrome P450 CYP2D6 “extensive metabolizer” or “poor metabolizer” phenotype or genotype; however, CYP2D6 poor metabolizers had even lower levels of unconjugated RSD1385. The impact of CYP2D6 metabolizer status on vernakalant exposure was explored in patients with atrial fibrillation or atrial flutter who received a therapeutic regimen (3 mg/kg initially via 10‐minute intravenous infusion followed by a second 2 mg/kg 10‐minute infusion if atrial fibrillation persisted after a 15‐minute observation period). In the subset that received 2 vernakalant infusions, there was little difference in vernakalant maximum plasma concentration or area under the plasma concentration—time curve from the start of the first infusion to 90 minutes between CYP2D6 poor metabolizers and extensive metabolizers or between those who did or did not receive concomitant CYP2D6‐inhibitor medications. Gender, age, and renal function did not have a clinically significant influence on the pharmacokinetics of vernakalant. These results suggest that an assessment of CYP2D6 expression may not be needed when vernakalant is administered acutely and intravenously to patients with atrial fibrillation.

Kinetics of rate‐dependent shortening of action potential duration in guinea‐pig ventricle; effects of IK1 and IKr blockade

The kinetics of shortening of action potential duration (APD) following an increase in pacing rate, from 2 to 3.3 Hz, was characterized in guinea‐pig ventricular preparations. Terikalant (RP62719), an inhibitor of the inwardly rectifying K+ current (IK1), and dofetilide, a specific inhibitor of the rapidly activating delayed‐rectifier current (IKr), were applied to determine the effect of inhibition of these ion currents on slow APD shortening. Action potentials were recorded from isolated guinea‐pig ventricular myocytes using the perforated‐patch patch‐clamp technique, and monophasic action potentials were recorded from Langendorff‐perfused guinea‐pig ventricles using a contact epicardial probe. Under control conditions, after an increase in pacing rate, APD immediately decreased, and then shortened slowly with an exponential time course. In ventricular myocytes, the time constant of this exponential shortening was 28±4 s and the amount of slow shortening was 21.9±0.9 ms (n=8) for an increase in rate from 2 to 3.3 Hz. Similar values were observed in Langendorff‐perfused ventricles. Terikalant dose‐dependently increased APD and the increase was enhanced by rapid pacing (‘positive’ rate‐dependence). The drug dose‐dependently decreased the time constant of shortening and amount of slow APD shortening. In contrast, dofetilide, an inhibitor of IKr, which shows ‘reverse’ rate‐dependent APD widening, had no significant effect on the time constant or amount of slow shortening. These observations suggest that IK1 plays a role in rate‐dependent shortening of APD. The results appear to support the hypothesis that ‘reverse’ rate‐dependent effects of IKr blockers are due to these drugs not affecting the ion current(s) mediating intrinsic rate‐dependent slow shortening of APD.

Rate-dependent effects of sematilide on ventricular monophasic action potential duration and delayed rectifier K+ current in rabbits.

Our objective was to define the actions of sematilide in rabbits and to assess the contribution of the delayed rectifier (IK) to rate dependence of action potential duration (APD) in rabbit ventricular myocardium. In studies in vivo, New Zealand White rabbits were used to obtain dose/response curves of the effects of sematilide on APD from contact monophasic action potentials (MAP), ventricular effective refractory period (VERP), and ECG. Sematilide or placebo was administered as an i.v. bolus followed by a 45-min infusion in the following cumulative manner: infusion 1 (1 mg/kg bolus + 8 micrograms/kg/min); infusion 2 (2 mg/kg + 20 micrograms/kg/min); and infusion 3 (7 mg/kg + 68 micrograms/kg/min). At each infusion level, VERP and APD at 75% repolarization (APD75) were measured during cardiac pacing between 200- and 400-ms cycle length (CL). Serum sematilide levels were analyzed by high-performance liquid chromatography (HPLC). In studies in vitro, sematilides effects on the delayed rectifier were assessed in isolated rabbit ventricular myocytes by using patch-clamp techniques. Sematilide infusion in vivo resulted in stable serum levels of 1.3 +/- 0.5, 3.7 +/- 1.4, and 13.4 +/- 1.8 micrograms/ml during infusions 1, 2, and 3, respectively. Maximal effects occurred at infusion 2, such that at 400 ms CL, sematilide widened predrug APD75 (145 +/- 5 ms) by 27 +/- 4% (p < 0.001 vs. placebo), and at 200-ms CL, sematilide prolonged predrug APD75 (115 +/- 10 ms) by only 18 +/- 4% (p < 0.001 vs. placebo; p < 0.05 vs. 400-ms CL). Similar effects were observed in VERP. Sematilide enhanced rate dependence of APD and produced the same degree of APD prolongation at a given CL, during accommodation to and recovery from rapid pacing. Rabbit ventricular myocytes appeared to have at least two types of delayed rectifier. Sematilide selectively blocked IKr, and block was not relieved by repetitive stimulation. In conclusion, the APD-widening effect of sematilide was independent of previous pacing history. Sematilide had little influence on background processes likely responsible for shortening APD because of rapid repetitive stimulation.

Effects of Optical Enantiomers CK-4000(S) and CK 4001(R) on Defibrillation and Enhancement of Shock- Induced Extension of Action Potential Duration

Antiarrhythmic Drugs and DFT. Introduction: Class III antiarrhythmics have been reported to lower defibrillation threshold (DFT); however, the mechanism(s) of this effect is unknown. Recent evidence suggests that DFT strength DC shocks may terminate reentrant arrhythmias through prolongation of action potential duration and refractory periods. Since Class III antiarrhythmic drugs prolong repolarization, we examined the hypothesis that these drugs enhance shock‐induced action potential duration extension (APDE), which might contribute to lowering of DFT.

Comparison of the intrinsic vasorelaxant and inotropic effects of the antiarrhythmic agents vernakalant and flecainide in human isolated vascular and cardiac tissues.

Abstract: This study explored the intrinsic vasorelaxant and inotropic effects of the mixed potassium and sodium channel blocker atrial antiarrhythmic vernakalant and the class IC antiarrhythmic agent flecainide in human isolated subcutaneous resistance artery and in ventricular trabecular muscle preparations. At test concentrations encompassing free plasma concentrations associated with clinical efficacy for conversion of atrial fibrillation, vernakalant (1–10 &mgr;M) displayed no significant direct effects on human resistance artery tone or ventricular contractility. In contrast, tested at equimolar concentrations, flecainide significantly reduced peak isometric contractile force (10 &mgr;M) and maximal rates of force development and decline (3 and 10 &mgr;M) in the human ventricular muscle preparation while displaying no significant effect on human resistance artery tone. The lack of effects of vernakalant on human resistance artery tone and ventricular muscle contractile function suggests that direct vasorelaxant and inotropic effects do not underlie the rare hypotensive events observed clinically with vernakalant, raising the possibility that secondary (eg, reflex) effects may mediate these events. The demonstration of negative inotropic effects with flecainide in the human ventricular muscle preparations in the absence of an effect on resistance artery tone suggests that the hemodynamic effects of flecainide observed clinically result primarily from direct negative inotropic effects.

Class III antiarrhythmic effects of LY-190147 on defibrillation threshold

Defibrillation strength shocks delivered within an action potential (AP) delay repolarization. Shock-induced AP duration extension (APDE) may prolong refractoriness and terminate or prevent reinitiation of reentry, favoring defibrillation. This study examined LY-190147 (LY) effects on defibrillation threshold (DFT) in 11 dogs. Ventricular effective refractory period (VERP) and epicardial monophasic AP duration at 75% repolarization (APD75) were recorded at 300-, 400-, 500-, and 600-ms pacing cycle length (CL). APDE was measured as the time to 50% repolarization after a DFT strength shock delivered at 50, 25, and 0 ms before or 25 ms after VERP during pacing at 300 ms CL in 4 of the dogs. We made all recordings before drug administration and after infusions of 0.03, 0.3, and 3.0 mg/kg LY, using 1.5-h dosing intervals. LY lowered DFT in a saturating dose-response manner whether expressed as shock peak voltage (V) or energy. LY decreased DFT-V from 357 +/- 77 V before drug to 331 +/- 60 V (-6 +/- 12%), 290 +/- 43 V (-17 +/- 13%, p < 0.001), and 312 +/- 45 V (-11 +/- 12%, p < 0.05) at 0.03, 0.3, and 3.0 mg/kg, respectively. Similarly, LY treatment decreased defibrillation energy requirements from 6.9 +/- 2.7 J before drug by 7 +/- 25%, 26 +/- 24%, and 12 +/- 25% at the same doses. At 300-600 ms CL, LY prolonged APD75 by an average of 10 +/- 8% at 0.03 mg/kg, 17 +/- 6% at 0.3 mg/kg, and 24 +/- 9% at 3 mg/kg. At these CL, LY prolonged VERP by an average of 4 +/- 6% at 0.03 mg/kg, 15 +/- 10% at 0.3 mg/kg, and 11 +/- 9% at 3 mg/kg. APDE was increased from 62 +/- 9 ms before to 68 +/- 14, 80 +/- 16 (p < 0.001) and 72 +/- 13 ms (p < 0.05) at 0.03, 0.3, and 3.0 mg/kg LY, respectively. Therefore, LY prolonged VERP and APDE and affected DFT in the same saturating dose-response manner. LY may facilitate defibrillation by increasing the duration of postshock refractoriness.

Efficacy and safety of vernakalant for cardioversion of recent-onset atrial fibrillation in the Asia-Pacific region: a phase 3 randomized controlled trial.

Abstract: Atrial fibrillation (AF) is a common clinically significant cardiac arrhythmia. This phase 3 randomized, double-blind, placebo-controlled trial assessed the efficacy and safety of vernakalant hydrochloride for the pharmacological conversion of AF to sinus rhythm in patients with recent-onset (>3 hours to ⩽7 days) symptomatic AF from the Asia–Pacific region. Patients received an infusion of vernakalant (3 mg/kg) or placebo for 10 minutes. If AF had not been terminated 15 minutes later, a second infusion of vernakalant (2 mg/kg) or placebo for 15 minutes was administered. The primary efficacy end point was conversion of AF to sinus rhythm for >1 minute within 90 minutes. The study was terminated early for administrative reasons; 123 patients from Korea, Taiwan, and India were randomized to receive vernakalant (n = 55) or placebo (n = 56). A greater proportion of patients who received vernakalant (52.7%) than placebo (12.5%) met the primary end point (P < 0.001), and cardioversion was faster in the vernakalant group than in the placebo group (P < 0.001). Vernakalant was generally well tolerated; the incidence of treatment-emergent adverse events was similar between the groups. We conclude that vernakalant is efficacious in the rapid cardioversion of recent-onset AF in patients from the Asia–Pacific region.