Effect Of Nifekalant Research Articles

Effect of nifekalant on life-threatening ventricular arrhythmias in patients with cardiopulmonary resuscitation or during the perioperative state

Effect of nifekalant on life-threatening ventricular arrhythmias in patients with cardiopulmonary resuscitation or during the perioperative state

Effect of nifekalant on life-threatening ventricular arrhythmias in patients with cardiopulmonary resuscitation or during the perioperative state

Background: Nifekalant is a unique class III anti-arrhythmic agent with a strong effect on prolonging the myocardial refractoriness, but its clinical effect is still unclear. In this study, we evaluated the effect of nifekalant on life-threatening ventricular arrhythmias and compared the clinical background between the effective and non-effective patients in order to clarify the clinical factors which may have an influence on the efficacy of nifekalant. Methods: The study population consisted of 47 consecutive patients who underwent nifekalant administration for life-threatening ventricular arrhythmias (VT/VF). Their clinical characteristics and ECG parameters were retrospectively compared between patients with and without an effective result with the nifekalant administration. Results: Nifekalant was effective for refractory VT/VF in 26/47 patients. There was no significant difference in the age, gender or left ventricular ejection fraction, but the incidence of ischemic heart disease was higher in the effective group (17/26) than non-effective group (9/21, p=0.004). The incidence of in-hospital events was higher in the effective group than non-effective group (20/26 vs 10/21, p=0.037). A significant prolongation in the QTc interval was observed in all patients and the degree of QTc prolongation was greater in the effective group than in the non-effective group (0.46 ± 0.04 vs 0.43 ± 0.02 sec 1/2 , p=0.026). Conclusion: Nifekalant was effective in 55% of the patients for refractory VT/VF. It was considered that nifekalant was more effective for patients with ischemic heart disease, during the perioperative period or in those experiencing in-hospital events. The prolongation of the QTc interval might also be useful as an index for the efficacy of nifekelant administration.

Reduced Inotropic Effect of Nifekalant in Failing Hearts in Rats

Class III antiarrhythmic agents have been widely used to suppress ventricular tachyarrhythmias in patients with heart failure because they have been shown to have positive inotropic effects as well. However, it remains to be examined whether those agents also exert positive inotropic effects in failing hearts. We addressed this important issue in a rat model of heart failure. We used Nifekalant as a representative class III antiarrhythmic agent. Four weeks after a s.c. injection of 60 mg/kg monocrotaline (MCT) or vehicle (Ctr) into rats, we obtained trabeculae from right ventricles and measured the developed force and intracellular Ca(2+) ([Ca(2+)](i)) by the fura-2 microinjection method. The sarcoplasmic reticulum (SR) Ca(2+) content was assessed by the rapid-cooling contracture (RCC) technique. MCT rats exhibited right ventricular hypertrophy induced by pressure overload. The protein expression of SR Ca(2+) ATPase type 2 (SERCA2) and the SERCA2/phospholamban ratio in MCT rats was lower with a slower decline of Ca(2+) transients and a reduced amplitude of RCCs. Nifekalant concentration-dependently increased the force, peak [Ca(2+)](i), and the amplitude of RCCs in Ctr rats but not in MCT rats with identical prolongation of the action potential. Under the SR inhibited with cyclopiazonic acid and ryanodine, Nifekalant increased the force in Ctr rats but not in MCT rats. These results indicate that the positive inotropic effects of Nifekalant is reduced in failing hearts, probably due to the depressed SR Ca(2+) uptake and reduced reserve of the trans-sarcolemmal Ca(2+) transport, warranting a caution in the antiarrhythmic therapy with a class III antiarrhythmic agent in heart failure.

Molecular Determinants of hERG Channel Block

Drug-induced block of cardiac hERG K+ channels causes acquired long QT syndrome. Here, we characterized the molecular mechanism of hERG block by two low-potency drugs (Nifekalant and bepridil) and two high-potency drugs 1-[2-(6-methyl-2pyridyl)ethyl]-4-(4-methylsulfonyl aminobenzoyl)piperidine (E-4031) and dofetilide). Channels were expressed in Xenopus laevis oocytes, and currents were measured using the two-microelectrode voltage-clamp technique. All four drugs progressively reduced hERG current during a 20-s depolarization to 0 mV after a 10-min pulse-free period, consistent with the preferential block of open channels. Recovery from block in response to pulses to -160 mV was observed for D540K hERG channels but not for wild-type hERG channels, suggesting that all four drugs are trapped in the central cavity by closure of the activation gate. The molecular determinants of hERG channel block were defined by using a site-directed mutagenesis approach. Mutation to alanine of three residues near the pore helix (Thr623, Ser624, and Val625) and four residues in Ser6 (Gly648, Tyr652, Phe656, and Val659) reduced channel sensitivity to block by dofetilide and E-4031, effects identical with those reported previously for two other methanesulfonanilides, (+)- N -[1' -(6-cyano-1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro(2H -1-benzopyran-2,4' -piperidin)-6-yl]-methanesulfonamide] monohydrochloride (MK-499) and ibutilide. The effect of nifekalant on mutant channels was similar, except that V659A retained normal sensitivity and I655A channels were less sensitive. Finally, mutation of the three residues near the pore helix and Phe656 in the Ser6 domain reduced channel block by bepridil. We conclude that the binding site is not identical for all drugs that preferentially block hERG in the open state.

Can Nifekalant Hydrochloride be Used as a First-Line Drug for Cardiopulmonary Arrest (CPA)?

Early defibrillation of ventricular tachycardia and fibrillation (VT/VF) is an urgent and most important method of resuscitation for survival in cardiopulmonary arrest (CPA). We have previously reported that nifekalant (NIF), a specific I(Kr) blocker developed in Japan, is effective for lidocaine (LID) resistant VT/VF in out-of-hospital CPA (OHCPA). However, little is known about the differences in the effect of NIF on OHCPA with acidosis and in-hospital CPA (IHCPA) without acidosis. The present study enrolled 91 cases of DC shock resistant VT/VF among 892 cases of CPA that occurred between June 2000 and May 2003. NIF was used (0.15-0.3 mg/kg) after LID according to the cardiopulmonary resuscitation (CPR) algorithm of Tokai University. The defibrillation rate was higher in the NIF group for both OHCPA and IHCPA than for LID alone, and the VT/VF rate reduction effect could be maintained even with acidosis. However, sinus bradycardia in OHCPA, and torsades de pointes in IHCPA were occasionally observed. These differences in adverse effects might be related to the amount of epinephrine, serum potassium levels, serum pH, and interaction with LID. NIF had a favorable defibrillating effect in both CPA groups, and it shows promise of becoming a first-line drug for CPR.

Effect of IKr Blocker Nifekalant on Atrial Action Potential Duration After Successful Internal Cardioversion of Chronic Atrial Fibrillation

Chronic atrial fibrillation (AF) is characterized by a marked decrease in the atrial effective refractory period (ERP) and in the ERP adaptation to rate as well as a decrease in the atrial conduction velocity. Little information is available about the ionic mechanisms underlying AF in humans. We studied the effect of IKr blocker nifekalant on the rate-dependent changes in atrial action potential duration in 11 patients after successful internal cardioversion of chronic AF of >2 months duration and in 7 patients without AF. In AF patients, right atrial (RA) monophasic action potential (MAP) was recorded at pacing cycle lengths (CLs) of 800-250 ms before and after administration of nifekalant. In control patients, RAMAP was recorded at CLs of 600 and 350 ms before and after administration of nifekalant. Nifekalant significantly increased RAMAPD at 90% repolarization (RAMAPD90) at CLs of 800-300 ms in the AF patients. The increase in RAMAPD90 by nifekalant became significantly smaller at shorter CLs (42.5 +/- 12.4 ms at a CL of 600 ms vs 32.8 +/- 14.5 ms at a CL of 350 ms, P < 0.05). Effect of nifekalant on RAPMAPD was attenuated at CL of 600 ms in AF patients in comparison to control patients (increase in RAMAPD in control; 73.0 +/- 36.6 ms vs increase in RAMAPD in AF; 42.5 +/- 12.4 ms, P < 0.05); however, it was similar at a CL of 350 ms between control and AF patients. Electrophysiological effects of nifekalant are significantly attenuated in the chronically remodeled human atrium at slower heart rates, but the beneficial effect of RAMAPD prolongation by IKr blocker was well-preserved even at shorter CLs after chronic AF.

Effect of Nifekalant, a Class III Anti-Arrhythmic Agent, on Ca2+ Waves in Rat Intact Trabeculae

Nifekalant, a class III anti-arrhythmic agent, has been used clinically at serum concentrations of 1-10 micromol/L in patients with ventricular arrhythmias. However, the effect of nifekalant on triggered arrhythmias has not yet been established. Trabeculae were dissected from the right ventricles of 16 rat hearts. The force was measured using a silicon strain gauge, the membrane potential using ultra-compliant microelectrodes, and the regional intracellular Ca2+ ([Ca2+]i) using electrophoretically microinjected fura-2 and an image intensified CCD camera at a sarcomere length of 2.1 microm. Rapid cooling contractures (RCCs) were measured to estimate the Ca2+ content in the sarcoplasmic reticulum. Ca2+ waves and aftercontractions were measured after the induction of reproducible Ca2+ waves. Nifekalant at 1, 10 and 250 micromol/L increased significantly the action potential duration, the peak [Ca2+]i, the developed force and the amplitude of RCCs in a concentration-dependent manner (stimulus interval = 2 s, [Ca2+]o = 0.7 mmol/L, 26.0+/-0.2 degrees C). Nifekalant at 10 and 250 micromol/L increased significantly the velocity of Ca2+ waves with an enhancement of the aftercontractions (stimulus interval = 0.5 s for 7.5 s, [Ca2+]o = 1.8+/-0.1 mmol/L, 22.3+/-0.5 degrees C). Nifekalant, even at a therapeutic concentration, can increase muscle contraction, but may worsen triggered arrhythmias because of the acceleration of Ca2+ waves under Ca2+-overloaded conditions.

Effect of nifekalant for out-of–hospital cardiac arrest with shock-resistant ventricular fibrillation

Nifekalant (NIF) is predominantly a Vaughan Williams Class III antiarrhythmic agent that is synthesized in Japan as a pure K channel blocker without a negative inotropic effect [1]. NIF has been the most effective antiarrhythmic drug recommended for patients with ventricular fibrillation (VF) resistant to some other antiarrhythmic drugs in Japan. However, whether NIF improves the rate of successful resuscitation after out-of-hospital cardiac arrest with shock-resistant VF has not been determined. Our preliminary study found a significant improvement in the proportion of patients surviving to the emergency department following out-of-hospital cardiac arrest in NIF-treated patients [2]. Our protocol is as follows: for out-of-hospital cardiac arrest patients with shock-resistant VF or pulseless VT (after three or more precordial shocks), epinephrine (1 mg bolus) and then NIF (0.3 mg/kg bolus followed by 0.4 mg/kg/hour infusion) are administered. We showed 31% of out-of-hospital cardiac arrest patients with shock-resistant VF could survive by treatment with this protocol [2]. We will show the details of the clinical course of successfully recovered patients treated with this protocol.