Characterization of hERG K+ channel inhibition by the new class III antiarrhythmic drug cavutilide.

Cavutilide (niferidil, refralon) is a new class III antiarrhythmic drug which effectively terminates persistent atrial fibrillation (AF; 84.6% of patients, mean AF duration 3 months) and demonstrates low risk of torsade de pointes (1.7%). ERG channels of rapid delayed rectifier current(IKr) are the primary target of cavutilide, but the particular reasons of higher effectiveness and lower proarrhythmic risk in comparison with other class III IKr blockers are unclear. The inhibition of hERG channels expressed in CHO-K1 cells by cavutilide was studied using whole-cell patch-clamp. The present study demonstrates high sensitivity of IhERG expressed in CHO-K1 cells to cavutilide (IC50 = 12.8 nM). Similarly to methanesulfonanilide class III agents, but unlike amiodarone and related drugs, cavutilide does not bind to hERG channels in their resting state. However, in contrast to dofetilide, cavutilide binds not only to opened, but also to inactivated channels. Moreover, at positive constantly set membrane potential (+ 60 mV) inhibition of IhERG by 100 nM cavutilide develops faster than at 0 mV and, especially, - 30 mV (τ of inhibition was 78.8, 103, and 153 ms, respectively). Thereby, cavutilide produces IhERG inhibition only when the cell is depolarized. During the same period of time, cavutilide produces greater block of IhERG when the cell is depolarized with 2 Hz frequency, if compared to 0.2 Hz. We suggest that, during the limited time after injection, cavutilide produces stronger inhibition of IKr in fibrillating atrium than in non-fibrillating ventricle. This leads to beneficial combination of antiarrhythmic effectiveness and low proarrhythmicity of cavutilide.

Intravenous Cavutilide for Pharmacological Conversion of Paroxysmal and Persistent Atrial Fibrillation in Patients with Heart Failure.

This work aimed to study the efficacy and safety of the class III antiarrhythmic agent cavutilide (Niferidil, Refralon) for pharmacological cardioversion in patients with paroxysmal and persistent atrial fibrillation (AF) and heart failure (HF). METHODS AND RESULTS: In this retrospective cohort study, 58 patients with stable HF (aged 69 [61;73] years, 30 males, 78% with persistent AF) and 274 patients without HF (aged 63 [57;70] years, 196 males, 56% with persistent AF) were included. The median AF duration in the group with HF was 35.5 [10.6;124] days, and that in the group without HF was 14.5 [3.6;90] days. All patients received 5-30 µg/kg cavutilide intravenously in one to four (if needed) boluses of 5-5-10-10 µg/kg at 15 min intervals. Subsequent boluses were not administered if the patient's sinus rhythm (SR) was restored or if bradycardia, QT prolongation > 500 ms or evidence of proarrhythmia was observed. Holter electrocardiogram monitoring was started before infusion and was continued for 24 h. The main criterion for an antiarrhythmic effect was sinus rhythm restoration within 24 h of the initial bolus. RESULTS: Cavutilide converted AF to SR in 37.9% of patients with HF after bolus 1 (5 µg/kg), in 58.6% after bolus 2 (cumulative dose = 10 µg/kg), in 74% of cases after bolus 3 (cumulative dose = 20 µg/kg) and in 92.8% of cases after bolus 4 (cumulative dose = 30 µg/kg). Cavutilide was effective in 89% of cases with persistent AF with a median duration of 70.5 [30;159] days and in 92% of cases with paroxysmal AF with a median duration of 36 [24;102] h. In the group of patients without HF, the effectiveness of bolus 1 was 36.9%, that of the bolus 2 was 58%, that of the bolus 3 was 77% and that of the bolus 4 was 90.1%. Cavutilide restored SR in 90% of patients with persistent AF with a median duration of 82.5 [28;180] days and in 90% of cases with paroxysmal AF with a median duration of 50 [24;120] h. No statistically significant difference in the probability of SR restoration or the effectiveness of each bolus of cavutilide was found between patients with and without HF. The median time to restoration of SR in patients with HF was 23 [11;55] min, and that in patients without HF was 22 [10;45] min (p = 0.424). No cases of symptomatic/severe bradycardia were observed in either group. QT prolongation over 500 ms after cavutilide injection was registered in 19% of patients without HF and in 15.5% of those with HF (p = 0.58). Short runs of Torsade de pointes tachycardia occurred in one patient (0.4%) without HF after 10 µg cavutilide administration and were successfully treated with MgSO4. CONCLUSIONS: Cavutilide demonstrated a high likelihood of AF conversion to SR in paroxysmal (92%) and persistent (89%) arrhythmia and HF. Concomitant HF and its severity do not affect the efficacy and safety of cavutilide.

Phosphate Dysregulation and Metabolic Syndrome.

Phosphorus is one of the most abundant minerals in the human body. It is essential for almost all biochemical activities through ATP formation, intracellular signal transduction, cell membrane formation, bone mineralization, DNA and RNA synthesis, and inflammation modulation through various inflammatory cytokines. Phosphorus levels must be optimally regulated, as any deviations may lead to substantial derangements in glucose homeostasis. Clinical studies have reported that hyperphosphatemia can increase an individual's risk of developing metabolic syndrome. High phosphate burden has been shown to impair glucose metabolism by impairing pancreatic insulin secretion and increasing the risk of cardiometabolic disorders. Phosphate toxicity deserves more attention as metabolic syndrome is being seen more frequently worldwide and should be investigated further to determine the underlying mechanism of how phosphate burden may increase the cardiometabolic risk in the general population.

Rare Cause of Wide QRS Tachycardia.

Cardiac involvement is a well-known feature of neuromuscular diseases. Most commonly cardiac manifestations occur later in the course of the disease. Occasionally severe cardiac disease, including conduction disturbances, life-threatening arrhythmias, and cardiomyopathy, with its impact on prognosis, may be dissociated from peripheral myopathy. We report a case of bundle branch reentrant ventricular tachycardia as primary manifestation of myotonic dystrophy and discuss associated diagnostic and treatment challenges.

Efficacy of a new class III drug niferidil in cardioversion of persistent atrial fibrillation and flutter.

AIMS: To study the efficacy and safety of the new class III antiarrhythmic agent niferidil for pharmacological cardioversion in patients with persistent atrial fibrillation (AF) and atrial flutter (AFl). METHODS AND RESULTS: One hundred thirty-four adults (aged 57.8 ± 11 years, 90 males) were included with median AF duration of 3 (1.5-6) months. All patients received a total of 10-30 µg/kg, niferidil, intravenously, in 1-3 (if needed) consecutive boluses at 15-minute intervals. Holter electrocardiogram monitoring was started before infusion and was continued for 24 hours. The criterion for an antiarrhythmic effect was sinus rhythm restoration within 24 hours of the initial bolus. Niferidil converted AF to sinus rhythm in 47.7% of cases after bolus 1, in 62% of cases after bolus 2, and in 84.6% of cases bolus 3. Niferidil induced a 100% recovery rate in patients with AFl and a 91.8% recovery rate in patients with AF of duration from 8 days to 3 months. Nonsustained torsade de pointes occurred in 1 patient (0.7%), and nonsustained monomorphic ventricular tachycardia was observed in 5 patients (3.7%). CONCLUSIONS: The new intravenous class III drug niferidil demonstrated high conversion rates of 84.6% in patients with persistent AF and 100% in patients with persistent AFl. Niferidil may be used as a possible alternative to electrical cardioversion for pharmacological cardioversion of persistent AF/AFl.

Biomimetic cooperative interactions of dried cross-linked poly(N-6-aminohexylacrylamide) with binary mixtures of solvent vapors.

Biomimetic cooperativity of hydration effect and effect of ethanol favorable for binding of bad organic sorbates were observed for their vapor sorption by cross-linked poly(N-6-aminohexylacrylamide) (PNAHAA) in the absence of liquid phase. The vapor sorption isotherms were determined for these systems by the static method of gas chromatographic headspace analysis at 298 K. The hydration above 0.09-0.13 g of H(2)O/(g of polymer) gives a cooperative increase in the PNAHAA binding affinity for benzene, cyclohexane, dioxane, and propanols up to a level which does not change by further hydration, indicating the polymer antiplasticization. Bad sorbates (dioxane, benzene) were observed to have a biomimetic cooperative influence on the binding of ethanol by the dried PNAHAA. This cooperativity does not occur in ternary systems with good nonhydroxylic sorbate acetonitrile.

Effects of hydration, lipids, and temperature on the binding of the volatile aroma terpenes by beta-lactoglobulin powders.

The binding properties of dry proteins are relatively poorly known. Many proteins are present in emulsions and suspensions and also in dry forms. This is particularly true of dairy proteins, which are often stored and sold in powdered form. In the present work, the binding of three terpenes (alpha-terpinene, gamma-terpinene, and terpinolene), which belong to the basic aroma components, and of decane by powdered beta-lactoglobulin (BLG) was studied at different hydration levels (0.05-0.40 g of H(2)O/g of protein) and temperatures (298 and 309.5 K), in the presence or absence of lipids and small concentrations of ethanol. Vapor sorption isotherms were determined for these systems by a static method of headspace gas chromatographic analysis. A cooperative effect of hydrophobic hydration was observed for the binding of aroma terpenes and decane by the solid BLG. The temperature increase from 298 to 309.5 K reduced the observed hydration threshold of BLG by 0.05-0.08 g of H(2)O/g of protein. Lipids (1.2% w/w) in hydrated BLG gave at least a 2-fold increase in its binding affinity for the hydrocarbons studied, and synergic effects of the hydration and lipid on this affinity were observed.