Objective: To determine the electrophysiological effects and related mechanisms of late sodium current inhibitors on hearts with short QT intervals. Methods: The electrophysiological study was performed on isolated Langendorff perfused rabbit hearts. A total of 80 New Zealand White rabbits were used and 34 hearts without drug treatment were defined as control group A, these hearts were then treated with I_KATP opener pinacidil, defined as pinacidil group A. Then, 27 hearts from pinacidil group A were selected to receive combined perfusion with sodium channel inhibitors or quinidine, a traditional drug used to treat short QT syndrome, including ranolazine combined group (n=9), mexiletine combined group (n=9), and quinidine combined group (n=9). Nineteen out of the remaining 46 New Zealand rabbits were selected as control group B (no drug treatments, n=19), and then treated with pinacidil, defined as pinacidil group B (n=19). The remaining 27 rabbits were treated with sodium inhibitors or quinidine alone, including ranolazine alone group (n=9), mexiletine alone group (n=9), and quinidine alone group (n=9). Electrocardiogram (ECG) physiological parameters of control group A and pinacidil group A were collected. In control group B and pinacidil group B, programmed electrical stimulation was used to induce ventricular arrhythmias and ECG was collected. ECG physiological parameters and ventricular arrhythmia status of various groups were analyzed. The concentrations of pinacidil, ranolazine, mexiletine and quinidine used in this study were 30, 10, 30 and 1 μmol/L, respectively. Results: Compared with control group A, the QT interval, 90% of the repolarization in epicardial and endocardial monophasic action potential duration (MAPD₉₀-Epi, MAPD₉₀-Endo) was shortened, the transmural dispersion of repolarization (TDR) was increased, and the effective refractor period (ERP) and post-repolarization refractoriness (PRR) were reduced in pinacidil group A (all P<0.05). Compared with the pinacidil group A, MAPD₉₀-Epi, MAPD₉₀-Endo, QT interval changes were reversed in quinidine combined group and mexiletine combined group (all P<0.05), but not in ranolazine combined group. All these three drugs reversed the pinacidil-induced increases of TDR and the decreases of ERP and PRR. The induced ventricular arrhythmia rate was 0 in control group B, and increased to 10/19 (χ²=13.6, P<0.05) in pinacidil group B during programmed electrical stimulation. Compared with the pinacidil group B, incidences of ventricular arrhythmia decreased to 11% (1/9), 11% (1/9) and 0 (0/9) (χ²=4.5, 4.5, 7.4, P<0.05) respectively in ranolazine group, mexiletine group and quinidine group. Conclusions: Inhibition of late sodium current does not increase but even decreases the risk of malignant arrhythmia in hearts with a shortened QT interval. The antiarrhythmic mechanism might be associated with the reversal of the increase of TDR and the decrease of refractoriness (including both ERP and PRR) of hearts with shortened QT interval.
Rabbits ; Animals ; Quinidine/therapeutic use* ; Mexiletine/therapeutic use* ; Pinacidil/therapeutic use* ; Sodium ; Ranolazine/therapeutic use* ; Electrophysiologic Techniques, Cardiac ; Arrhythmias, Cardiac/drug therapy*

Anti-Arrhythmia Agents ; Brugada Syndrome/complications* ; Bundle-Branch Block/complications* ; Electrocardiography ; Humans ; Quinidine ; Ventricular Fibrillation

Nuedexta (dextromethorphan and quinidine) is an Food and Drug Administration approved medication for pseudobulbar affect. Interestingly, this drug was recently reported to improve speech, swallowing, and the ability to handle oral secretions along with emotional lability in amyotrophic lateral sclerosis (ALS) patients with bulbar symptoms. We report a Korean ALS patient whose bulbar function improved after administering Nuedexta for 6 months, extending therapeutic choice of approach in treating ALS patients.
Amyotrophic Lateral Sclerosis ; Deglutition ; Dextromethorphan ; Humans ; Quinidine ; United States Food and Drug Administration

Epilepsy of infancy with migrating focal seizure (MFEI) is an early-onset epileptic encephalopathy characterized by randomly migrating focal seizures and psychomotor deterioration. It is associated with mutations in a variety of genes, with potassium sodium-activated channel subfamily T member 1 (KCNT1) being an example. Previously reported KCNT1 mutations in MFEI are gain-of-function mutations. Therefore, quinidine therapy targeted at reduction of pathologically increased KCNT1 channel-mediated potassium conductance has been proposed as a target treatment for MEFI with KCNT1 mutation. The authors report a case involving a patient with MFEI and a missense mutation in KCNT1 (c.7129G>A; p.Phe346Leu) treated with quinidine therapy. Seizure activity was poorly responsive to quinidine.
Brain Diseases ; Epilepsy* ; Humans ; Mutation, Missense ; Potassium ; Quinidine* ; Seizures*

Neferine, a bisbenzylisoquinoline alkaloid in Lotus Plumule, was proved to have a wide range of biological activities. In the present study, using whole-cell patch-clamp technique, we investigated the effects of neferine on Nav1.5 channels that are stably expressed in HEK 293 cells. We found that neferine potently and reversibly inhibited Nav1.5 currents in a concentration dependent manner with a half-maximal inhibition (IC50) being 26.15 μmol/L. The inhibitory effects of neferine on Nav1.5 currents were weaker than those of quinidine at the same concentration. The steady-state inactivation curve was significantly shifted towards hyperpolarizing direction in the presence of 30 μmol/L neferine, while the voltage-dependent activation was unaltered. Neferine prolonged the time to peak of activation, increased the inactivation time constants of Nav1.5 currents and markedly slowed the recovery from inactivation. The inhibitory effect of neferine could be potentiated in a frequency-dependent manner. These results suggested that neferine can block Nav1.5 channels under the open state and inactivating state and it is an open channel blocker of Nav1.5 channels.
Benzylisoquinolines ; administration & dosage ; Gene Expression Regulation ; drug effects ; HEK293 Cells ; Humans ; NAV1.5 Voltage-Gated Sodium Channel ; biosynthesis ; Patch-Clamp Techniques ; Quinidine ; administration & dosage

We report the case of a 19-year-old male who successfully recovered from sudden cardiac arrest. Careful evaluation did not reveal any electrical or structural abnormalities. He underwent implantable cardioverter defibrillator (ICD) implantation, with a diagnosis of idiopathic ventricular fibrillation (VF). Three months later, VF recurred and was successfully terminated by ICD shock. Electrocardiogram (ECG) revealed a slurred type J point elevation at the inferolateral leads with a horizontal/descending ST segment change, which was not present during the initial hospitalization. Cilostazol was prescribed to prevent further lethal ventricular arrhythmias. Subsequently, no arrhythmic events were reported, and the J wave disappeared at the follow-up ECG. However, recurrent VF episodes with an interval of 1–2 weeks occurred 1 year later, and were terminated by ICD shock. Simultaneous ECG revealed a J point elevation at the inferolateral leads. Cilostazol was replaced by quinidine. Subsequently, no arrhythmic event recurred for over 12 months. Serial follow-up ECG is needed to identify masked inherited primary arrhythmic syndromes in sudden cardiac arrest survivors diagnosed with idiopathic VF. Cilostazol and quinidine might be good therapeutic options to prevent further lethal events in cases where the J wave syndrome is present with recurrent ventricular arrhythmias.
Anti-Arrhythmia Agents ; Arrhythmias, Cardiac ; Death, Sudden, Cardiac* ; Defibrillators ; Diagnosis ; Electrocardiography ; Follow-Up Studies ; Heart Arrest ; Hospitalization ; Humans ; Male ; Masks ; Quinidine ; Shock ; Survivors ; Ventricular Fibrillation ; Young Adult

Myometrial relaxation of mouse via expression of two-pore domain acid sensitive (TASK) channels was studied. In our previous report, we suggested that two-pore domain acid-sensing K⁺ channels (TASK-2) might be one of the candidates for the regulation of uterine circular smooth muscles in mice. In this study, we tried to show the mechanisms of relaxation via TASK-2 channels in marine myometrium. Isometric contraction measurements and patch clamp technique were used to verify TASK conductance in murine myometrium. Western blot and immunehistochemical study under confocal microscopy were used to investigate molecular identity of TASK channel. In this study, we showed that TEA and 4-AP insensitive non-inactivating outward K⁺ current (NIOK) may be responsible for the quiescence of murine pregnant longitudinal myometrium. The characteristics of NIOK coincided with two-pore domain acid-sensing K⁺ channels (TASK-2). NIOK in the presence of K⁺ channel blockers was inhibited further by TASK inhibitors such as quinidine, bupivacaine, lidocaine, and extracellular acidosis. Furthermore, oxytocin and estrogen inhibited NIOK in pregnant myometrium. When compared to non-pregnant myometrium, pregnant myometrium showed stronger inhibition of NIOK by quinidine and increased immunohistochemical expression of TASK-2. Finally, TASK-2 inhibitors induced strong myometrial contraction even in the presence of L-methionine, a known inhibitor of stretch-activated channels in the longitudinal myometrium of mouse. Activation of TASK-2 channels seems to play an essential role for relaxing uterus during pregnancy and it might be one of the alternatives for preventing preterm delivery.
Acidosis ; Animals ; Blotting, Western ; Bupivacaine ; Estrogens ; Female ; Isometric Contraction ; Lidocaine ; Methionine ; Mice* ; Microscopy, Confocal ; Muscle, Smooth ; Myometrium ; Oxytocin ; Pregnancy ; Quinidine ; Relaxation* ; Tea ; Uterine Contraction ; Uterus

BACKGROUND/AIMS: The aim of this study was to investigate the inconveniences and potential improvements in the use of orphan drugs for the treatment of infectious diseases, as determined by a survey of medical professionals. METHODS: An email was sent twice to the members of the Korean Society for Chemotherapy, and an online survey was conducted. The data collected were analyzed in terms of the frequency of drug use and associated difficulties as well as the scope for improvement. RESULTS: A total of 77 medical professionals participated in this survey. Rabies vaccine (n = 52), rabies immunoglobulin (n = 47), and foscarnet injection (n = 43) were supplied mainly through the Korea Orphan Drug Center (KODC), while artesunate (n = 29), quinine sulfate capsule (n = 24), quinine dihydrochloride injection (n = 23), and quinidine gluconate injection (n = 21) were supplied mainly through the National Medical Center (NMC). Difficulties in obtaining orphan drugs through the KODC were related to the KODC drug retrieval system (n = 67, 95.7% of respondents), lack of supplies on holidays (n = 66, 94.3%), complicated application procedures and documents (n = 61, 87.1%), and shipping inconveniences (n = 61, 87.1%). With regard to the use of orphan drugs supplied through the NMC, 52 participants (98.1%) responded that a staff visit should be mandatory for obtaining the drugs. CONCLUSIONS: Antivirals and antimalarial drugs are major orphan drugs used for the treatment of rare infections. It is necessary to establish a more efficient system to ensure a stable supply of orphan drugs, including on holidays, to enhance the smart drug searching system, and to simplify related administrative procedures.
Antimalarials ; Antiviral Agents ; Child ; Child, Orphaned* ; Communicable Diseases* ; Drug Therapy ; Electronic Mail ; Equipment and Supplies ; Foscarnet ; Holidays ; Humans ; Immunoglobulins ; Infectious Disease Medicine ; Korea ; Orphan Drug Production* ; Quinidine ; Quinine ; Rabies ; Rabies Vaccines ; Rare Diseases ; Ships

Brugada syndrome is a rare channelopathy associated with the SCN5A gene that causes fatal ventricular arrhythmias. This case of Brugada syndrome, in which ventricular tachycardia (VT) was provoked by high fever, is the first report in a Korean child. The boy had retinoblastoma of his left eye diagnosed at 16 months of age. After chemotherapy, he contracted a catheter-related infection with a high fever up to 41degrees C leading to monomorphic VT. This was characterized as having right bundle branch block morphology, superior axis deviation, and a heart rate of 212/min. Direct current cardioversion recovered the VT to sinus rhythm after a lack of response to amiodarone and lidocaine. A second attack of VT that was not controlled by cardioversion, however, responded to lidocaine. The baseline electrocardiogram showed a long PR interval and QRS duration, and the patient's grandfather had a history of Brugada syndrome. A mutation in SCN5A was identified in this patient, his father, and his grandfather. The patient was treated with quinidine and followed up for 1 year.
Amiodarone ; Arrhythmias, Cardiac ; Axis, Cervical Vertebra ; Brugada Syndrome* ; Bundle-Branch Block ; Catheter-Related Infections ; Channelopathies ; Child ; Drug Therapy ; Electric Countershock ; Electrocardiography ; Fathers ; Fever ; Heart Rate ; Humans ; Lidocaine ; Male ; Quinidine ; Retinoblastoma ; Tachycardia, Ventricular*

Plasma pH can be altered during pregnancy and at labor. Membrane excitability of smooth muscle including uterine muscle is suppressed by the activation of K+ channels. Because contractility of uterine muscle is regulated by extracellular pH and humoral factors, K+ conductance could be connected to factors regulating uterine contractility during pregnancy. Here, we showed that TASK-2 inhibitors such as quinidine, lidocaine, and extracellular acidosis produced contraction in uterine circular muscle of mouse. Furthermore, contractility was significantly increased in pregnant uterine circular muscle than that of non-pregnant muscle. These patterns were not changed even in the presence of tetraetylammonium (TEA) and 4-aminopyridine (4-AP). Finally, TASK-2 inhibitors induced strong myometrial contraction even in the presence of L-methionine, a known inhibitor of stretchactivated channels in myometrium. When compared to non-pregnant myometrium, pregnant myometrium showed increased immunohistochemical expression of TASK-2. Therefore, TASK-2, seems to play a key role during regulation of myometrial contractility in the pregnancy and provides new insight into preventing preterm delivery.
4-Aminopyridine ; Acidosis ; Animals ; Contracts ; Female ; Hydrogen-Ion Concentration ; Lidocaine ; Membranes ; Methionine ; Mice ; Muscle, Smooth ; Muscles ; Myometrium ; Plasma ; Pregnancy ; Quinidine ; Relaxation ; Uterine Contraction ; Uterus