Precision therapy for epilepsy due to KCNT1 mutations: A randomized trial of oral quinidine.

OBJECTIVE: To evaluate quinidine as a precision therapy for severe epilepsy due to gain of function mutations in the potassium channel gene KCNT1. METHODS: A single-center, inpatient, order-randomized, blinded, placebo-controlled, crossover trial of oral quinidine included 6 patients with severe autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) due to KCNT1 mutation. Order was block randomized and blinded. Four-day treatment blocks were used with a 2-day washout between. Dose started at 900 mg over 3 divided doses then, in subsequent participants, was reduced to 600 mg, then 300 mg. Primary outcome was seizure frequency measured on continuous video-EEG in those completing the trial. RESULTS: Prolonged QT interval occurred in the first 2 patients at doses of 900 and 600 mg quinidine per day, respectively, despite serum quinidine levels well below the therapeutic range (0.61 and 0.51 µg/mL, reference range 1.3-5.0 µg/mL). Four patients completed treatment with 300 mg/d without adverse events. Patients completing the trial had very frequent seizures (mean 14 per day, SD 7, median 13, interquartile range 10-18). Seizures per day were nonsignificantly increased by quinidine (median 2, 95% confidence interval -1.5 to +5, p = 0.15) and no patient had a 50% seizure reduction. CONCLUSION: Quinidine did not show efficacy in adults and teenagers with ADNFLE. Dose-limiting cardiac side effects were observed even in the presence of low measured serum quinidine levels. Although small, this trial suggests use of quinidine in ADNFLE is likely to be ineffective coupled with considerable cardiac risks. CLINICAL TRIALS REGISTRATION: Australian Therapeutic Goods Administration Clinical Trial Registry (trial number 2015/0151). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for persons with severe epilepsy due to gain of function mutations in the potassium channel gene KCNT1, quinidine does not significantly reduce seizure frequency.

An integrated anti-arrhythmic target network of compound Chinese medicine Wenxin Keli revealed by combined machine learning and molecular pathway analysis [corrected].

Wenxin Keli (WK), a Chinese patent medicine, is known to be effective against cardiac arrhythmias and heart failure. Although a number of electrophysiological findings regarding its therapeutic effect have been reported, the active components and system-level characterizations of the component-target interactions of WK have yet to be elucidated. In the current study, we present the first report of a new protective effect of WK on suppressing anti-arrhythmic-agent-induced arrhythmias. In a model of isolated guinea pig hearts, rapid perfusion of quinidine altered the heart rate and prolonged the Q-T interval. Pretreatment with WK significantly prevented quinidine-induced arrhythmias. To explain the therapeutic and protective effects of WK, we constructed an integrated multi-target pharmacological mechanism prediction workflow in combination with machine learning and molecular pathway analysis. This workflow had the ability to predict and rank the probability of each compound interacting with 1715 target proteins simultaneously. The ROC value statistics showed that 97.786% of the values for target prediction were larger than 0.8. We applied this model to carry out target prediction and network analysis for the identified components of 5 herbs in WK. Using the 124 potential anti-arrhythmic components and the 30 corresponding protein targets obtained, an integrative anti-arrhythmic molecular mechanism of WK was proposed. Emerging drug/target networks suggested ion channel and intracellular calcium and autonomic nervous and hormonal regulation had critical roles in WK-mediated anti-arrhythmic activity. A validation of the proposed mechanisms was achieved by demonstrating that calaxin, one of the WK components from Gansong, dose-dependently blocked its predicted target CaV1.2 channel in an electrophysiological assay.

Dextromethorphan/quinidine for the treatment of pseudobulbar affect.

OBJECTIVE: To evaluate the role of dextromethorphan/quinidine (DM/Q; Nuedexta™) in the treatment of pseudobulbar affect (PBA). DATA SOURCES: A literature search of MEDLINE/PubMed (January 1966-June 2013) was conducted using search terms pseudobulbar affect, pathological laughing and/or crying, emotional lability, dextromethorphan, and quinidine. STUDY SELECTION AND DATA EXTRACTION: English language clinical trials and case reports evaluating the safety and efficacy of DM/Q in PBA were included for review. Bibliographies of all relevant articles were reviewed for additional citations. DATA SYNTHESIS: PBA, a poorly understood disorder, is characterized by involuntary crying and/or laughing. In the past, antidepressants and antiepileptics have been used off-label with mixed results. Four clinical trials have evaluated the use of DM/Q for the treatment of PBA. Although the therapeutic outcomes with DM/Q have been positive, interpretation of the published evidence is limited by small sample size and short treatment duration. CONCLUSIONS: Based on the data available, DM/Q may be a viable, short-term treatment alternative for PBA. Long-term safety and efficacy data are lacking.

Long-term follow-up of asymptomatic Brugada patients with inducible ventricular fibrillation under hydroquinidine.

AIMS: To evaluate the long-term efficacy and safety of an electrophysiologically guided therapy, based on a strategy of treatment using hydroquinidine (HQ) among asymptomatic Brugada patients with inducible ventricular fibrillation (VF). METHODS AND RESULTS: In two French reference centres, consecutive asymptomatic type 1 Brugada patients with inducible VF were treated with HQ (600 mg/day, targeting a therapeutic range between 3 and 6 µmol/L) and enroled in a specific follow-up (mean 6.6 ± 3 years), including a second programmed ventricular stimulation (PVS) under HQ. An implantable cardioverter defibrillator (ICD) was eventually implanted in patients inducible under HQ, or during follow-up in case of HQ intolerance, as well as occurrence of arrhythmic events. From a total of 397 Brugada patients, 44 were enroled (47 ± 10 years, 95% male). Of these, 34 (77%) were no more inducible (Group PVS-), and were maintained under HQ alone during a mean follow-up of 6.2 ± 3 years. In this group, an ICD was eventually implanted in four patients (12%), with occurrence of appropriate ICD therapies in one. Among the 10 other patients (22%), who remained inducible and received ICD (Group PVS+), none of them received appropriate therapy during a mean follow-up of 7.7 ± 2 years. The overall annual rate of arrhythmic events was 1.04% (95% confidence interval 0.00-2.21), without any significant difference according to the result of PVS under HQ. One-third of patients experienced device-related complications. CONCLUSION: Our long-term follow-up results emphasize that the rate of arrhythmic events among asymptomatic Brugada patients with inducible VF remains low over time. Our results also suggest that residual inducibility under HQ is of limited value to predict events during follow-up.

Dextromethorphan/quinidine: in pseudobulbar affect.

Pseudobulbar affect is characterized by uncontrollable, inappropriate laughing and/or crying that is either unrelated or out of proportion to the emotions felt by the patient and occurs in patients with neurological disorders, such as amyotrophic lateral sclerosis (ALS), multiple sclerosis or traumatic brain injury. Dextromethorphan/quinidine is indicated in the US for the treatment of pseudobulbar affect. Dextromethorphan, when its metabolism is inhibited by the coadministration of quinidine, has been shown to have a positive effect on the symptoms of pseudobulbar affect. Dextromethorphan/quinidine 20 mg/10 mg twice daily was associated with a significantly greater decrease in the rate of pseudobulbar affect episodes per day (primary endpoint) than placebo in the 12-week, randomized, double-blind, placebo-controlled, multicentre STAR trial (Safety, Tolerability, And efficacy Results trial of AVP-923 in PBA [pseudobulbar affect]) involving patients with pseudobulbar affect and ALS or multiple sclerosis. Moreover, the mean change from baseline in Center for Neurologic Study-Lability Scale score at 12 weeks was significantly greater among recipients of dextromethorphan/quinidine 20 mg/10 mg twice daily than those receiving placebo. Dextromethorphan/quinidine 20 mg/10 mg twice daily was generally well tolerated. The drug has been shown to cause dosage-dependent corrected QT interval (QTc) prolongation; however, in the STAR trial, dextromethorphan/quinidine 20 mg/10 mg twice daily appeared to be well tolerated with regard to QTc prolongation.

It's nothing to laugh about: understanding disorders of emotional expression.

Sudden outbursts of laughing, crying, or other emotional expression without an apparent triggering stimulus have been recorded in the literature for decades. Confusing nomenclature and a paucity of clinical research, however, have had clinicians wondering whether this syndrome may be both under-recognized and undertreated. Treatment options, including antidepressants, levodopa, and dextromethorphan/quinidine, may show promise in ameliorating symptoms for patients plagued with disorders of emotional expression.

Randomized, controlled trial of dextromethorphan/quinidine for pseudobulbar affect in multiple sclerosis.

OBJECTIVE: To evaluate the efficacy and safety of DM/Q (capsules containing dextromethorphan [DM] and quinidine [Q]) compared with placebo, taken twice daily, for the treatment of pseudobulbar affect over a 12-week period in multiple sclerosis patients. METHODS: A total of 150 patients were randomized in a double-blind, placebo-controlled study to assess pseudobulbar affect with the validated Center for Neurologic Study-Lability Scale. Each patient also recorded the number of episodes experienced between visits, estimated quality of life and quality of relationships on visual analog scales, and completed a pain rating scale. RESULTS: Patients receiving DM/Q had greater reductions in Center for Neurologic Study-Lability Scale scores than those receiving placebo (p < 0.0001) at all clinic visits (days 15, 29, 57, and 85). All secondary end points also favored DM/Q, including the number of crying or laughing episodes (p

QT-screen: high-throughput cardiac safety pharmacology by extracellular electrophysiology on primary cardiac myocytes.

Cardiac safety pharmacology focuses mostly on the drug-induced prolongation of the QT interval in the electrocardiogram. A prolonged QT interval is an important indicator for an increased risk of severe ventricular arrhythmia. Guidelines demand safety tests addressing QT prolongation in vitro and in vivo before a drug enters clinical trials. If safety risks will be detected not until an advanced stage of preclinical drug development, a considerable sum of money has already been invested into the drug development process. To prevent this, high-throughput systems have been developed to obtain information on the potential toxicity of a substance earlier. We will discuss in this publication that the QT-Screen system, which is based on primary cardiac myocytes, is able to provide a sufficient throughput for secondary screening. With this system, extracellular field potentials can be recorded from spontaneously beating cultures of mammalian or avian ventricular cardiac myocytes simultaneously on 96 channels. The system includes software-controlled and automated eight-channel liquid handling, data acquisition, and analysis. These features allow a user-friendly and unsupervised operation. The throughput is over 100 compounds in six replicates and with full dose-response relationships per day. This equals a maximum of approximately 6,000 data points per day at an average cost for consumables of 0.20 US pennies (U.S.) per data point. The system is intended for a non-good laboratory practice-compliant screening; however, it can be adapted to be used in a good laboratory practice environment.

Síndrome antifosfolípido: presentación de un caso con lesiones kaposiformes / Antiphospholipid syndrome: a case report with Kaposi-like lesions

Se comunica una paciente de 44 años de edad que presentaba lesiones kaposiformes profusas, manifestación cutánea infrecuente del síndrome antifosfolípido. Se describen las características clínicas, los hallazgos de laboratorio, así como el tratamiento de esta enfermedad multisistémica (AU)

Quinidine enhances digitalis toxicity at therapeutic serum digoxin levels.

OBJECTIVE: To determine the effect of the digoxin-quinidine interaction on rate of in-hospital digitalis toxicity. METHODS: This was a prospective observational study over 9 months, set in two general medical wards. We studied consecutive patients (n = 141) who were receiving digoxin. Measurements included digitalis toxicity, defined by ECG criteria and resolution after stopping digoxin; all additional medications (including antiarrhythmics) continued. The observer was "blinded" to serum digoxin level and to concomitant drugs. RESULTS: Digitalis toxicity rates were as follows: digoxin alone, 4.9% (5 of 101 patients); with amiodarone or verapamil, 5.0% (1 of 20 patients); with quinidine, 50% (10 of 20 patients) (p < 0.01). No toxicity was seen at digoxin levels < 1.0 ng/ml. Toxicity at 1.0 to 2.0 ng/ml was as follows: digoxin alone, 1 of 41 patients; with quinidine, 4 of 15 patients (p = 0.014). Toxicity was similar at levels > 2.0 ng/ml: 4 of 8 patients and 7 of 11 patients, respectively. Independent relative risks and 95% confidence intervals (CI) of digitalis toxicity were as follows: serum digoxin, 9.1 (95% CI, 2.9 to 13.0); concurrent quinidine, 24.3 (95% CI, 3.4 to 124). There was a significant (p < 0.01) interaction between concurrent quinidine, serum digoxin of 1.0 to 2.0 ng/ml, and digitalis toxicity. CONCLUSION: The digoxin-quinidine interaction significantly increases digitalis toxicity, even in the therapeutic range of serum digoxin levels.

[Pseudoporphyria]. / Pseudoporfyri.

Pseudoporphyria with formation of bullae and vulnerability of skin exposed to light, particularly the backs of the hands, may be provoked medicinally by nalidixinic acid, tetracyclin, nabumeton, pyridoxine, dapsone and high-dosage furosemide and by excessive use of solaria. The present article demonstrates that the condition may also be precipitated by quinidine and ibuprophen.