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British Journal of Clinical Pharmacology Dec 2022Despite numerous studies on quinidine therapies for epilepsies associated with KCNT1 gene mutations, there is no consensus on its clinical utility. Thus, we reviewed... (Review)
Review
AIMS
Despite numerous studies on quinidine therapies for epilepsies associated with KCNT1 gene mutations, there is no consensus on its clinical utility. Thus, we reviewed studies evaluating the efficacy and safety of quinidine in KCNT1-related epileptic disorders.
METHODS
Electronic databases were queried for in vivo and in vitro studies on quinidine therapy in KCNT1-related epilepsies published on or before 1 May 2022. The evaluation of evidence was done as per the American Academy of Neurology's classification scheme. Identification of significant factors that possibly influenced therapeutic effects of quinidine were performed using χ tests.
RESULTS
Twenty-seven studies containing 82 patient records were reviewed. Records of 80 patients with 33 KCNT1 mutations were analysed, of which 20 patients had gained ≥50% seizure reduction due to quinidine therapy. However, quinidine therapy often had different effects on patients with the same KCNT1 mutation. Age, genotypes of KCNT1 mutations, seizure types and brain MRI did not significantly influence the therapeutic effect of quinidine. Prolonged QTc was the most common among all adverse events with quinidine. Notably, results of in vitro quinidine tests did not correspond with in vivo tests.
CONCLUSIONS
Therapeutic effects of quinidine on KCNT1-related epilepsies remained indefinite as contradictory results were detected in similar patients. Age, seizure types, genotypes of KCNT1 mutations and brain MRI did not influence the therapeutic effects of quinidine. Insensitivity to quinidine by a certain Kcnt1 genotype in molecular tests is predictive of its inefficacy in human populations of the respective mutation.
Topics: Humans; Quinidine; Potassium Channels, Sodium-Activated; Anticonvulsants; Nerve Tissue Proteins; Epilepsy; Seizures; Mutation
PubMed: 35940594
DOI: 10.1111/bcp.15479 -
JACC. Clinical Electrophysiology Oct 2021This study aimed to review the utility of quinidine in patients presenting with recurrent sustained ventricular arrhythmia (VA) and limited antiarrhythmic drug (AAD)... (Review)
Review
OBJECTIVES
This study aimed to review the utility of quinidine in patients presenting with recurrent sustained ventricular arrhythmia (VA) and limited antiarrhythmic drug (AAD) options.
BACKGROUND
Therapeutic options are often limited in patients with structural heart disease and recurrent VAs. Quinidine has an established role in rare arrhythmic syndromes, but its potential use in other difficult VAs has not been assessed in the present era.
METHODS
We performed a retrospective analysis of 37 patients who had in-hospital quinidine initiation after multiple other therapies failed for VA suppression at our tertiary referral center. Clinical data and outcomes were obtained from the medical record.
RESULTS
Of 30 patients with in-hospital quantifiable VA episodes, quinidine reduced acute VA from a median of 3 episodes (interquartile range [IQR]: 2 to 7.5) to 0 (IQR: 0 to 0.5) during medians of 3 days before and 4 days after quinidine initiation (p < 0.001). VA events decreased from a median of 10.5 episodes per day (IQR: 5 to 15) to 0.5 episodes (IQR: 0 to 4) after quinidine initiation in the 12 patients presenting with electrical storm (p = 0.004). Among the 24 patients discharged on quinidine, 13 (54.2%) had VA recurrence during a median of 138 days. Adverse effects in 9 of the 37 patients (24.3%) led to drug discontinuation, most commonly gastrointestinal intolerance.
CONCLUSIONS
In patients with recurrent VAs and structural heart disease who have limited treatment options, quinidine can be useful, particularly as a short-term therapy.
Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Humans; Quinidine; Retrospective Studies; Ventricular Fibrillation
PubMed: 34217656
DOI: 10.1016/j.jacep.2021.03.024 -
Clinical Pharmacology in Drug... Jul 2022Rimegepant (Nurtec ODT)-an orally administered, small-molecule calcitonin gene-related peptide receptor antagonist indicated for the acute and preventive treatment of... (Randomized Controlled Trial)
Randomized Controlled Trial
Rimegepant (Nurtec ODT)-an orally administered, small-molecule calcitonin gene-related peptide receptor antagonist indicated for the acute and preventive treatment of migraine-is a substrate for both the P-glycoprotein and breast cancer resistance protein transporters in vitro. We evaluated the effects of concomitant administration of strong inhibitors of these transporters on the pharmacokinetics of rimegepant in healthy subjects. This single-center, open-label, randomized study was conducted in 2 parts, both of which were 2-period, 2-sequence, crossover studies. Part 1 (n = 15) evaluated the effect of a single oral dose of 200-mg cyclosporine, a strong inhibitor of the P-glycoprotein and breast cancer resistance protein transporters, on the pharmacokinetics of rimegepant 75 mg. Part 2 (n = 12) evaluated the effect of a single oral dose of 600-mg quinidine, a strong selective P-glycoprotein transporter, on the pharmacokinetics of rimegepant 75 mg. Coadministration with cyclosporine showed an increase in rimegepant area under the plasma concentration-time curve from time 0 to infinity and maximum observed concentration based on geometric mean ratios (90% confidence intervals [CIs]) of 1.6 (1.49-1.72) and 1.41 (1.27-1.57), respectively, versus rimegepant alone. Coadministration with quinidine showed an increase in rimegepant area under the plasma concentration-time curve from time 0 to infinity and maximum observed concentration geometric mean ratios (90% CIs) of 1.55 (1.40-1.72) and 1.67 (1.46-1.91), respectively, versus rimegepant alone. Strong P-glycoprotein inhibitors (cyclosporine, quinidine) increased rimegepant exposures (>50%, <2-fold). In parts 1 and 2, rimegepant coadministration was well tolerated and safe. The similar effect of cyclosporine and quinidine coadministration on rimegepant exposure suggests that inhibition of breast cancer resistance protein inhibition may have less influence on rimegepant exposure.
Topics: ATP Binding Cassette Transporter, Subfamily B; Breast Neoplasms; Cross-Over Studies; Cyclosporine; Female; Healthy Volunteers; Humans; Membrane Transport Proteins; Neoplasm Proteins; Piperidines; Pyridines; Quinidine
PubMed: 35304977
DOI: 10.1002/cpdd.1088 -
Drug Design, Development and Therapy 2019Eliglustat, a new oral substrate-reduction therapy, was recently approved as a first-line therapy for Gaucher's disease type 1 (GD1) patients.
BACKGROUND
Eliglustat, a new oral substrate-reduction therapy, was recently approved as a first-line therapy for Gaucher's disease type 1 (GD1) patients.
PURPOSE
The purpose of the present study was to develop and validate a simple UPLC-MS/MS method for the measurement of plasma-eliglustat concentration and to investigate the effects of amiodarone and quinidine on eliglustat metabolism in rats.
METHODS
Eighteen rats were randomly divided into three groups (n=6): control (0.5% CMC-Na, group A), amiodarone (60 mg/kg, group B), and quinidine (100 mg/kg, group C). Thirty minutes later, 10 mg/kg eliglustat was orally administered to each rat and concentrations of eliglustat in the rats determined by our UPLC-MS/MS method.
RESULTS
Amiodarone and quinidine increased the main pharmacokinetic parameters (AUC0→ , AUC, and C) of eliglustat significantly and decreased clearance obviously.
CONCLUSION
Amiodarone and quinidine can elevate eliglustat exposure and have an inhibitory effect on eliglustat metabolism. Clearly, appropriate pharmacological studies of eliglustat in patients treated with amiodarone or quinidine should be done in future.
Topics: Amiodarone; Animals; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Drug Interactions; Male; Molecular Structure; Pyrrolidines; Quinidine; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Tandem Mass Spectrometry
PubMed: 31849452
DOI: 10.2147/DDDT.S226948 -
JACC. Clinical Electrophysiology Mar 2019This study sought to determine the nature of quinidine use and accessibility in a national network of inherited arrhythmia clinics.
OBJECTIVES
This study sought to determine the nature of quinidine use and accessibility in a national network of inherited arrhythmia clinics.
BACKGROUND
Quinidine is an antiarrhythmic medication that has been shown to be beneficial in select patients with Brugada syndrome, early repolarization syndrome, and idiopathic ventricular fibrillation. Because of the low prevalence of these conditions and restricted access to quinidine through a single regulatory process, quinidine use is rare in Canada.
METHODS
Subjects prescribed quinidine were identified through the Hearts in Rhythm Organization that connects the network of inherited arrhythmia clinics across Canada. Cases were retrospectively reviewed for patient characteristics, indications for quinidine use, rate of recurrent ventricular arrhythmia, and issues with quinidine accessibility.
RESULTS
In a population of 36 million, 46 patients are currently prescribed quinidine (0.0000013%, age 48.1 ± 16.1 years, 25 are male). Brugada syndrome, early repolarization syndrome, and idiopathic ventricular fibrillation constituted a diagnosis in 13 subjects (28%), 6 (13%), and 21 (46%), respectively. Overall, 37 subjects (81%) had cardiac arrest as an index event. After initial presentation, subjects experienced 7.47 ± 12.3 implantable cardioverter-defibrillator shocks prior to quinidine use over 34.3 ± 45.9 months, versus 0.86 ± 1.69 implantable cardioverter-defibrillator shocks in 43.8 ± 41.8 months while on quinidine (risk ratio: 8.7, p < 0.001). Twenty-two patients access quinidine through routes external to Health Canada's Special Access Program.
CONCLUSIONS
Quinidine use is rare in Canada, but it is associated with a reduction in recurrent ventricular arrhythmias in patients with Brugada syndrome, early repolarization syndrome, and idiopathic ventricular fibrillation, with minimal toxicity necessitating discontinuation. Drug interruption is associated with frequent breakthrough events. Access to quinidine is important to deliver this potentially lifesaving therapy.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Arrhythmia Agents; Brugada Syndrome; Child; Death, Sudden, Cardiac; Female; Humans; Male; Middle Aged; Practice Guidelines as Topic; Quinidine; Retrospective Studies; Young Adult
PubMed: 30898241
DOI: 10.1016/j.jacep.2018.10.007 -
Canadian Medical Association Journal Dec 1963Benign familial atrial fibrillation is of rare occurrence. A family in which three members manifested this disorder is reported. Apart from this, all three are in...
Benign familial atrial fibrillation is of rare occurrence. A family in which three members manifested this disorder is reported. Apart from this, all three are in excellent health.The relative frequency of non-familial atrial fibrillation in otherwise well people, free from cardiac and metabolic disorders, is stressed. Only too frequently such cases have been and continue to be labelled with the stigma of serious disease with an unhappy prognosis. Serious injustice may be occasioned in such cases in many respects; for example, in the influence that this medical judgment may have on the insurability of young people so afflicted.Methods of exclusion of organic causes of this disorder are outlined and principles of management and treatment are discussed.
Topics: Atrial Fibrillation; Digitalis; Digitalis Glycosides; Genetics; Geriatrics; Pathology; Quinidine
PubMed: 14098892
DOI: No ID Found -
Neurotherapeutics : the Journal of the... Jul 2019Pathogenic variants in KCNT1 represent an important cause of treatment-resistant epilepsy, for which an effective therapy has been elusive. Reports about the...
Pathogenic variants in KCNT1 represent an important cause of treatment-resistant epilepsy, for which an effective therapy has been elusive. Reports about the effectiveness of quinidine, a candidate precision therapy, have been mixed. We sought to evaluate the treatment responsiveness of patients with KCNT1-related epilepsy. We performed an observational study of 43 patients using a collaborative KCNT1 patient registry. We assessed treatment efficacy based upon clinical seizure reduction, side effects of quinidine therapy, and variant-specific responsiveness to treatment. Quinidine treatment resulted in a > 50% seizure reduction in 20% of patients, with rare patients achieving transient seizure freedom. Multiple other therapies demonstrated some success in reducing seizure frequency, including the ketogenic diet and vigabatrin, the latter particularly in patients with epileptic spasms. Patients with the best quinidine response had variants that clustered distal to the NADP domain within the RCK2 domain of the protein. Half of patients did not receive a quinidine trial. In those who did, nearly half did not achieve therapeutic blood levels. More favorable response to quinidine in patients with KCNT1 variants distal to the NADP domain within the RCK2 domain may suggest a variant-specific response.
Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Drug Resistant Epilepsy; Female; Humans; Infant; Male; Nerve Tissue Proteins; Potassium Channels, Sodium-Activated; Quinidine; Registries; Treatment Outcome
PubMed: 31054119
DOI: 10.1007/s13311-019-00739-y -
Journal of Electrocardiology Oct 2005The short QT syndrome is a new congenital entity associated with familial atrial fibrillation and/or sudden death or syncope. Three different gain-of-function mutations... (Review)
Review
The short QT syndrome is a new congenital entity associated with familial atrial fibrillation and/or sudden death or syncope. Three different gain-of-function mutations in genes encoding for cardiac potassium channels (KCNH2, KCNQ1, and KCNJ2) have been identified up to now to cause short QT syndrome. The syndrome is characterized electrocardiographically by a shortened QTc interval less than 300 to 320 milliseconds and a lack of adaptation during increasing heart rates. During programmed electrical stimulation, atrial and ventricular effective refractory periods are shortened, and in a high percentage, ventricular tachyarrhythmias are inducible. Sudden cardiac death occurs in all age groups and even in newborns. Therapy for choice seems to be the implantable cardioverter-defibrillator because of the high incidence of sudden death. However, ICD therapy may be associated with an increased risk of inappropriate therapies for T wave oversensing, which, however, can be resolved by reprogramming ICD detection algorithms. The impact of sotalol, ibutilide, flecainide, and quinidine on QT prolongation has been evaluated. But only quinidine effectively suppressed gain-of-function in IKr, along with prolongation of the QT interval. Furthermore, in patients with a mutation in HERG (SQT1), quinidine rendered ventricular tachyarrhythmias noninducible and restored the QT interval/heart rate relationship toward a reference range. It may serve as an adjunct to ICD therapy or as possible alternative treatment especially for children and newborns.
Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Defibrillators, Implantable; Electrocardiography; Genotype; Heart Conduction System; Humans; Phenotype; Quinidine
PubMed: 16226079
DOI: 10.1016/j.jelectrocard.2005.06.009 -
Orphanet Journal of Rare Diseases Sep 2006A novel clinical entity characterized by ST segment elevation in right precordial leads (V1 to V3), incomplete or complete right bundle branch block, and susceptibility... (Review)
Review
A novel clinical entity characterized by ST segment elevation in right precordial leads (V1 to V3), incomplete or complete right bundle branch block, and susceptibility to ventricular tachyarrhythmia and sudden cardiac death has been described by Brugada et al. in 1992. This disease is now frequently called "Brugada syndrome" (BrS). The prevalence of BrS in the general population is unknown. The suggested prevalence ranges from 5/1,000 (Caucasians) to 14/1,000 (Japanese). Syncope, typically occurring at rest or during sleep (in individuals in their third or fourth decades of life) is a common presentation of BrS. In some cases, tachycardia does not terminate spontaneously and it may degenerate into ventricular fibrillation and lead to sudden death. Both sporadic and familial cases have been reported and pedigree analysis suggests an autosomal dominant pattern of inheritance. In approximately 20% of the cases BrS is caused by mutations in the SCN5A gene on chromosome 3p21-23, encoding the cardiac sodium channel, a protein involved in the control of myocardial excitability. Since the use of the implantable cardioverter defibrillator (ICD) is the only therapeutic option of proven efficacy for primary and secondary prophylaxis of cardiac arrest, the identification of high-risk subjects is one of the major goals in the clinical decision-making process. Quinidine may be regarded as an adjunctive therapy for patients at higher risk and may reduce the number of cases of ICD shock in patients with multiple recurrences.
Topics: Anti-Arrhythmia Agents; Brugada Syndrome; Defibrillators, Implantable; Humans; Muscle Proteins; Mutation; NAV1.5 Voltage-Gated Sodium Channel; Quinidine; Sodium Channels
PubMed: 16972995
DOI: 10.1186/1750-1172-1-35 -
Drugs of Today (Barcelona, Spain : 1998) Sep 2008A new agent containing a combination of dextromethorphan (DM) and quinidine (Q) is currently under development for the treatment of pseudobulbar affect (PBA). PBA is a... (Review)
Review
A new agent containing a combination of dextromethorphan (DM) and quinidine (Q) is currently under development for the treatment of pseudobulbar affect (PBA). PBA is a disorder of emotional regulation, characterized by uncontrollable outbursts of laughing and/or crying that are disproportionate to the emotions being experienced. The pathophysiology of PBA is currently unknown, although the disorder is thought to occur exclusively in the setting of neurological disease. The most influential theory on PBA posits that emotional outbursts are being generated autonomously in the brain stem due to loss of regulatory control by the frontal lobe. Although rarely life-threatening, PBA can have significant impact on patient quality of life, and thus merits treatment. There are currently no approved treatments for PBA. Several agents have been found to be effective in small placebo-controlled trials and case series, with the most commonly used agents being tricyclic antidepressants and selective serotonin reuptake inhibitors. Both these treatments are inexpensive and relatively low-risk, although the quality and quantity of data available on their efficacy are not optimal. DM has several pharmacological mechanisms of action relevant to the brain. It is an N-methyl-D-aspartate (NMDA) receptor antagonist, which prompted investigators to study its potential for slowing progression in amyotrophic lateral sclerosis (ALS), where glutamate toxicity is thought to be a factor. The combination agent DM/Q was developed to slow the metabolism of DM by P450 2D6 enzymes in the liver. DM/Q was not effective in slowing ALS progression, but patients noted that it helped to control their emotional outbursts, suggesting it might be useful as a treatment for PBA. DM is also a sigma-1 receptor agonist. These receptors are widely distributed in the brain, but probably most heavily in the limbic system, suggesting that DM may exert its emotion-controlling effects via these receptors. The endogenous ligands for sigma-1 receptors are not altogether known, although they appear to include gonadal steroids. DM/Q was recently shown to be effective in reducing the severity of PBA in two large studies of ALS and multiple sclerosis, which are probably the most common neurological settings. These are the largest treatment studies of PBA ever done. The agent was safe and relatively well tolerated. Further studies are being conducted to see if efficacy can be maintained with lower doses of quinidine. If DM/Q is approved by the U.S. Food and Drug Administration for treatment of PBA, it would be the first agent approved for this purpose. Currently, the antidepressants are probably the most attractive pharmacologic options for treatment of PBA. The choice of whether to use DM/Q in this setting will likely depend on individual patient factors as well as cost.
Topics: Antidepressive Agents, Tricyclic; Clinical Trials as Topic; Dextromethorphan; Drug Combinations; Humans; Pseudobulbar Palsy; Quinidine; Selective Serotonin Reuptake Inhibitors
PubMed: 19137121
DOI: 10.1358/dot.2008.44.9.1258664