ALSUntangled #71: Nuedexta.

Nuedexta is a combination of dextromethorphan hydrobromide and quinidine sulfate and was approved by the Food and Drug Administration (FDA) in 2010 to treat pseudobulbar affect (PBA). There have since been anecdotal case reports of bulbar function improvements after Nuedexta treatment. Here, we review the off-label use of Nuedexta for improving bulbar function in people with ALS. Nuedexta has plausible mechanisms for protecting brain stem motor neurons via its effects on S1R and glutamate excitotoxicity. Recent clinical trials support that Nuedexta can improve bulbar function in PALS, with or without PBA. Nuedexta causes mild to moderate side effects. Based on this information, we support considering Nuedexta treatment for bulbar dysfunction in ALS patients with or without PBA.

Dextromethorphan/quinidine for the treatment of bulbar impairment in amyotrophic lateral sclerosis.

OBJECTIVE: No efficacious treatments exist to improve or prolong bulbar functions of speech and swallowing in persons with amyotrophic lateral sclerosis (pALS). This study evaluated the short-term impact of dextromethorphan/quinidine (DMQ) treatment on speech and swallowing function in pALS. METHODS: This was a cohort trial conducted between August 2019 to August 2021 in pALS with a confirmed diagnosis of probable-definite ALS (El-Escorial Criteria-revisited) and bulbar impairment (ALS Functional Rating Scale score ≤ 10 and speaking rate ≤ 140 words per minute) who were DMQ naïve. Efficacy of DMQ was assessed via pre-post change in the ALS Functional Rating Scale-Revised bulbar subscale and validated speech and swallowing outcomes. Paired t-tests, Fisher's exact, and χ2 tests were conducted with alpha at 0.05. RESULTS: Twenty-eight pALS enrolled, and 24 participants completed the 28-day trial of DMQ. A significant increase in ALSFRS-R bulbar subscale score pre- (7.47 ± 1.98) to post- (8.39 ± 1.79) treatment was observed (mean difference: 0.92, 95% CI: 0.46-1.36, p < 0.001). Functional swallowing outcomes improved, with a reduction in unsafe (75% vs. 44%, p = 0.003) and inefficient swallowing (67% vs. 58%, p = 0.002); the relative speech event duration in a standard reading passage increased, indicating a greater duration of uninterrupted speech (mean difference: 0.33 s, 95% CI: 0.02-0.65, p = 0.035). No differences in diadochokinetic rate or speech intelligibility were observed (p > 0.05). INTERPRETATION: Results of this study provide preliminary evidence that DMQ pharmacologic intervention may have the potential to improve or maintain bulbar function in pALS.

Bayesian Network Meta-analysis of Randomized Controlled Trials on the Efficacy of Antiarrhythmics in the Pharmacological Cardioversion of Paroxysmal Atrial Fibrillation.

PURPOSE: Since atrial fibrillation (AF) is one of the major arrhythmias managed in hospitals worldwide, it has a major impact on public health. The guidelines agree on the desirability of cardioverting paroxysmal AF episodes. This meta-analysis aims to answer the question of which antiarrhythmic agent is most effective in cardioverting a paroxysmal AF. MATERIALS AND METHODS: A systematic review and Bayesian network meta-analysis, searching MEDLINE, Embase, and CINAHL, were performed, including randomized controlled trials (RCTs) enrolling a population of unselected adult patients with a paroxysmal AF that compared at least two pharmacological regimes to restore the sinus rhythm or a cardioversion agent against a placebo. The main outcome was efficacy in restoring sinus rhythm. RESULTS: Sixty-one RCTs (7988 patients) were included in the quantitative analysis [deviance information criterion (DIC) 272.57; I2 = 3%]. Compared with the placebo, the association verapamil-quinidine shows the highest SUCRA rank score (87%), followed by antazoline (86%), vernakalant (85%), tedisamil at high dose (i.e., 0.6 mg/kg; 80%), amiodarone-ranolazine (80%), lidocaine (78%), dofetilide (77%), and intravenous flecainide (71%). Taking into account the degree of evidence of each individual comparison between pharmacological agents, we have drawn up a ranking of pharmacological agents from the most effective to the least effective. CONCLUSIONS: In comparing the antiarrhythmic agents used to restore sinus rhythm in the case of paroxysmal AF, vernakalant, amiodarone-ranolazine, flecainide, and ibutilide are the most effective medications. The verapamil-quinidine combination seems promising, though few RCTs have studied it. The incidence of side effects must be taken into account in the choice of antiarrhythmic in clinical practice. CLINICAL TRIAL REGISTRATION: PROSPERO: International prospective register of systematic reviews, 2022, CRD42022369433 (Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022369433 ).

A potent ion channel blocker, hydroquinidine, exhibits strong anti-cancer activity on colon, pancreatic, and hepatocellular cancer cells.

BACKGROUND: Despite recent advances in drug discovery, cancer is still one of the most lethal health problems worldwide. In most cases, standard therapy methods and multi-modal treatments fail, and new therapeutic approaches are required. Ion channels are essential in multiple cellular processes regulating cell division, differentiation, and death. Recent studies on ion-channel modulators emphasize their potential to suppress tumor growth. In that regard, we reasoned that an underinvestigated potassium channel modulator, Hydroquinidine (HQ), may exhibit an anti-carcinogenic activity. METHODS AND RESULTS: HQ's potential as an anti-neoplastic compound was examined using colony formation assay, wound healing assay, soft agar assay, and Annexin-V assay in the colon, pancreatic, and hepatocellular carcinomas. Our findings unveiled a remarkable anti-cancer activity of HQ by decreasing colony-forming ability, migration capacity, tumorigenicity, and proliferation and stimulating cellular death. HQ significantly reduced the formed colonies and tumorigenicity for all cells. It displayed a significant anti-migrative effect on hepatocellular carcinoma cells and promoted apoptosis in pancreatic and liver cancer cells. The altered gene expression profile upon HQ treatment was in accordance with observed cellular effects. Cells incubated with HQ downregulated the genes acting in cell division and survival, whereas the expression level of genes functioning in cell cycle arrest and apoptosis was elevated. CONCLUSION: Our data indicate HQ's competency to limit cancer growth and suggest its utilization as a novel potent anti-carcinogenic agent. Future studies are necessary to provide new insights into the HQ action mechanism and to evaluate its capacity in in-vivo.

New use for an old drug: quinidine in KCNT1-related epilepsy therapy.

KCNT1 has been known to encode a subunit of the tetrameric sodium activated potassium channel (KNa1.1). Pathogenic variants of KCNT1, especially gain-of-function (GOF) variants, are associated with multiple epileptic disorders which are often refractory to conventional anti-seizure medications and summarized as KCNT1-related epilepsy. Although the detailed pathogenic mechanisms of KCNT1-related epilepsy remain unknown, increasing studies attempt to find effective medications for those patients by utilizing quinidine to inhibit hyperexcitable KNa1.1. However, it has been shown that controversial outcomes among studies and partial success in some individuals may be due to multiple factors, such as poor blood-brain barrier (BBB) penetration, mutation-dependent manner, phenotype-genotype associations, and rational therapeutic schedule. In recent years, with higher resolution of KNa1.1 structure in different activation states and advanced synthetic techniques, it improves the process performance of therapy targeting at KNa1.1 channel to achieve more effective outcomes. Here, we systematically reviewed the study history of quinidine on KCNT1-related epilepsy and its corresponding therapeutic effects. Then, we analyzed and summarized the possible causes behind the different outcomes of the application of quinidine. Finally, we outlooked the recent advances in precision medicine treatment for KCNT1-related epilepsy.

[Impact of late sodium current inhibition on cardiac electrophysiology parameters and ventricular arrhythmias in isolated Langendorff perfused rabbit hearts with short QT interval].

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 IKATP 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.

Dextromethorphan: From Cough Suppressant to Antidepressant.

Dextromethorphan (DXM) has been re-purposed several times over the past 7 decades: first as a cough suppressant, then as a compounded formulation with quinidine for treatment of pseudobulbar affect, and most recently as a compounded formulation with bupro-pion for treatment of major depressive disorder. The current article describes the history and purported mechanisms of action of DXM for each use and the uniquely rapid action and safety profile of the oral dextromethorphan- bupropion antidepressant formulation. [Journal of Psychosocial Nursing and Mental Health Services, 60(11), 9-11.].

Computational analysis of arrhythmogenesis in KCNH2 T618I mutation-associated short QT syndrome and the pharmacological effects of quinidine and sotalol.

Short QT syndrome (SQTS) is a rare but dangerous genetic disease. In this research, we conducted a comprehensive in silico investigation into the arrhythmogenesis in KCNH2 T618I-associated SQTS using a multi-scale human ventricle model. A Markov chain model of IKr was developed firstly to reproduce the experimental observations. It was then incorporated into cell, tissue, and organ models to explore how the mutation provided substrates for ventricular arrhythmias. Using this T618I Markov model, we explicitly revealed the subcellular level functional alterations by T618I mutation, particularly the changes of ion channel states that are difficult to demonstrate in wet experiments. The following tissue and organ models also successfully reproduced the changed dynamics of reentrant spiral waves and impaired rate adaptions in hearts of T618I mutation. In terms of pharmacotherapy, we replicated the different effects of a drug under various conditions using identical mathematical descriptions for drugs. This study not only simulated the actions of an effective drug (quinidine) at various physiological levels, but also elucidated why the IKr inhibitor sotalol failed in SQT1 patients through profoundly analyzing its mutation-dependent actions.

Intolerance to quinidine in a n-of-1 trial for KCNT1 associated epilepsy of infancy with migrating focal seizures.

Quinidine has been proposed as a repurposed licensed drug for the treatment of seizures in KCNT1 gain-of-function associated Epilepsy of Infancy with Migrating Focal Seizures (EIMFS). Sparse evidence from case reports suggests limited effectiveness and tolerability. Here we report the adaptation of a n-of-1 trial protocol and results of adjunctive quinidine intervention. We adapted a n-of-1 trial protocol from two unpublished protocols and with expert advice including input from pediatric neurology, cardiology and pharmacy colleagues. We tailored this protocol to a severely disabled patient with EIMFS and a de novo c.1420C>T p.Arg474Lys missense variant. We discussed outcome measures with the family of the patient and initiated adjunctive inpatient quinidine treatment with appropriate safety measures. The trial was terminated as a result of intolerable gastrointestinal adverse effects following the initiation dose. Subsequent reports suggest that quinidine may not be effective for this genotype. Quinidine is poorly tolerated across cardiological and neurological indications. Current pooled evidence suggests limited effectiveness for KCNT1 associated epilepsies at doses ≤40mg/kg/d. It is important to report all clinical evidence in precision medicine trials, whether positive or negative, to counter publication bias. This study highlights universal issues around outcome measurement and the evaluation of evidence in rare disease interventions.

Retrospective review of atrial fibrillation in Standardbred racehorses at a tertiary care facility in Atlantic Canada.

Atrial fibrillation (AF) is the most clinically relevant cardiac arrhythmia identified in the Standardbred racehorse. However, there is limited literature regarding athletic ability in Standardbred racehorses following AF conversion. To investigate this issue, the objectives of this review were to: i) determine the success rate in using quinidine sulphate to treat AF in a population of hospitalized equine patients in Atlantic Canada between January 2008 and December 2019; and ii) measure return to athletic ability (using racetrack earnings and top-3 finishes) following cardioversion with quinidine sulphate in a population of Standardbred racehorses. Overall, 73% (16/22) of AF instances in this study were successfully treated with enteral quinidine sulphate. No significant difference was detected in racetrack earnings or number of top-3 finishes for each horse that raced at least 5 times pre- and post-conversion. Key clinical message: To the authors' knowledge, this is the first published review to assess the athletic ability of Standardbred racehorses following cardioversion with enteral quinidine sulphate. Based on the current information, it does not appear that treatment of AF with quinidine sulphate affects future athletic performance in horses that achieved cardioversion.

Examen rétrospectif de la fibrillation auriculaire chez des chevaux de course Standardbred dans un établissement de soins tertiaires au Canada Atlantique. La fibrillation auriculaire (FA) est l'arythmie cardiaque la plus cliniquement pertinente identifiée chez le cheval de course Standardbred. Cependant, il existe peu de littérature concernant la capacité athlétique des chevaux de course Standardbred après la conversion de l'FA. Pour étudier cette question, les objectifs de cette revue étaient de : i) déterminer le taux de réussite de l'utilisation du sulfate de quinidine pour traiter la FA dans une population de patients équins hospitalisés au Canada Atlantique entre janvier 2008 et décembre 2019; et ii) mesurer le retour à la capacité athlétique (en utilisant les gains en hippodrome et les trois premiers résultats) après une cardioversion avec du sulfate de quinidine dans une population de chevaux de course Standardbred. Dans l'ensemble, 73 % (16/22) des cas de FA dans cette étude ont été traités avec succès avec du sulfate de quinidine entérale. Aucune différence significative n'a été détectée dans les revenus de l'hippodrome ou le nombre de classements parmi les trois premiers pour chaque cheval ayant couru au moins cinq fois avant et après la conversion.Message clinique clé :À la connaissance des auteurs, il s'agit de la première revue publiée évaluant la capacité athlétique des chevaux de course Standardbred après une cardioversion avec sulfate de quinidine entérale. Sur la base des informations actuelles, il ne semble pas que le traitement de la FA avec du sulfate de quinidine affecte les performances sportives futures des chevaux ayant cardioversion réussie.(Traduit par Dr Serge Messier).

Pathological laughter and crying in neurological disorders: recognition and treatment.

Pathological laughter and crying is a disabling symptom complex associated with damage to various central nervous system pathways that control the reflex motor component of emotional expression. Many underlying conditions-including neurodegenerative diseases, CNS inflammation, vascular lesions and traumatic brain injury-can be associated with disinhibition of emotional reflex control. This suggests a disruption of anatomical and functional networks, rather than any specific unifying pathological process. There is a wide differential diagnosis, including depression, dementia and other forms of behavioural disturbance. Diagnostic criteria and rating scales can help with clinical assessments and facilitate clinical trials. There is now good-quality evidence for a combination of dextromethorphan and quinidine, with weaker evidence for tricyclic and selective serotonin reuptake inhibitor antidepressants. Pathological laughter and crying is disabling and underdiagnosed but potentially treatable, and its wider recognition is important.

Small-molecule inhibitors of Slack potassium channels as potential therapeutics for childhood epilepsies.

Slack channels are sodium-activated potassium channels that are encoded by the KCNT1 gene. Several KCNT1 gain of function mutations have been linked to malignant migrating partial seizures of infancy. Quinidine is an anti-arrhythmic drug that functions as a moderately potent inhibitor of Slack channels; however, quinidine use is limited by its poor selectivity, safety and pharmacokinetic profile. Slack channels represent an interesting target for developing novel therapeutics for the treatment of malignant migrating partial seizures of infancy and other childhood epilepsies; thus, ongoing efforts are directed toward the discovery of small-molecules that inhibit Slack currents. This review summarizes patent applications published in 2020-2021 that describe the discovery of novel small-molecule Slack inhibitors.

Early repolarization syndrome, epilepsy, and atrial fibrillation in a young girl with novel KCND3 mutation managed with quinidine.

A 6-year-old girl presented with a difficult to control epilepsy syndrome. On evaluation, additional presyncope episodes associated with polymorphic ventricular tachycardia were also noted. A diagnosis of early repolarization syndrome (ERS) was made with an early repolarization pattern on electrocardiogram, documented VT episodes, and clinical presyncope (proposed Shanghai score 7). Paroxysmal atrial fibrillation (AF) was also noted on 24-h Holter recordings. The child was stabilized with isoprenaline infusion and was later discharged with arrhythmia control on quinidine and cilostazol. The genetic evaluation revealed a potassium channel KCND3 gene missense mutation. The case highlights the association of epilepsy syndrome and AF with ERS; the possible association of KCND3 gene mutation with a malignant phenotype; and management issues in a small child.

Arrhythmic storm from ischemic ventricular fibrillation treated with intravenous quinidine.

We present a case who developed an acute right ventricular infarction. The leads demonstrating ST-segment elevation were different than those expected based on previous publications. We explain why this happened with the aid of 3-dimentional imaging. Our case then developed an arrhythmic storm caused by ischemic ventricular fibrillation (VF). Emergency revascularization failed and the VF-storm failed to respond to sedation, lidocaine and amiodarone but responded to intravenous quinidine.

Rational Small Molecule Treatment for Genetic Epilepsies.

Genetic testing has yielded major advances in our understanding of the causes of epilepsy. Seizures remain resistant to treatment in a significant proportion of cases, particularly in severe, childhood-onset epilepsy, the patient population in which an underlying causative genetic variant is most likely to be identified. A genetic diagnosis can be explanatory as to etiology, and, in some cases, might suggest a therapeutic approach; yet, a clear path from genetic diagnosis to treatment remains unclear in most cases. Here, we discuss theoretical considerations behind the attempted use of small molecules for the treatment of genetic epilepsies, which is but one among various approaches currently under development. We explore a few salient examples and consider the future of the small molecule approach for genetic epilepsies. We conclude that significant additional work is required to understand how genetic variation leads to dysfunction of epilepsy-associated protein targets, and how this impacts the function of diverse subtypes of neurons embedded within distributed brain circuits to yield epilepsy and epilepsy-associated comorbidities. A syndrome- or even variant-specific approach may be required to achieve progress. Advances in the field will require improved methods for large-scale target validation, compound identification and optimization, and the development of accurate model systems that reflect the core features of human epilepsy syndromes, as well as novel approaches towards clinical trials of such compounds in small rare disease cohorts.