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ABSTRACT Background Methods Results Conclusion Muscle cramps are common in patients with cirrhosis. Despite their prevalence and impact on health‐related quality of life, there are no widely used clinical practice guidelines for management of muscle cramps in cirrhosis. The aim of this review was to critically evaluate current evidence regarding treatment of muscle cramps in cirrhosis.A systematic review using PubMed, MEDLINE (Ovid), Embase, and Scopus databases was performed on 30 June by two independent reviewers to identify randomised controlled trials (RCTs) reporting interventions for muscle cramps in cirrhotic patients.Twelve RCTs evaluating 13 distinct interventions were identified. Baclofen, methocarbamol, orphenadrine, and taurine supplementation reduced cramp frequency, severity, and duration when compared to placebo. Human albumin, pregabalin, and quinidine reduced cramp frequency compared to placebo. Pickle juice reduced cramp severity compared to placebo. BCAA supplementation and calcium carbonate were found to reduce cramp frequency compared to baseline. Stretching demonstrated a signal towards reducing cramp severity and frequency, and meditation had a signal towards reducing severity only when compared to baseline. Electro‐acupuncture was the only intervention which demonstrated no therapeutic effect. Pregabalin was the only agent associated with significant side effects that limited its use.Methocarbamol, orphenadrine, and taurine supplementation were found in placebo‐controlled RCTs to be effective in reducing cramp frequency, severity, and duration in cirrhotic patients. All other interventions reported aside from electro‐acupuncture demonstrated a positive impact on cramps. High‐quality RCTs are needed to further investigate the use of these treatments in terms of comparative efficacy and safety. [ABSTRACT FROM AUTHOR]

Introduction: Quinidine (QND) sulfate is an effective treatment for atrial fibrillation (AF) in horses, and several dosage regimens have been proposed to address its wide variability in response and potential adverse effects. The purpose of this study was to analyze the variability in plasma quinidine concentrations using population pharmacokinetics to determine an effective and safe dosage regimen for Thoroughbred horses. Methods: Six healthy Thoroughbred horses were treated with 20mg/kg quinidine sulfate dihydrate (16.58mg/kg QND base) administered PO or 5mg/kg quinidine hydrochloride monohydrate (4.28mg/kg QND base) administered IV (single administration), and blood samples were taken regularly. Four healthy horses were treated with 20mg/kg quinidine sulfate dihydrate administered twice (every 6h) via PO route. For the other 19 Thoroughbred racehorses that developed AF, blood samples were taken during quinidine therapy. Quinidine concentrations were measured in all plasma samples using liquid chromatography with tandem mass spectrometry, and the data from 29 horses were modeled using a nonlinear mixed-effects model, followed by Monte Carlo simulations (MCS). Results: The median quinidine concentration for successful sinus rhythm conversion was 2.0 µg/mL (range: 0.5-2.7 µg/mL) in AF horses, while a median concentration of 3.8 µg/mL (range: 1.6-5.1 µg/mL) showed adverse effects. MCS predicted that plasma quinidine concentrations for quinidine sulfate dihydrate PO administration (loading dose: 30 mg/kg, maintenance dose: 6.5 mg/kg q 2 h) reached 1.4, 2.0 and 2.7 µg/mL in 90, 50 and 10% of the horse populations, respectively. Increasing the loading dose to 45 mg/kg and the maintenance dose to 9 mg/kg q 2 h, the plasma concentrations achieved were 1.9, 2.8, and 3.8 µg/mL in 90, 50, and 10% of horse populations, respectively. Discussion: Using simulations, different empirical dosing regimens were proposed to achieve plasma quinidine concentrations immediately or progressively, representing a tradeoff between optimizing therapeutic effects and minimizing adverse effects. A combination of these dosing regimens is recommended to gradually increase the therapeutic concentration levels of quinidine for safe and effective treatment of AF in racehorses. [ABSTRACT FROM AUTHOR]

Objectives. Our study aimed to explore the role of the potassium channel KCNK1 in head and neck squamous cell carcinoma, focusing on its impact on tumor growth, invasion, and metastasis. We also investigated the therapeutic potential of quinidine, a known KCNK1 inhibitor, in both in vitro cell lines and a zebrafish patient-derived xenograft (PDX) model. Methods. We established primary cell cultures from head and neck cancer tissues and employed the FaDu cell line for in vitro studies, modulating KCNK1 expression through overexpression and knockdown techniques. We evaluated cell migration, invasion, and proliferation. Additionally, we developed a zebrafish PDX model to assess the impact of quinidine on tumor growth and metastasis in vivo. RNA sequencing and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to elucidate the molecular mechanisms underlying the role of KCNK1 in cancer progression. Results. Overexpression of KCNK1 in FaDu cells resulted in enhanced cell migration and invasion, whereas its knockdown diminished these processes. In the zebrafish PDX model, quinidine markedly inhibited tumor growth and metastasis, demonstrating a significant reduction in tumor volume and micrometastasis rates compared to the control groups. The molecular analyses indicated that KCNK1 plays a role in critical signaling pathways associated with tumor growth, such as the Ras and MAPK pathways. Conclusion. Our findings highlight the critical role of KCNK1 in promoting tumor growth and metastasis in head and neck cancer. The inhibitory effect of quinidine on tumor progression in the zebrafish PDX model highlights the therapeutic potential of targeting KCNK1. These results suggest that KCNK1 could serve as a valuable therapeutic target for head and neck cancer, warranting further investigation into treatments that target KCNK1.

Futibatinib, an inhibitor of fibroblast growth factor receptor 1–4, is approved for the treatment of patients with advanced cholangiocarcinoma with FGFR2 fusions/rearrangements. In this phase I drug–drug interaction study, the effects of futibatinib on P‐glycoprotein (P‐gp) and breast cancer resistance protein (BCRP) substrates, and of P‐gp inhibition on futibatinib pharmacokinetics (PK) were investigated in healthy adults aged 18–55 years. In part 1, 20 participants received digoxin (P‐gp substrate) and rosuvastatin (BCRP substrate). Following a ≥10‐day washout, futibatinib was administered for 7 days, with digoxin and rosuvastatin coadministered on the third day. In part 2, 24 participants received futibatinib. Following a ≥3‐day washout, quinidine (P‐gp inhibitor) was administered for 4 days, with futibatinib coadministered on day 4. Blood samples were collected predose and for 24 (futibatinib), 72 (rosuvastatin), and 120 h (digoxin) postdose. Urine samples (digoxin) were collected predose and for 120 h postdose. PK parameters were compared between treatments using analysis of variance. Coadministration with futibatinib had no effect on the PK of digoxin and rosuvastatin, and coadministration with quinidine had minimal effects on the PK of futibatinib. Differences in Cmax and AUC with and without futibatinib and quinidine, respectively, were <20%. The most common treatment‐emergent adverse events were diarrhea (80%) and increased blood phosphorous (75%) in part 1 and prolonged electrocardiogram QT interval (38%) in part 2. The data show that futibatinib has no clinically meaningful effects on the PK of P‐gp or BCRP substrates and that the effect of P‐gp inhibition on futibatinib PK is not clinically relevant. [ABSTRACT FROM AUTHOR]

Atogepant, an oral calcitonin gene‐related peptide receptor antagonist, is approved for the preventive treatment of migraine. Atogepant is a substrate of P‐glycoprotein (P‐gp), breast cancer resistance protein, organic anion transporting polypeptide transporters, and cytochrome P450 (CYP)3A4 and 2D6. Quinidine is a strong P‐gp and CYP2D6 inhibitor. A phase 1 open‐label study evaluated the effect of P‐gp and CYP2D6 inhibition by quinidine on the pharmacokinetics of atogepant, and the safety and tolerability of atogepant and quinidine gluconate (QG) when co‐administered and when given alone in 33 healthy adults. There was no significant change in the atogepant maximum plasma concentration with QG co‐administration. The overall systemic exposure, the area under the plasma concentration‐time curve (from time 0 to time t or to infinity), of atogepant increased by 25% when co‐administered with QG. However, such an increase was not considered clinically relevant. Atogepant did not alter the mean plasma concentration of quinidine at steady state. The incidence of treatment‐emergent adverse events (TEAEs) was highest when QG was administered alone (42.4%), which was primarily due to QT prolongation. Most TEAEs reported were mild in severity and resolved within 1‐2 days. Co‐administration of atogepant with QG did not result in any unexpected tolerability findings in this phase 1 study in healthy participants. The increase in atogepant exposure during QG co‐administration could be due to inhibition of CYP2D6 (a minor contributor to atogepant clearance) as well as inhibition of P‐gp. [ABSTRACT FROM AUTHOR]

This account summarizes the author's endeavors in target-oriented synthesis at Seoul National University since 2011. A collection of the most celebrated molecules in total synthesis are revisited and the author's solutions to these historical challenges are presented. In particular, the unique perception of their molecular frameworks and unprecedented bond-forming sequences form the basis of the newly developed strategies. Together with a 'personal touch' on these selected stories, the author hopes that this account will offer new insights and fresh perspectives for all levels of enthusiasts of target-oriented total synthesis. 1 Introduction 2.1 Synthesis of Strychnine 2.2 Synthesis of Actinophyllic Acid 2.3 Synthesis of Dendrobine 2.4 Synthesis of Communesin 2.5 Synthesis of Morphinans 2.6 Synthesis of Reserpine 2.7 Synthesis of Quinine and Quinidine 2.8 Synthesis of Haouamine 2.9 Future Work 3 Summary and Outlook 4 Abbreviations [ABSTRACT FROM AUTHOR]

This open‐label, phase 1 study was conducted with healthy adult participants to evaluate the potential drug‐drug interaction between rilzabrutinib and quinidine (an inhibitor of P‐glycoprotein [P‐gp] and CYP2D6) or rifampin (an inducer of CYP3A and P‐gp). Plasma concentrations of rilzabrutinib were measured after a single oral dose of rilzabrutinib 400 mg administered on day 1 and again, following a wash‐out period, after co‐administration of rilzabrutinib and quinidine or rifampin. Specifically, quinidine was given at a dose of 300 mg every 8 hours for 5 days from day 7 to day 11 (N = 16) while rifampin was given as 600 mg once daily for 11 days from day 7 to day 17 (N = 16) with rilzabrutinib given in the morning of day 10 (during quinidine dosing) or day 16 (during rifampin dosing). Quinidine had no significant effect on rilzabrutinib pharmacokinetics. Rifampin decreased rilzabrutinib exposure (the geometric mean of Cmax and AUC0‐∞ decreased by 80.5% and 79.5%, respectively). Single oral doses of rilzabrutinib, with or without quinidine or rifampin, appeared to be well tolerated. These findings indicate that rilzabrutinib is a substrate for CYP3A but not a substrate for P‐gp. [ABSTRACT FROM AUTHOR]

The article describes the case of a 71-year-old male presented with acute-onset uncontrollable laughter, which had been persistent for 3-4 hours and occurred in episodes lasting few seconds. Topics discussed include clinical description of pathological laughter, initial diagnosis of gelastic seizures made in view of acute onset of uncontrollable laughter, and drugs commonly used in the treatment of poststroke pathological laughter.

Tipepidine, an antitussive drug, has been reported to have central pharmacological effects and can be expected to be safely repositioned as treatment for psychiatric disorders. Since tipepidine requires three doses per day, development of a once-daily medication would be highly beneficial. Previously, we reported that combination use with quinidine, a CYP2D6 inhibitor, prolongs the half-life of tipepidine in chimeric mice with humanised liver. In this study, to predict this combination effect in humans, a physiologically based pharmacokinetic (PBPK) model was developed, and quantitative simulation was conducted. The simulation results indicated that concomitant administration of tipepidine with quinidine increased the predicted Cmax, AUC, and t1/2 of tipepidine in the Japanese population by 3.4-, 6.6-, and 2.4-fold, respectively. Furthermore, to compare with another approach that aims to prolong the half-life, the PK profile of tipepidine administered in hypothetical extended-release form was simulated. Extended-release form was predicted to be more influenced by CYP2D6 genotype than combination with quinidine, and the predicted plasma exposure was markedly increased in poor metabolizers, potentially leading to adverse effects. In conclusion, quantitative simulation using the PBPK model suggests the feasibility of the safe repositioning of tipepidine as a once-daily medication in combination with quinidine. [ABSTRACT FROM AUTHOR]

The lethality of torsades de pointes (TdP) by drugs is one of main reasons that some drugs were withdrawn from the market. In order to assess drug‐induced TdP risks, a model of cardiac ionic current suppression in human ventricular myocytes (ToR‐ORd model), combined with the maximum effective free therapeutic plasma concentration or the maximum effective free therapeutic myocyte concentration was often used, with the latter proved to be more relevant and more accurate. We aimed to develop a whole‐body physiologically‐based pharmacokinetic (PBPK) model, incorporated with a human cardiomyocyte pharmacodynamic (PD) model, to provide a comprehensive assessment of drug‐induced TdP risks in normal and specific scenarios. Quinidine served as an example to validate the PBPK‐PD model via predicting plasma quinidine concentrations and quinidine‐induced changes in QT interval (ΔQTc). The predicted plasma quinidine concentrations and ΔQTc values following oral administration or intravenous administration of quinidine were comparable to clinic observations. Visual predictive checks showed that most of the observed plasma concentrations and ΔQTc values fell within the 5th and 95th percentiles of simulations. The validated PBPK‐PD model was further applied to assess the TdP risks using frequencies of early afterdepolarization and long‐QT syndrome occurrence in 4 scenarios, such as therapeutic dose, supra‐therapeutic dose, alkalosis, and hyperkalemia in 200 human subjects. In conclusion, the developed PBPK‐PD model may be applied to predict the quinidine pharmacokinetics and quinidine‐induced TdP risks in healthy subjects, but also simulate quinidine‐induced TdP risks under disease conditions, such as hypokalemia and alkalosis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Quinidine has been used as an anticonvulsant to treat patients with KCNT1-related epilepsy by targeting gain-of-function KCNT1 pathogenic mutant variants. However, the detailed mechanism underlying quinidine's blockade against KCNT1 (Slack) remains elusive. Here, we report a functional and physical coupling of the voltage-gated sodium channel NaV1.6 and Slack. NaV1.6 binds to and highly sensitizes Slack to quinidine blockade. Homozygous knockout of NaV1.6 reduces the sensitivity of native sodium-activated potassium currents to quinidine blockade. NaV1.6-mediated sensitization requires the involvement of NaV1.6's N- and C-termini binding to Slack's C-terminus and is enhanced by transient sodium influx through NaV1.6. Moreover, disrupting the Slack-NaV1.6 interaction by viral expression of Slack's C-terminus can protect against SlackG269S-induced seizures in mice. These insights about a Slack-NaV1.6 complex challenge the traditional view of 'Slack as an isolated target' for anti-epileptic drug discovery efforts and can guide the development of innovative therapeutic strategies for KCNT1-related epilepsy. [ABSTRACT FROM AUTHOR]

Background Cerebral malaria, caused by Plasmodium falciparum, can lead to severe neurological complications. It is more frequently observed in children than in adults. Because cerebral malaria is rare and has no specific symptoms or neurologic findings, it is not easy to diagnose. Case report We report a case of a 61-year-old male who returned from the Democratic Republic of the Congo with fever, fatigue, and confusion. With considering cerebral malaria, a peripheral blood smear confirmed P. falciparum infection (initial parasite load, 760,800/μL; ring form, 100%). Cerebrospinal fluid analyses showed high protein level (103.2 mg/dL). Electroencephalograms showed background slowing activity. Brain magnetic resonance imaging showed signal changes and cerebral swelling. The initial doxycycline and quinidine treatment for malaria was successful without sequalae. Conclusion Physicians must have high suspicion about the symptoms and the necessity for screening in individuals traveling to malaria-endemic regions when experiencing changes in consciousness.

Racemic carboxylic acid, a Diels‐Alder cycloadduct derived from 5‐bromo‐3‐phenyl‐α‐pyrone and acrylate dienophile, was resolved into enantiomers by diastereomeric salt crystallization. Quinidine was used as a sole resolving base. The salt of (+)‐acid crystallized from aqueous acetonitrile solution. Once this salt was separated by filtration, quinidine salt with (−)‐acid crystallized from mother liquor. As a result, both enantiomers of Diels‐Alder cycloadduct were isolated in high enantiomeric purity. [ABSTRACT FROM AUTHOR]

A first catalytic preparation of the popular antiplatelet drug (S)‐clopidogrel, known with the tradename of Plavix, has been developed in a one‐pot and innovative approach. The synthesis can be performed using commercially available ortho‐chlorobenzaldehyde, 1‐naphthylsulfonyl acetonitrile, tert‐butyl hydroperoxide (TBHP), 4,5,6,7‐tetrahydrothieno[3,2‐c]pyridine and 20 mol % of a quinidine derived organocatalyst in a single solvent. A Knoevenagel/asymmetric epoxidation/domino ring‐opening esterification (DROE) sequence enabled to obtain (S)‐clopidogrel in 61 % overall yield and 62 % ee. Fine optimization of the reaction conditions proved to be crucial to set up a selective and efficient process. [ABSTRACT FROM AUTHOR]

Brugada wave is a special ECG pattern that presents as a “triad” of right bundle branch block, STsegment elevation in the right chest lead, and T wave inversion. It could lead to arrhythmia and sudden cardiac death. It has been previously considered that Brugada wave is associated with genetics, electrophysiological mechanism, nerve crest hypothesis and so on. The latest studies have found that mutations in mitochondrial DNA and tRNA, inflammation, and myocardial stroma abnormalities may also be involved in the occurrence and development of Brugada wave. This paper mainly reviews the latest research progress of the electrocardiographic mechanism of Brugada wave. [ABSTRACT FROM AUTHOR]

Short-coupled idiopathic ventricular fibrillation (IVF) is a subtype of IVF in which episodes of polymorphic ventricular tachycardia or ventricular fibrillation are initiated by short-coupled premature ventricular contractions (PVCs). Our understanding of the pathophysiology is evolving, with evidence suggesting that these malignant PVCs originate from the Purkinje system. In most cases, the genetic underpinning has not been identified. Whereas the implantation of an implantable cardioverter-defibrillator is uncontroversial, the choice of pharmacological treatment is the subject of discussion. In this review, we summarize the available knowledge on pharmacological therapy in short-coupled IVF and provide our recommendations for management of patients with this syndrome.

The present study was designed to test the hypothesis that the selectivity of blocking the late Na+ current (INaL) over the peak Na+ current (INaP) is related to the fast offset kinetics of the Na+ channel inhibitor. Therefore, the effects of 1 µM GS967 (INaL inhibitor), 20 µM mexiletine (I/B antiarrhythmic) and 10 µM quinidine (I/A antiarrhythmic) on INaL and INaP were compared in canine ventricular myocardium. INaP was estimated as the maximum velocity of action potential upstroke (V+max). Equal amounts of INaL were dissected by the applied drug concentrations under APVC conditions. The inhibition of INaL by mexiletine and quinidine was comparable under a conventional voltage clamp, while both were smaller than the inhibitory effect of GS967. Under steady-state conditions, the V+max block at the physiological cycle length of 700 ms was 2.3% for GS967, 11.4% for mexiletine and 26.2% for quinidine. The respective offset time constants were 110 ± 6 ms, 456 ± 284 ms and 7.2 ± 0.9 s. These results reveal an inverse relationship between the offset time constant and the selectivity of INaL over INaP inhibition without any influence of the onset rate constant. It is concluded that the selective inhibition of INaL over INaP is related to the fast offset kinetics of the Na+ channel inhibitor. [ABSTRACT FROM AUTHOR]

Polymorphic ventricular tachycardia (PMVT) is a highly lethal arrhythmia which is commonly caused by acute myocardial ischaemia. PMVT mediated by short-coupled ventricular ectopy patients with ischaemic heart disease but in the absence of acute ischaemia may relate to transient peri-infarct Purkinje fibre irritability and has been termed 'Angry Purkinje Syndrome'. We present a case series of three patients with PMVT storm 3–5 days following coronary artery bypass graft surgery (CABG). In all three cases, recurrent episodes of PMVT were initiated by monomorphic ventricular ectopy with a short coupling interval. Acute coronary ischaemia was excluded in all three patients with a coronary angiogram and graft study. Two out of three of the patients commenced oral quinidine sulphate with subsequent rapid suppression of arrhythmia. Implantable cardiac defibrillators were implanted in all three patients and revealed no recurrence of PMVT following hospital discharge. The Angry Purkinje Syndrome is a rare but important cause of ventricular tachycardia storm after CABG surgery and is mediated by short-coupled ventricular ectopy in the absence of acute myocardial ischaemia. This arrhythmia may be highly responsive to quinidine. [ABSTRACT FROM AUTHOR]

Objective: Pathogenic variants in KCNT2 are rare causes of developmental epileptic encephalopathy (DEE). We herein describe the phenotypic and genetic features of patients with KCNT2‐related DEE, and the in vitro functional and pharmacological properties of KCNT2 channels carrying 14 novel or previously untested variants. Methods: Twenty‐five patients harboring KCNT2 variants were investigated: 12 were identified through an international collaborative network, 13 were retrieved from the literature. Clinical data were collected and included in a standardized phenotyping sheet. Novel variants were detected using exome sequencing and classified using ACMG criteria. Functional and pharmacological studies were performed by whole‐cell electrophysiology in HEK‐293 and SH‐SY5Y cells. Results: The phenotypic spectrum encompassed: (a) intellectual disability/developmental delay (21/22 individuals with available information), ranging from mild to severe/profound; (b) epilepsy (15/25); (c) neurological impairment, with altered muscle tone (14/22); (d) dysmorphisms (13/20). Nineteen pathogenic KCNT2 variants were found (9 new, 10 reported previously): 16 missense, 1 in‐frame deletion of a single amino acid, 1 nonsense, and 1 frameshift. Among tested variants, 8 showed gain‐of‐function (GoF), and 6 loss‐of‐function (LoF) features when expressed heterologously in vitro. Quinidine and fluoxetine blocked all GoF variants, whereas loxapine and riluzole activated some LoF variants while blocking others. Interpretation: We expanded the phenotypic and genotypic spectrum of KCNT2‐related disorders, highlighting novel genotype–phenotype associations. Pathogenic KCNT2 variants cause GoF or LoF in vitro phenotypes, and each shows a unique pharmacological profile, suggesting the need for in vitro functional and pharmacological investigation to enable targeted therapies based on the molecular phenotype. ANN NEUROL 2023;94:332–349 [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The antiarrhythmic agent quinidine is a potent inhibitor of cytochrome P450 (CYP) 2D6 and P‐glycoprotein (P‐gp) and is therefore recommended for use in clinical drug–drug interaction (DDI) studies. However, as quinidine is also a substrate of CYP3A4 and P‐gp, it is susceptible to DDIs involving these proteins. Physiologically‐based pharmacokinetic (PBPK) modeling can help to mechanistically assess the absorption, distribution, metabolism, and excretion processes of a drug and has proven its usefulness in predicting even complex interaction scenarios. The objectives of the presented work were to develop a PBPK model of quinidine and to integrate the model into a comprehensive drug–drug(–gene) interaction (DD(G)I) network with a diverse set of CYP3A4 and P‐gp perpetrators as well as CYP2D6 and P‐gp victims. The quinidine parent‐metabolite model including 3‐hydroxyquinidine was developed using pharmacokinetic profiles from clinical studies after intravenous and oral administration covering a broad dosing range (0.1–600 mg). The model covers efflux transport via P‐gp and metabolic transformation to either 3‐hydroxyquinidine or unspecified metabolites via CYP3A4. The 3‐hydroxyquinidine model includes further metabolism by CYP3A4 as well as an unspecific hepatic clearance. Model performance was assessed graphically and quantitatively with greater than 90% of predicted pharmacokinetic parameters within two‐fold of corresponding observed values. The model was successfully used to simulate various DD(G)I scenarios with greater than 90% of predicted DD(G)I pharmacokinetic parameter ratios within two‐fold prediction success limits. The presented network will be provided to the research community and can be extended to include further perpetrators, victims, and targets, to support investigations of DD(G)Is. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

The present study was conducted to provide evidence of conditioned taste aversion learning (CTA) in the snail Cornu aspersum, using quinidine as the aversive stimulus in a procedure of Pavlovian Conditioning of Tentacle Lowering. Subjects were split into two groups: paired and unpaired. During the devaluation phase, subjects from the "paired group" received the US followed by the quinidine exposure, while subjects from the "unpaired group" received the quinidine and, 30 min later, the US. Subjects which had received the US paired with the quinidine showed a decrease of the conditioned response (CR), in contrast to subjects which had received the quinidine and the US unpaired. These results provide a useful CTA procedure in terrestrial snails. The implication of the results for learning and the physiological correlates is discussed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The discovery of novel chiral selectors always fascinates us. This work describes the chiral separation performances of a new chiral selector (kasugamycin, KAS) in capillary electrophoresis (CE) for six pairs of stereoisomers, including ephedrine and pseudoephedrine, quinine and quinidine, cinchonine and cinchonidine, and amlodipine, promethazine and ofloxacin enantiomers. Kasugamycin, an aminoglycoside antibiotic in agriculture, shows significant biological activity against rice blast with low toxicity. As it turns out, this new chiral selector possesses good CE compatibility and stereoselectivity towards model analytes. In this work, we systematically investigated several separation parameters including kasugamycin concentration, buffer pH, separation voltage and the composition of the buffer solution. A detailed discussion about the chiral recognition mechanism was made based on Statistical Product and Service Solution (SPSS) analysis, NMR experiments (1D and 2D) and molecular modeling. This is the first time that kasugamycin is utilized as a chiral selector in CE, and the development of new chiral selectors from agricultural or veterinary antibiotics deserves more attention. [ABSTRACT FROM AUTHOR]

[Display omitted] The retinal pigment epithelial (RPE) cell monolayer forms the outer blood–retinal barrier and has a crucial role in ocular pharmacokinetics. Although several RPE cell models are available, there have been no systematic comparisons of their barrier properties with respect to drug permeability. We compared the barrier properties of RPE secondary cell lines (ARPE19, and ARPE19mel) and both primary (hfRPE) and stem-cell derived RPE (hESC-RPE) cells by investigating the permeability of nine drugs (aztreonam, ciprofloxacin, dexamethasone, fluconazole, ganciclovir, ketorolac, methotrexate, voriconazole, and quinidine) across cell monolayers. ARPE19, ARPE19mel, and hfRPE cells displayed a narrow P app value range, with relatively high permeation rates (5.2–26 × 10−6 cm/s). In contrast, hESC-RPE cells efficiently restricted the drug flux, and displayed even lower P app values than those reported for bovine RPE-choroid, with the range of 0.4–32 cm−6/s. Therefore, ARPE19, ARPE19mel, and hfRPE cells failed to form a tight barrier, whereas hESC-RPE cells restricted the drug flux to a similar extent as bovine RPE-choroid. Therefore, hESC-RPE cells are valuable tools in ocular drug discovery. [ABSTRACT FROM AUTHOR]

Reaction of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) with bis-tetrafluoroborates of quinine and/or quinidine in the presence of sodium bicarbonate gave a pair of pseudo-enantiomeric coupling reagents: N,N'-bis-(4,6-dimethoxy-1,3,5-triazin-2-yl)quinine bis-tetrafluoroborate (2DMT/quinine/2BF4-) and N,N'-bis-(4,6- dimethoxy-1,3,5-triazin-2-yl)quinidine bis-tetrafluoroborate (2DMT/quinidine/2BF4-). The reagents activate the opposite enantiomers of racemic N-protected amino acids. By their reaction with two equivalents of racemic carboxylic components and diverse esters of amino acids, protected dipeptides were obtained with a predictable configuration and 95-99% enantiomeric homogeneity. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) and sinus bradycardia have been reported in patients with short QT syndrome variant 2 (SQT2), which is underlain by gain-of-function mutations in KCNQ1 encoding the α subunit of channels carrying slow delayed rectifier potassium current, I Ks. However, the mechanism(s) underlying the increased atrial arrhythmogenesis and impaired cardiac pacemaking activity arising from increased I Ks remain unclear. Possible pharmacological interventions of AF in the SQT2 condition also remain to be elucidated. Using computational modelling, we assessed the functional impact of SQT2 mutations on human sinoatrial node (SAN) pacemaking, atrial repolarisation and arrhythmogenesis, and efficacy of the anti-arrhythmic drug quinidine. Markov chain formulations of I Ks describing two KCNQ1 mutations - V141M and V307L - were developed from voltage-clamp experimental data and then incorporated into contemporary action potential (AP) models of human atrial and SAN cells, the former of which were integrated into idealised and anatomically detailed tissue models. Both mutations shortened atrial AP duration (APD) through distinct I Ks gain-of-function mechanisms, whereas SAN pacemaking rate was slowed markedly only by the V141M mutation. Differences in APD restitution steepness influenced re-entry dynamics in tissue - the V141M mutation promoted stationary and stable spiral waves whereas the V307L mutation promoted non-stationary and unstable re-entrant waves. Both mutations shortened tissue excitation wavelength through reduced effective refractory period but not conduction velocity, which served to increase the lifespan of re-entrant excitation in a 3D anatomical human atria model, as well as the dominant frequency (DF), which was higher for the V141M mutation. Quinidine was effective at terminating arrhythmic excitation waves associated with the V307L but not V141M mutation, and reduced the DF in a dose-dependent manner under both mutation conditions. This study provides mechanistic insights into different AF/bradycardia phenotypes in SQT2 and the efficacy of quinidine pharmacotherapy.

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 χ2 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The aberrant expression of aldo keto reductases (AKR1B1 & AKR1B10) has been extensively studied in different types of cancer especially the colon cancer but a very few studies have yet been reported regarding the discovery of inhibitors for the treatment of colon cancer by targeting these isozymes. Therefore, there is a need of selective inhibitors of both targets for the eradication of colon cancer. Currently, the study is focused on the exploration of two quinolone compounds i.e., (S)-(6-Methoxyquinolin-4-yl)[(1S,2R,4S,5R)-5-vinylquinuclidin-2-yl]methanol (Quinidine) and (R)-(6-Methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methanol (Quinine) as the potential inhibitors of AKR1B1 and AKR1B10 via detailed in-silico approach. The structural properties including vibrational frequencies, dipole moment, polarizability and the optimization energies were estimated using density functional theory (DFT) calculations; where both compounds were found chemically reactive. After that, the optimized structures were used for the molecular docking studies and here quinidine was found more selective towards AKR1B1 and quinine exhibited maximum inhibition of AKR1B10. The results of molecular docking studies were validated by molecular dynamics simulations which provided the deep insight of stability of protein ligand complex. At the end, the ADMET properties were determined to demonstrate the druglikeness properties of both selected compounds. These findings suggested further exploration of both compounds at molecular level using different in-vivo and in-vitro approaches that will lead to the designing of potential inhibitor of AKR1B1/AKR1B10 for curing colon cancer and related malignancies. [ABSTRACT FROM AUTHOR]

Background and Purpose: Before advancing to clinical trials, new drugs are screened for their pro-arrhythmic potential using a method that is overly conservative and provides limited mechanistic insight. The shortcomings of this approach can lead to the mis-classification of beneficial drugs as pro-arrhythmic.Experimental Approach: An in silico-in vitro pipeline was developed to circumvent these shortcomings. A computational human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) model was used as part of a genetic algorithm to design experiments, specifically electrophysiological voltage clamp (VC) protocols, to identify which of several cardiac ion channels were blocked during in vitro drug studies. Such VC data, along with dynamically clamped action potentials (AP), were acquired from iPSC-CMs before and after treatment with a control solution or a low- (verapamil), intermediate- (cisapride or quinine) or high-risk (quinidine) drug.Key Results: Significant AP prolongation (a pro-arrhythmia marker) was seen in response to quinidine and quinine. The VC protocol identified block of IKr (a source of arrhythmias) by all strong IKr blockers, including cisapride, quinidine and quinine. The protocol also detected block of ICaL by verapamil and Ito by quinidine. Further demonstrating the power of the approach, the VC data uncovered a previously unidentified If block by quinine, which was confirmed with experiments using a HEK-293 expression system and automated patch-clamp.Conclusion and Implications: We developed an in silico-in vitro pipeline that simultaneously identifies pro-arrhythmia risk and mechanism of ion channel-blocking drugs. The approach offers a new tool for evaluating cardiotoxicity during preclinical drug screening. [ABSTRACT FROM AUTHOR]