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The Journal of Pharmacology and... Mar 2023The cardiac sodium channel Na1.5 is a key contributor to the cardiac action potential, and dysregulations in Na1.5 can lead to cardiac arrhythmias. Na1.5 is a target of...
The cardiac sodium channel Na1.5 is a key contributor to the cardiac action potential, and dysregulations in Na1.5 can lead to cardiac arrhythmias. Na1.5 is a target of numerous antiarrhythmic drugs (AADs). Previous studies identified the protein 14-3-3 as a regulator of Na1.5 biophysical coupling. Inhibition of 14-3-3 can remove the Na1.5 functional coupling and has been shown to inhibit the dominant-negative effect of Brugada syndrome mutations. However, it is unknown whether the coupling regulation is involved with AADs' modulation of Na1.5. Indeed, AADs could reveal important structural and functional information about Na1.5 coupling. Here, we investigated the modulation of Na1.5 by four classic AADs, quinidine, lidocaine, mexiletine, and flecainide, in the presence of 14-3-3 inhibition. The experiments were carried out by high-throughput patch-clamp experiments in an HEK293 Na1.5 stable cell line. We found that 14-3-3 inhibition can enhance acute block by quinidine, whereas the block by other drugs was not affected. We also saw changes in the use- and dose-dependency of quinidine, lidocaine, and mexiletine when inhibiting 14-3-3. Inhibiting 14-3-3 also shifted the channel activation toward hyperpolarized voltages in the presence of the four drugs studied and slowed the recovery of inactivation in the presence of quinidine. Our results demonstrated that the protein 14-3-3 and Na1.5 coupling could impact the effects of AADs. Therefore, 14-3-3 and Na1.5 coupling are new mechanisms to consider in the development of drugs targeting Na1.5. SIGNIFICANCE STATEMENT: The cardiac sodium channel Na1.5 is a target of commonly used antiarrhythmic drugs, and Na1.5 function is regulated by the protein 14-3-3. The present study demonstrated that the regulation of Na1.5 by 14-3-3 influences Na1.5's response to antiarrhythmic drugs. This study provides detailed information about how 14-3-3 differentially regulated Na1.5 functions under the influence of different drug subtypes. These findings will guide future molecular studies investigating Na1.5 and antiarrhythmic drugs outcomes.
Topics: Humans; Anti-Arrhythmia Agents; Mexiletine; 14-3-3 Proteins; Quinidine; HEK293 Cells; Lidocaine; Sodium Channels
PubMed: 36460339
DOI: 10.1124/jpet.122.001407 -
Molecules (Basel, Switzerland) Jan 2021The Food and Drug Administration (FDA) approved a new class of anti-diabetic medication (a sodium-glucose co-transporter 2 (SGLT2) inhibitor) in 2013. However, SGLT2...
The Food and Drug Administration (FDA) approved a new class of anti-diabetic medication (a sodium-glucose co-transporter 2 (SGLT2) inhibitor) in 2013. However, SGLT2 inhibitor drugs are under evaluation due to their associative side effects, such as urinary tract and genital infection, urinary discomfort, diabetic ketosis, and kidney problems. Even clinicians have difficulty in recommending it to diabetic patients due to the increased probability of urinary tract infection. In our study, we selected natural SGLT2 inhibitors, namely acerogenin B, formononetin, (-)-kurarinone, (+)-pteryxin, and quinidine, to explore their potential against an emerging uropathogenic bacterial therapeutic target, i.e., FimH. FimH plays a critical role in the colonization of uropathogenic bacteria on the urinary tract surface. Thus, FimH antagonists show promising effects against uropathogenic bacterial strains via their targeting of FimH's adherence mechanism with less chance of resistance. The molecular docking results showed that, among natural SGLT2 inhibitors, formononetin, (+)-pteryxin, and quinidine have a strong interaction with FimH proteins, with binding energy (∆G) and inhibition constant (ki) values of -5.65 kcal/mol and 71.95 µM, -5.50 kcal/mol and 92.97 µM, and -5.70 kcal/mol and 66.40 µM, respectively. These interactions were better than those of the positive control heptyl α-d-mannopyranoside and far better than those of the SGLT2 inhibitor drug canagliflozin. Furthermore, a 50 ns molecular dynamics simulation was conducted to optimize the interaction, and the resulting complexes were found to be stable. Physicochemical property assessments predicted little toxicity and good drug-likeness properties for these three compounds. Therefore, formononetin, (+)-pteryxin, and quinidine can be proposed as promising SGLT2 inhibitors drugs, with add-on FimH inhibition potential that might reduce the probability of uropathogenic side effects.
Topics: Adhesins, Escherichia coli; Computational Biology; Computer Simulation; Coumarins; Diabetes Mellitus, Type 2; Escherichia coli Infections; Fimbriae Proteins; Humans; Isoflavones; Molecular Docking Simulation; Quinidine; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Urinary Tract Infections; Uropathogenic Escherichia coli
PubMed: 33499241
DOI: 10.3390/molecules26030582 -
NPJ Systems Biology and Applications Nov 2022Short QT syndrome (SQTS) is a rare but dangerous genetic disease. In this research, we conducted a comprehensive in silico investigation into the arrhythmogenesis in...
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 I 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 I inhibitor sotalol failed in SQT1 patients through profoundly analyzing its mutation-dependent actions.
Topics: Humans; Quinidine; Sotalol; Anti-Arrhythmia Agents; Action Potentials; Mutation; ERG1 Potassium Channel
PubMed: 36333337
DOI: 10.1038/s41540-022-00254-5 -
Journal of the American College of... Dec 2017
Topics: Arrhythmias, Cardiac; Humans; Quinidine; Rare Diseases
PubMed: 29241490
DOI: 10.1016/j.jacc.2017.10.023 -
Antimicrobial Agents and Chemotherapy Jan 2013The 9-epimers of quinine (QN) and quinidine (QD) are known to exhibit poor cytostatic potency against P. falciparum (Karle JM, Karle IL, Gerena L, Milhous WK,...
Relative to quinine and quinidine, their 9-epimers exhibit decreased cytostatic activity and altered heme binding but similar cytocidal activity versus Plasmodium falciparum.
The 9-epimers of quinine (QN) and quinidine (QD) are known to exhibit poor cytostatic potency against P. falciparum (Karle JM, Karle IL, Gerena L, Milhous WK, Antimicrob. Agents Chemother. 36:1538-1544, 1992). We synthesized 9-epi-QN (eQN) and 9-epi-QD (eQD) via Mitsunobu esterification-saponification and evaluated both cytostatic and cytocidal antimalarial activities. Relative to the cytostatic activity of QN and QD, we observed a large decrease in cytostatic activity (higher 50% inhibitory concentration [IC(50)s]) against QN-sensitive strain HB3, QN-resistant strain Dd2, and QN-hypersensitive strain K76I, consistent with previous work. However, we observed relatively small changes in cytocidal activity (the 50% lethal dose), similar to observations with chloroquine (CQ) analogues with a wide range of IC(50)s (see the accompanying paper [A. P. Gorka, J. N. Alumasa, K. S. Sherlach, L. M. Jacobs, K. B. Nickley, J. P. Brower, A. C. de Dios, and P. D. Roepe, Antimicrob. Agents Chemother. 57:356-364, 2013]). Compared to QN and QD, the 9-epimers had significantly reduced hemozoin inhibition efficiency and did not affect pH-dependent aggregation of ferriprotoporphyrin IX (FPIX) heme. Magnetic susceptibility measurements showed that the 9-epimers perturb FPIX monomer-dimer equilibrium in favor of monomer, and UV-visible (VIS) titrations showed that eQN and eQD bind monomer with similar affinity relative to QN and QD. However, unique ring proton shifts in the presence of zinc(II) protoporphyrin IX (ZnPIX) indicate that binding of the 9-epimers to monomeric heme is via a distinct geometry. We isolated eQN- and eQD-FPIX complexes formed under aqueous conditions and analyzed them by mass, fluorescence, and UV-VIS spectroscopies. The 9-epimers produced low-fluorescent adducts with a 2:1 stoichiometry (drug to FPIX) which did not survive electrospray ionization, in contrast to QN and QD complexes. The data offer important insight into the relevance of heme interactions as a drug target for cytostatic versus cytocidal dosages of quinoline antimalarial drugs and further elucidate a surprising structural diversity of quinoline antimalarial drug-heme complexes.
Topics: Antimalarials; Cells, Cultured; Crystallization; Cytostatic Agents; Cytotoxins; Erythrocytes; Heme; Hemeproteins; Humans; Hydrogen-Ion Concentration; Inhibitory Concentration 50; Kinetics; Mass Spectrometry; Plasmodium falciparum; Quinidine; Quinine; Spectrometry, Fluorescence
PubMed: 23114754
DOI: 10.1128/AAC.01234-12 -
Journal of the American College of... Jun 1987The efficacy and tolerance of tocainide used alone and in combination with quinidine were studied in 20 patients with coronary artery disease and frequent (greater than...
The efficacy and tolerance of tocainide used alone and in combination with quinidine were studied in 20 patients with coronary artery disease and frequent (greater than 30/h) ventricular premature complexes. Holter electrocardiographic monitoring was performed at baseline and during therapy with tocainide alone, quinidine alone and a combination of tocainide and quinidine. During single drug therapy, the dose of tocainide was 1,680 +/- 437 mg/day and that of quinidine was 1,340 +/- 235 mg/day. During combination therapy, with smaller doses of tocainide (1,350 +/- 394 mg/day) and quinidine (1,060 +/- 268 mg/day) in many patients, no patient had side effects. At baseline before therapy, the mean ventricular premature complexes/h were 629 +/- 567, couplets/h were 23.9 +/- 29.7 and nonsustained ventricular tachycardias/24 h were 60.5 +/- 152.2. Compared with baseline values (100%), the frequency of ventricular premature complexes was reduced to 33 +/- 44% with quinidine, 39 +/- 30% with tocainide and 10 +/- 16% with combination therapy (p less than 0.01 for combination versus quinidine or tocainide alone; p = NS for quinidine versus tocainide). Individually, an effective regimen (greater than 83% reduction of ventricular premature complexes and abolition of nonsustained ventricular tachycardia) was found in 3 (15%) of 20 patients receiving tocainide alone, in 6 (30%) receiving quinidine alone and in 16 (80%) receiving combination therapy (p less than 0.01 for tocainide versus combination, quinidine versus combination; p = NS for tocainide versus quinidine). Thus, the antiarrhythmic effects of quinidine and tocainide are additive.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Aged; Arrhythmias, Cardiac; Coronary Disease; Drug Combinations; Drug Evaluation; Drug Tolerance; Electrocardiography; Female; Humans; Lidocaine; Male; Middle Aged; Quinidine; Tocainide
PubMed: 3108345
DOI: 10.1016/s0735-1097(87)80480-1 -
Clinical Cardiology Feb 1979Following the development of digoxin radioimmunoassay, we noted that serum digoxin concentrations appeared to rise in patients given quinidine. To further evaluate this...
Following the development of digoxin radioimmunoassay, we noted that serum digoxin concentrations appeared to rise in patients given quinidine. To further evaluate this important possible interaction between digoxin and quinidine, charts from 863 cardiology patients were reviewed. Ninety two patients received both drugs after having been on digoxin alone; 38 were ineligible for the study because of insufficient data and 27 were excluded because of changing renal function and/or concomitant antiarrhythmic drug therapy, leaving 27. Serum digoxin increased in 25 of the 27 study patients (93%) during quinidine therapy; mean serum digoxin rose from 1.4 ng/ml before quinidine to 3.2 ng/ml during quinidine. Anorexia, nausea and/or vomiting developed in 16 patients (59%) during quinidine therapy, but disappeared in all 10 patients in whom digoxin alone was reduced in dose, suggesting that digoxin had a causative role in the appearance of these symptoms although they developed only after quinidine had begun. Three of thirteen patients with only atrial arrhythmias on digoxin prior to quinidine developed new ventricular premature depolarizations (VPD) after starting quinidine; two of these three as well as four patients with prior VPDs developed new ventricular tachycardia, ventricular fibrillation, asystole, or sudden death. When starting quinidine in patients who are taking digoxin, the clinical course, ECG and serum digoxin should be followed closely.
Topics: Adult; Aged; Digoxin; Drug Interactions; Female; Heart Diseases; Humans; Male; Middle Aged; Quinidine; Retrospective Studies
PubMed: 498605
DOI: 10.1002/clc.4960020107 -
Journal of the American College of... Jul 1985To assess the effects of digoxin as single therapy and in combination with quinidine in the treatment of atrial fibrillation, the atrial fibrillation threshold was...
To assess the effects of digoxin as single therapy and in combination with quinidine in the treatment of atrial fibrillation, the atrial fibrillation threshold was determined from the right atrial appendage and Bachmann's bundle in 11 open chest dogs. In group 1 (six dogs), the atrial fibrillation threshold was determined at baseline, post-quinidine (10 mg/kg intravenously) and then post-digoxin (50 micrograms/kg intravenously). In group 2 (five dogs), the order of drug administration was reversed. The results of this study were: 1) Digoxin had no significant effect on the atrial fibrillation threshold when given alone. 2) Quinidine significantly increased the atrial fibrillation threshold (p less than 0.002) and the addition of digoxin resulted in a further increase in threshold (p less than 0.002). 3) Quinidine produced greater suppression of atrial fibrillation induction at the right atrial site than at the Bachmann's bundle site, suggesting differential effects of quinidine on atrial fibers.
Topics: Animals; Atrial Fibrillation; Differential Threshold; Digoxin; Dogs; Drug Combinations; Drug Interactions; Electric Stimulation; Quinidine
PubMed: 4008768
DOI: 10.1016/s0735-1097(85)80262-x -
Journal of the American College of... Apr 1992Rapid, reliable and safe reestablishment of sinus rhythm is the major aim of pharmacologic treatment in patients with chronic atrial fibrillation. The mainstay of... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
Rapid, reliable and safe reestablishment of sinus rhythm is the major aim of pharmacologic treatment in patients with chronic atrial fibrillation. The mainstay of therapy in this arrhythmia has been quinidine. More recently, amiodarone was shown in non-comparative studies to be superior to class IA agents under certain conditions. In 40 patients with atrial fibrillation persisting for 4 weeks up to 2 years, the efficacy and safety of either quinidine and verapamil (days 1 to 3, quinidine 1,500 mg/day; days 4 to 6, quinidine 1,500 mg + verapamil 240 mg/day) or amiodarone therapy (days 1 to 3, amiodarone 1,200 mg/day intravenously; days 4 to 14, amiodarone 800 mg/day orally) were randomly examined. Responders continued on their effective medication for 3 months. Thereafter, all patients were treated with a fixed regimen of quinidine (480 mg/day) plus verapamil (240 mg/day) for up to 2 years. During atrial fibrillation, quinidine reduced mean ventricular cycle length by 40 ms (-5%), quinidine and verapamil increased mean cycle length by 57 ms (8%) and amiodarone by 192 ms (28%, p less than 0.01). In addition, quinidine and verapamil had a characteristic "rate-smoothing" effect on atrioventricular conduction during atrial fibrillation. The rhythm was converted to sinus rhythm after quinidine in 5 (25%) of 20 patients and after the combination of quinidine and verapamil in 11 (55%) of 20 patients. Amiodarone restored sinus rhythm in 12 (60%) of 20 patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Amiodarone; Atrial Fibrillation; Chronic Disease; Drug Therapy, Combination; Electrocardiography; Female; Follow-Up Studies; Heart Diseases; Humans; Male; Middle Aged; Prospective Studies; Quinidine; Treatment Outcome; Verapamil
PubMed: 1552095
DOI: 10.1016/0735-1097(92)90294-w -
The Journal of Clinical Psychiatry Sep 2016Pseudobulbar affect (PBA) is a socially debilitating condition that primarily affects people with neurologic diseases, such as Alzheimer's disease or multiple sclerosis.... (Review)
Review
Pseudobulbar affect (PBA) is a socially debilitating condition that primarily affects people with neurologic diseases, such as Alzheimer's disease or multiple sclerosis. This condition is characterized by uncontrolled, exaggerated expressions of laughing or crying-often when the situation does not warrant this behavior. Although the true prevalence of PBA is surprisingly high, this condition remains widely misdiagnosed and underdiagnosed. While its exact etiology is unknown, PBA likely results from disruptions in the brain structures and/or neurotransmitters that regulate emotions. Differential diagnosis of PBA includes ruling out depression or other psychiatric conditions. Treatment of PBA has traditionally centered on antidepressant therapies, but newer therapeutic options include combination agents employing multiple modalities. Therapy should include patient counseling to reassure patients and families that PBA is not the fault of the individual. Counseling should also emphasize safety precautions to minimize adverse events and maximize appropriate adherence to the selected therapies.
Topics: Affective Symptoms; Crying; Dextromethorphan; Drug Combinations; Female; Humans; Laughter; Middle Aged; Multiple Sclerosis; Neurotransmitter Agents; Quinidine
PubMed: 27780330
DOI: 10.4088/JCP.15136tx1cj