Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.619
Filtrar
1.
Elife ; 122024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38289338

RESUMO

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.


Assuntos
Epilepsia , Canal de Sódio Disparado por Voltagem NAV1.6 , Quinidina , Animais , Humanos , Camundongos , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Homozigoto , Canal de Sódio Disparado por Voltagem NAV1.6/genética , Proteínas do Tecido Nervoso/genética , Quinidina/farmacologia , Sódio
2.
J Chromatogr A ; 1717: 464664, 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38271770

RESUMO

Chiral resolution of polar organic compounds such as amino acids and peptides represents an important chromatographic task due to increasing significance of natural species, which play important signaling and regulatory roles in the living organisms. Despite the number of available chiral stationary phases, this task remains challenging, since not many of the commercially available systems are capable to resolve non-derivatized zwitterionic species. In this study, we present a target-oriented design of a new class of chiral selectors. Pursuing the goal to separate amino acids, and especially short peptides, we have combined Cinchona alkaloids - quinine and quinidine - with three different biogenic dipeptides. We have synthesized six different chiral stationary phases, with selector loading of ∼200 µmol g-1, and tested their chiral recognition capabilities for acidic, basic and zwitterionic analytes using various mobile phases. We have observed that all chiral stationary phases retain the chiral anion exchange capability known for commercially available Cinchona-based columns leading to baseline or partial resolution of six out of ten analytes. The performance in chiral resolution of basic analytes is not optimum due to the weak cation exchange character of the peptidic residue. However, we report on encouraging results in the chiral resolution of short peptides, for which, depending on their structure, we see the chiral resolution of up to three stereoisomers (from four possible) in a preliminary screening.


Assuntos
Alcaloides de Cinchona , Cinchona , Dipeptídeos , Alcaloides de Cinchona/química , Quinina/química , Quinidina , Aminoácidos/química , Aminas , Estereoisomerismo , Cromatografia Líquida de Alta Pressão/métodos
3.
Biomacromolecules ; 25(1): 486-501, 2024 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-38150323

RESUMO

Nucleic acid delivery with cationic polymers is a promising alternative to expensive viral-based methods; however, it often suffers from a lower performance. Herein, we present a highly efficient delivery system based on cinchona alkaloid natural products copolymerized with 2-hydroxyethyl acrylate. Cinchona alkaloids are an attractive monomer class for gene delivery applications, given their ability to bind to DNA via both electrostatics and intercalation. To uncover the structure-activity profile of the system, four structurally similar cinchona alkaloids were incorporated into polymers: quinine, quinidine, cinchonine, and cinchonidine. These polymers differed in the chain length, the presence or absence of a pendant methoxy group, and stereochemistry, all of which were found to alter gene delivery performance and the ways in which the polymers overcome biological barriers to transfection. Longer polymers that contained the methoxy-bearing cinchona alkaloids (i.e., quinine and quinidine) were found to have the best performance. These polymers exhibited the tightest DNA binding, largest and most abundant DNA-polymer complexes, and best endosomal escape thanks to their increased buffering capacity and closest nuclear proximity of the payload. Overall, this work highlights the remarkable efficiency of polymer systems that incorporate cinchona alkaloid natural products while demonstrating the profound impact that small structural changes can have on overcoming biological hurdles associated with gene delivery.


Assuntos
Produtos Biológicos , Alcaloides de Cinchona , Quinina/farmacologia , Quinidina , Polímeros , Alcaloides de Cinchona/química , Alcaloides de Cinchona/metabolismo , DNA/genética
4.
Clin Pharmacol Ther ; 115(3): 616-626, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38117225

RESUMO

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.


Assuntos
Alcalose , Síndrome do QT Longo , Torsades de Pointes , Humanos , Quinidina/efeitos adversos , Torsades de Pointes/tratamento farmacológico , Eletrocardiografia , Síndrome do QT Longo/tratamento farmacológico , Alcalose/tratamento farmacológico , Proteínas de Ligação a DNA/uso terapêutico
5.
J Clin Psychopharmacol ; 43(5): 422-427, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37683231

RESUMO

BACKGROUND: Approximately one third of individuals with major depressive disorder have treatment-resistant depression (TRD). Glutamatergic modulators such as the N -methyl- d -aspartate receptor antagonist ketamine have rapid and robust antidepressant effects, but their use has been limited by accessibility and route of administration. This open-label pilot study assessed the adjunctive antidepressant efficacy of dextromethorphan/quinidine (DM/Q) in TRD. METHODS: Inpatients with TRD (n = 17, 40.8 ± 12.3 years; 9 females/8 males) received adjunctive open-label DM/Q (20 mg/10 mg) up to 3 times daily. The study had no set endpoint; participants were followed until they discontinued DM/Q or were discharged. Montgomery-Asberg Depression Rating Scale (MADRS) scores were obtained at baseline (before DM/Q administration) and regularly during hospitalization. Full response was defined as a ≥50% reduction in baseline MADRS score, partial response as a 25% to 50% decrease in baseline MADRS score, and nonresponse as a <25% reduction or an increase in baseline MADRS score. RESULTS: The 17 inpatients received open-label DM/Q for 5.1 ± 2.7 weeks. Forty-seven percent of participants responded to DM/Q-12% achieved a full response and 35% achieved a partial response. The largest MADRS difference observed at any time point was -6.4 ± 8.4 (-21.0% ± 29.9%), and the MADRS difference observed at time of DM/Q discontinuation or hospital discharge was -4.8 ± 8.4 (-15.9% ± 29.7%). Twenty-four percent of participants experienced a nonserious adverse event; none experienced a serious adverse event. CONCLUSIONS: In this open-label pilot study, 47% of participants responded to adjunctive DM/Q, which was well tolerated. Larger placebo-controlled trials are needed to determine the real-world efficacy of DM/Q.


Assuntos
Transtorno Depressivo Maior , Transtorno Depressivo Resistente a Tratamento , Masculino , Feminino , Humanos , Quinidina/efeitos adversos , Dextrometorfano/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Resultado do Tratamento , Depressão , Projetos Piloto , Antidepressivos/efeitos adversos , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Método Duplo-Cego
6.
Drug Metab Bioanal Lett ; 16(2): 121-132, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37612873

RESUMO

BACKGROUND: Saccharolactone is used as a ß-glucuronidase inhibitor in in vitro microsomal and recombinant uridine diphosphoglucuronosyl transferases (rUGTs) incubations to enhance glucuronide pathway and, thereby, formation of glucuronide metabolites. We investigated its effect on CYP mediated metabolism of drugs (compound-174, phenacetin and quinidine) using human liver microsomes (HLM) supplemented with Phase-1 and Phase-2 co-factors. METHODS: Compounds were incubated in HLM supplemented with co-factors to assess Phase-1 (NADPH) and Phase-2 (NADPH, alamethicin, saccharolactone and UDPGA) metabolism. CYP phenotype assay for compound-174 was conducted in HLM (± 1-ABT) and human recombinant CYP isoforms. CYP inhibition profile of saccharolactone was also generated in HLM. RESULTS: The metabolism of compound-174, phenacetin and quinidine in HLM significantly decreased in reactions containing additional components like alamethicin, saccharolactone and UDPGA and indicated that the addition of saccharolactone inhibited the metabolism. Phenacetin and quinidine are known substrates of CYP1A2 and CYP3A4 isoforms. The metabolism of compound- 174 was significantly inhibited in the presence of 1-ABT in HLM, and CYP3A4 and CYP2C8 isoforms were found to be the predominant isoforms responsible for its metabolism. Further evaluation of CYP inhibition in HLM indicated saccharolactone to be a strong inhibitor of CYP1A2, 2D6, 3A4 and 2C8 isoforms with IC50 values of less than 4 mM. CONCLUSION: The findings indicated that saccharolactone being a strong inhibitor of CYP1A2, 2D6, 3A4 and 2C8 isoforms (IC50 < 4 mM), resulted in significant inhibition of the metabolism of compound-174, phenacetin and quinidine in HLM and caution should be exercised in using it with proper titration of the concentrations.


Assuntos
Citocromo P-450 CYP1A2 , Sistema Enzimático do Citocromo P-450 , Humanos , Citocromo P-450 CYP1A2/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Citocromo P-450 CYP3A/metabolismo , Glucuronídeos/metabolismo , Uridina Difosfato Ácido Glucurônico/metabolismo , Quinidina/farmacologia , Xenobióticos/farmacologia , NADP/metabolismo , Fenacetina/metabolismo , Microssomos Hepáticos , Isoformas de Proteínas/metabolismo , Peptaibols/metabolismo
7.
ACS Appl Bio Mater ; 6(8): 3117-3130, 2023 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-37498226

RESUMO

P-glycoprotein (P-gp) is a promiscuous small molecule transporter whose overexpression in cancer is associated with multidrug resistance (MDR). In these instances, anticancer drugs can select for P-gp-overexpressing cells, leading to cancer recurrence with an MDR phenotype. To avoid selection for MDR cancers and inform individual patient treatment plans, it is critical to noninvasively identify P-gp-overexpressing tumors prior to administration of chemotherapy. We report the facile free radical copolymerization of quinidine, a competitive inhibitor of P-gp, and acrylic acid to generate multiplexed polymeric P-gp-targeted imaging agents with tunable quinidine content. Copolymer targeting was demonstrated in a nude mouse xenograft model. In xenografts overexpressing P-gp, copolymer distribution was enhanced over two-fold compared to the negative control of poly(acrylic acid) regardless of quinidine content. In contrast, accumulation of the copolymers in xenografts lacking P-gp was equivalent to poly(acrylic acid). This work forms the foundation for a unique approach toward the phenotype-specific noninvasive imaging of MDR tumors and is the first in vivo demonstration of copolymer accumulation through the active targeting of P-gp.


Assuntos
Antineoplásicos , Neoplasias , Camundongos , Animais , Humanos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Quinidina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Antineoplásicos/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/farmacologia , Polímeros/farmacologia
8.
Ann Clin Transl Neurol ; 10(8): 1296-1304, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37265174

RESUMO

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.


Assuntos
Esclerose Amiotrófica Lateral , Humanos , Esclerose Amiotrófica Lateral/complicações , Esclerose Amiotrófica Lateral/tratamento farmacológico , Dextrometorfano/farmacologia , Dextrometorfano/uso terapêutico , Quinidina/farmacologia , Quinidina/uso terapêutico , Deglutição , Fala
9.
CPT Pharmacometrics Syst Pharmacol ; 12(8): 1143-1156, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37165978

RESUMO

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.


Assuntos
Citocromo P-450 CYP2D6 , Citocromo P-450 CYP3A , Humanos , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Quinidina , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Interações Medicamentosas , Modelos Biológicos , Inibidores do Citocromo P-450 CYP3A/farmacocinética
10.
Am J Cardiovasc Drugs ; 23(4): 355-377, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37233967

RESUMO

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 ).


Assuntos
Amiodarona , Fibrilação Atrial , Adulto , Humanos , Fibrilação Atrial/tratamento farmacológico , Quinidina/uso terapêutico , Flecainida/uso terapêutico , Cardioversão Elétrica , Ranolazina/uso terapêutico , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Revisões Sistemáticas como Assunto , Antiarrítmicos/efeitos adversos , Amiodarona/uso terapêutico , Verapamil/uso terapêutico
11.
Anim Cogn ; 26(3): 1097-1102, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36856894

RESUMO

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.


Assuntos
Cornus , Animais , Paladar/fisiologia , Aprendizagem da Esquiva/fisiologia , Quinidina , Caramujos
12.
Drug Metab Dispos ; 51(3): 318-328, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36810197

RESUMO

Drug absorption from the gastrointestinal tract is often restricted by efflux transport by P-glycoprotein (P-gp) and metabolism by CYP3A4. Both localize in the epithelial cells, and thus, their activities are directly affected by the intracellular drug concentration, which should be regulated by the ratio of permeability between apical (A) and basal (B) membranes. In this study, using Caco-2 cells with forced expression of CYP3A4, we assessed the transcellular permeation of A-to-B and B-to-A directions and the efflux from the preloaded cells to both sides of 12 representative P-gp or CYP3A4 substrate drugs and obtained the parameters for permeabilities, transport, metabolism, and unbound fraction in the enterocytes (fent) using simultaneous and dynamic model analysis. The membrane permeability ratios for B to A (RBA) and fent varied by 8.8-fold and by more than 3000-fold, respectively, among the drugs. The RBA values for digoxin, repaglinide, fexofenadine, and atorvastatin were greater than 1.0 (3.44, 2.39, 2.27, and 1.90, respectively) in the presence of a P-gp inhibitor, thus suggesting the potential involvement of transporters in the B membrane. The Michaelis constant for quinidine for P-gp transport was 0.077 µM for the intracellular unbound concentration. These parameters were used to predict overall intestinal availability (FAFG) by applying an intestinal pharmacokinetic model, advanced translocation model (ATOM), in which permeability of A and B membranes accounted separately. The model predicted changes in the absorption location for P-gp substrates according to its inhibition, and FAFG values of 10 of 12 drugs, including quinidine at varying doses, were explained appropriately. SIGNIFICANCE STATEMENT: Pharmacokinetics has improved predictability by identifying the molecular entities of metabolism and transport and by using mathematical models to appropriately describe drug concentrations at the locations where they act. However, analyses of intestinal absorption so far have not been able to accurately consider the concentrations in the epithelial cells where P-glycoprotein and CYP3A4 exert effects. In this study, the limitation was removed by measuring the apical and basal membrane permeability separately and then analyzing these values using new appropriate models.


Assuntos
Citocromo P-450 CYP3A , Quinidina , Humanos , Quinidina/farmacologia , Células CACO-2 , Citocromo P-450 CYP3A/metabolismo , Absorção Intestinal , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Permeabilidade
14.
Mol Biol Rep ; 50(3): 2611-2621, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36633730

RESUMO

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.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Neoplasias Pancreáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Quinidina/farmacologia , Quinidina/uso terapêutico , Apoptose , Carcinogênese , Colo/metabolismo , Proliferação de Células , Linhagem Celular Tumoral , Neoplasias Pancreáticas/metabolismo
15.
J Pharmacol Exp Ther ; 384(3): 417-428, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36460339

RESUMO

The cardiac sodium channel Nav1.5 is a key contributor to the cardiac action potential, and dysregulations in Nav1.5 can lead to cardiac arrhythmias. Nav1.5 is a target of numerous antiarrhythmic drugs (AADs). Previous studies identified the protein 14-3-3 as a regulator of Nav1.5 biophysical coupling. Inhibition of 14-3-3 can remove the Nav1.5 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 Nav1.5. Indeed, AADs could reveal important structural and functional information about Nav1.5 coupling. Here, we investigated the modulation of Nav1.5 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 Nav1.5 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 Nav1.5 coupling could impact the effects of AADs. Therefore, 14-3-3 and Nav1.5 coupling are new mechanisms to consider in the development of drugs targeting Nav1.5. SIGNIFICANCE STATEMENT: The cardiac sodium channel Nav1.5 is a target of commonly used antiarrhythmic drugs, and Nav1.5 function is regulated by the protein 14-3-3. The present study demonstrated that the regulation of Nav1.5 by 14-3-3 influences Nav1.5's response to antiarrhythmic drugs. This study provides detailed information about how 14-3-3 differentially regulated Nav1.5 functions under the influence of different drug subtypes. These findings will guide future molecular studies investigating Nav1.5 and antiarrhythmic drugs outcomes.


Assuntos
Antiarrítmicos , Mexiletina , Humanos , Antiarrítmicos/farmacologia , Mexiletina/farmacologia , Proteínas 14-3-3/metabolismo , Quinidina/farmacologia , Células HEK293 , Lidocaína/farmacologia , Canais de Sódio/metabolismo
16.
Neurol Sci ; 44(4): 1201-1206, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36437393

RESUMO

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.


Assuntos
Epilepsia , Quinidina , Humanos , Quinidina/uso terapêutico , Anticonvulsivantes/uso terapêutico , Canais de Potássio Ativados por Sódio/genética , Epilepsia/tratamento farmacológico , Epilepsia/genética , Canais de Potássio/genética , Canais de Potássio/uso terapêutico , Mutação , Proteínas do Tecido Nervoso/genética
17.
J Psychosoc Nurs Ment Health Serv ; 60(11): 9-11, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36317836

RESUMO

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.].


Assuntos
Antitussígenos , Transtorno Depressivo Maior , Humanos , Antitussígenos/farmacologia , Antitussígenos/uso terapêutico , Dextrometorfano/farmacologia , Dextrometorfano/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Quinidina/uso terapêutico , Antidepressivos/uso terapêutico
18.
Zhonghua Xin Xue Guan Bing Za Zhi ; 50(11): 1087-1093, 2022 Nov 24.
Artigo em Chinês | MEDLINE | ID: mdl-36418277

RESUMO

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.


Assuntos
Mexiletina , Quinidina , Coelhos , Animais , Quinidina/farmacologia , Quinidina/uso terapêutico , Mexiletina/farmacologia , Mexiletina/uso terapêutico , Pinacidil/farmacologia , Pinacidil/uso terapêutico , Sódio , Ranolazina/farmacologia , Ranolazina/uso terapêutico , Técnicas Eletrofisiológicas Cardíacas , Arritmias Cardíacas/tratamento farmacológico
19.
NPJ Syst Biol Appl ; 8(1): 43, 2022 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-36333337

RESUMO

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.


Assuntos
Quinidina , Sotalol , Humanos , Quinidina/farmacologia , Quinidina/uso terapêutico , Sotalol/farmacologia , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Potenciais de Ação/genética , Mutação/genética , Canal de Potássio ERG1/genética
20.
Can Vet J ; 63(10): 1051-1056, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36185789

RESUMO

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).


Assuntos
Fibrilação Atrial , Doenças dos Cavalos , Animais , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/veterinária , Canadá , Doenças dos Cavalos/tratamento farmacológico , Cavalos , Quinidina/uso terapêutico , Estudos Retrospectivos , Atenção Terciária à Saúde
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...