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[PMID]:29352276
[Au] Autor:Osadchii OE
[Ad] Endereço:Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
[Ti] Título:Arrhythmogenic drugs can amplify spatial heterogeneities in the electrical restitution in perfused guinea-pig heart: An evidence from assessments of monophasic action potential durations and JT intervals.
[So] Source:PLoS One;13(1):e0191514, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Non-uniform shortening of the action potential duration (APD90) in different myocardial regions upon heart rate acceleration can set abnormal repolarization gradients and promote arrhythmia. This study examined whether spatial heterogeneities in APD90 restitution can be amplified by drugs with clinically proved proarrhythmic potential (dofetilide, quinidine, procainamide, and flecainide) and, if so, whether these effects can translate to the appropriate changes of the ECG metrics of ventricular repolarization, such as JT intervals. In isolated, perfused guinea-pig heart preparations, monophasic action potentials and volume-conducted ECG were recorded at progressively increased pacing rates. The APD90 measured at distinct ventricular sites, as well as the JTpeak and JTend values were plotted as a function of preceding diastolic interval, and the maximum slopes of the restitution curves were determined at baseline and upon drug administration. Dofetilide, quinidine, and procainamide reverse rate-dependently prolonged APD90 and steepened the restitution curve, with effects being greater at the endocardium than epicardium, and in the right ventricular (RV) vs. the left ventricular (LV) chamber. The restitution slope was increased to a greater extent for the JTend vs. the JTpeak interval. In contrast, flecainide reduced the APD90 restitution slope at LV epicardium without producing effect at LV endocardium and RV epicardium, and reduced the JTpeak restitution slope without changing the JTend restitution. Nevertheless, with all agents, these effects translated to the amplified epicardial-to-endocardial and the LV-to-RV non-uniformities in APD90 restitution, paralleled by the increased JTend vs. JTpeak difference in the restitution slope. In summary, these findings suggest that arrhythmic drug profiles are partly attributable to the accentuated regional heterogeneities in APD90 restitution, which can be indirectly determined through ECG assessments of the JTend vs. JTpeak dynamics at variable pacing rates.
[Mh] Termos MeSH primário: Antiarrítmicos/efeitos adversos
Arritmias Cardíacas/induzido quimicamente
Arritmias Cardíacas/fisiopatologia
[Mh] Termos MeSH secundário: Potenciais de Ação/efeitos dos fármacos
Potenciais de Ação/fisiologia
Animais
Fenômenos Eletrofisiológicos
Feminino
Flecainida/efeitos adversos
Cobaias
Técnicas In Vitro
Perfusão
Fenetilaminas/efeitos adversos
Procainamida/efeitos adversos
Quinidina/efeitos adversos
Sulfonamidas/efeitos adversos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anti-Arrhythmia Agents); 0 (Phenethylamines); 0 (Sulfonamides); ITX08688JL (Quinidine); K94FTS1806 (Flecainide); L39WTC366D (Procainamide); R4Z9X1N2ND (dofetilide)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180121
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191514


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[PMID]:29241489
[Au] Autor:Mazzanti A; Maragna R; Vacanti G; Kostopoulou A; Marino M; Monteforte N; Bloise R; Underwood K; Tibollo V; Pagan E; Napolitano C; Bellazzi R; Bagnardi V; Priori SG
[Ad] Endereço:Molecular Cardiology, Department of Cardiology, IRCCS ICS Maugeri, Pavia, Italy; Department of Molecular Medicine, University of Pavia, Pavia, Italy.
[Ti] Título:Hydroquinidine Prevents Life-Threatening Arrhythmic Events in Patients With Short QT Syndrome.
[So] Source:J Am Coll Cardiol;70(24):3010-3015, 2017 Dec 19.
[Is] ISSN:1558-3597
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Short QT syndrome (SQTS) is a rare and life-threatening arrhythmogenic syndrome characterized by abbreviated repolarization. Hydroquinidine (HQ) prolongs the QT interval in SQTS patients, although whether it reduces cardiac events is currently unknown. OBJECTIVES: This study investigated whether long-term treatment with HQ reduces the occurrence of life-threatening arrhythmic events (LAE) (cardiac arrest or sudden cardiac death) in SQTS patients. METHODS: In this cohort study on consecutive SQTS patients, 2 analyses were performed: 1) a matched-period analysis for the occurrence of LAE in 17 SQTS patients who received long-term HQ; and 2) a comparison of the annual incidence of LAE off- and on-HQ in 16 SQTS patients who survived a cardiac arrest. RESULTS: A total of 17 patients (82% male, age 29 ± 3 years, QTc before treatment 331 ± 3 ms) received HQ therapy (584 ± 53 mg/day). Therapy was stopped in 2 cases (12%) due to gastrointestinal intolerance, and 15 patients continued treatment for 6 ± 1 year. QTc prolongation was observed in all patients (by 60 ± 6 ms; p < 0.001). We compared the occurrence of LAE during 6 ± 1 years before and after HQ, observing that patients on HQ experienced a reduction in both the rate of LAE from 40% to 0% (p = 0.03) and the number of LAE per patient from 0.73 ± 0.3 to 0 (p = 0.026). Furthermore, the annual rate of LAE in the 16 patients with a previous cardiac arrest dropped from 12% before HQ to 0 on therapy (p = 0.028). CONCLUSIONS: We demonstrated for the first time that treatment with HQ was associated with a lower incidence of LAE in SQTS patients. These data point to the importance that quinidine, that in several countries has been removed from the market, remains available worldwide for patients with SQTS. In the present study, therapy with HQ has been proven to be safe, with a relatively low rate of side effects.
[Mh] Termos MeSH primário: Arritmias Cardíacas/tratamento farmacológico
Morte Súbita Cardíaca/prevenção & controle
Quinidina/análogos & derivados
Fibrilação Ventricular/prevenção & controle
[Mh] Termos MeSH secundário: Adolescente
Adulto
Antiarrítmicos/administração & dosagem
Arritmias Cardíacas/complicações
Arritmias Cardíacas/fisiopatologia
Morte Súbita Cardíaca/epidemiologia
Morte Súbita Cardíaca/etiologia
Eletrocardiografia
Feminino
Seguimentos
Sistema de Condução Cardíaco/efeitos dos fármacos
Sistema de Condução Cardíaco/fisiopatologia
Frequência Cardíaca/efeitos dos fármacos
Seres Humanos
Incidência
Itália/epidemiologia
Masculino
Quinidina/administração & dosagem
Taxa de Sobrevida/tendências
Fibrilação Ventricular/complicações
Fibrilação Ventricular/epidemiologia
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Arrhythmia Agents); 8P68XPY4HG (hydroquinidine); ITX08688JL (Quinidine)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171227
[Lr] Data última revisão:
171227
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171216
[St] Status:MEDLINE


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[PMID]:28720332
[Au] Autor:Kim JH; Jeong HR; Jung DW; Yoon HB; Kim SY; Kim HJ; Lee KT; Gadotti VM; Huang J; Zhang FX; Zamponi GW; Lee JY
[Ad] Endereço:Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Republic of Korea.
[Ti] Título:Synthesis and biological evaluation of fluoro-substituted 3,4-dihydroquinazoline derivatives for cytotoxic and analgesic effects.
[So] Source:Bioorg Med Chem;25(17):4656-4664, 2017 Sep 01.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:As a bioisosteric strategy to overcome the poor metabolic stability of lead compound KYS05090S, a series of new fluoro-substituted 3,4-dihydroquinazoline derivatives was prepared and evaluated for T-type calcium channel (Ca 3.2) block, cytotoxic effects and liver microsomal stability. Among them, compound 8h (KCP10068F) containing 4-fluorobenzyl amide and 4-cyclohexylphenyl ring potently blocked Ca 3.2 currents (>90% inhibition) at 10µM concentration and exhibited cytotoxic effect (IC =5.9µM) in A549 non-small cell lung cancer cells that was comparable to KYS05090S. Furthermore, 8h showed approximately a 2-fold increase in liver metabolic stability in rat and human species compared to KYS05090S. Based on these overall results, 8h (KCP10068F) may therefore represent a good backup compound for KYS05090S for further biological investigations as novel cytotoxic agent. In addition, compound 8g (KCP10067F) was found to partially protect from inflammatory pain via a blockade of Ca 3.2 channels.
[Mh] Termos MeSH primário: Analgésicos/síntese química
Bloqueadores dos Canais de Cálcio/síntese química
Quinazolinas/química
Quinidina/análogos & derivados
[Mh] Termos MeSH secundário: Células A549
Analgésicos/química
Analgésicos/toxicidade
Animais
Bloqueadores dos Canais de Cálcio/química
Bloqueadores dos Canais de Cálcio/toxicidade
Canais de Cálcio Tipo T/química
Canais de Cálcio Tipo T/genética
Canais de Cálcio Tipo T/metabolismo
Sobrevivência Celular/efeitos dos fármacos
Estabilidade de Medicamentos
Flúor/química
Células HEK293
Seres Humanos
Concentração Inibidora 50
Microssomos Hepáticos/metabolismo
Técnicas de Patch-Clamp
Quinazolinas/síntese química
Quinazolinas/toxicidade
Quinidina/síntese química
Quinidina/química
Quinidina/toxicidade
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Analgesics); 0 (Calcium Channel Blockers); 0 (Calcium Channels, T-Type); 0 (KCP10068F); 0 (KYS 05090); 0 (Quinazolines); 284SYP0193 (Fluorine); 8P68XPY4HG (hydroquinidine); ITX08688JL (Quinidine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170720
[St] Status:MEDLINE


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[PMID]:28719377
[Au] Autor:Ferreira AO; Polonini H; da Silva SL; Aglio NCB; Abreu J; Fernandes BMA
[Ad] Endereço:Ortofarma - Quality Control Laboratories, Matias Barbosa, MG, Brazil.
[Ti] Título:Stability of Acetazolamide, Baclofen, Dipyridamole, Mebeverine Hydrochloride, Propylthiouracil, Quinidine Sulfate, and Topiramate Oral Suspensions in SyrSpend SF PH4.
[So] Source:Int J Pharm Compd;21(4):339-346, 2017 Jul-Aug.
[Is] ISSN:1092-4221
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The objective of this study was to evaluate the stability of 7 commonly used active pharmaceutical ingredients compounded in oral suspensions using an internationally used suspending vehicle (SyrSpend SF PH4): acetazolamide 25.0 mg/mL, baclofen 10.0 mg/mL, dipyridamole 10.0 mg/mL, mebeverine hydrochloride 10.0 mg/mL, propylthiouracil 5.0 mg/mL, quinidine sulfate 10.0 mg/mL, and topiramate 5.0 mg/mL. All suspensions were stored both at controlled refrigerated (2°C to 8°C) and room temperature (20°C to 25°C). Stability was assessed by measuring the percentage recovery at varying time points throughout a 90-day period. Active pharmaceutical ingredient quantification was performed by ultraviolet (UV) high-performance liquid chromatography, via a stability-indicating method. Given the percentage of recovery of the active pharmaceutical ingredients within the suspensions, the beyond-use date of the final products (active pharmaceutical ingredient + vehicle) was at least 90 days for all suspensions with regards to both temperatures. This suggests that SyrSpend SF PH4 is suitable for compounding active pharmaceutical ingredients from different pharmacological classes.
[Mh] Termos MeSH primário: Composição de Medicamentos
Estabilidade de Medicamentos
[Mh] Termos MeSH secundário: Acetazolamida/química
Administração Oral
Baclofeno/química
Cromatografia Líquida de Alta Pressão
Dipiridamol/química
Frutose/análogos & derivados
Frutose/química
Fenetilaminas/química
Propiltiouracila/química
Quinidina/química
Suspensões
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Phenethylamines); 0 (Suspensions); 0H73WJJ391 (topiramate); 30237-26-4 (Fructose); 64ALC7F90C (Dipyridamole); 721M9407IY (Propylthiouracil); 7F80CC3NNV (mebeverine); H789N3FKE8 (Baclofen); ITX08688JL (Quinidine); O3FX965V0I (Acetazolamide)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170719
[St] Status:MEDLINE


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[PMID]:28632743
[Au] Autor:Luo C; Wang K; Zhang H
[Ad] Endereço:School of Computer Science and Technology, Harbin Institute of Technology (HIT), Harbin, China.
[Ti] Título:In silico assessment of the effects of quinidine, disopyramide and E-4031 on short QT syndrome variant 1 in the human ventricles.
[So] Source:PLoS One;12(6):e0179515, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:AIMS: Short QT syndrome (SQTS) is an inherited disorder associated with abnormally abbreviated QT intervals and an increased incidence of atrial and ventricular arrhythmias. SQT1 variant (linked to the rapid delayed rectifier potassium channel current, IKr) of SQTS, results from an inactivation-attenuated, gain-of-function mutation (N588K) in the KCNH2-encoded potassium channels. Pro-arrhythmogenic effects of SQT1 have been well characterized, but less is known about the possible pharmacological antiarrhythmic treatment of SQT1. Therefore, this study aimed to assess the potential effects of E-4031, disopyramide and quinidine on SQT1 using a mathematical model of human ventricular electrophysiology. METHODS: The ten Tusscher et al. biophysically detailed model of the human ventricular action potential (AP) was modified to incorporate IKr Markov chain (MC) formulations based on experimental data of the kinetics of the N588K mutation of the KCNH2-encoded subunit of the IKr channels. The modified ventricular cell model was then integrated into one-dimensional (1D) strand, 2D regular and realistic tissues with transmural heterogeneities. The channel-blocking effect of the drugs on ion currents in healthy and SQT1 cells was modeled using half-maximal inhibitory concentration (IC50) and Hill coefficient (nH) values from literatures. Effects of drugs on cell AP duration (APD), effective refractory period (ERP) and pseudo-ECG traces were calculated. Effects of drugs on the ventricular temporal and spatial vulnerability to re-entrant excitation waves were measured. Re-entry was simulated in both 2D regular and realistic ventricular tissue. RESULTS: At the single cell level, the drugs E-4031 and disopyramide had hardly noticeable effects on the ventricular cell APD at 90% repolarization (APD90), whereas quinidine caused a significant prolongation of APD90. Quinidine prolonged and decreased the maximal transmural AP heterogeneity (δV); this led to the decreased transmural heterogeneity of APD across the 1D strand. Quinidine caused QT prolongation and a decrease in the T-wave amplitude, and increased ERP and decreased temporal susceptibility of the tissue to the initiation of re-entry and increased the minimum substrate size necessary to prevent re-entry in the 2D regular model, and further terminated re-entrant waves in the 2D realistic model. Quinidine exhibited significantly better therapeutic effects on SQT1 than E-4031 and disopyramide. CONCLUSIONS: The simulated pharmacological actions of quinidine exhibited antiarrhythmic effects on SQT1. This study substantiates a causal link between quinidine and QT interval prolongation in SQT1 and suggests that quinidine may be a potential pharmacological agent for treating SQT1 patients.
[Mh] Termos MeSH primário: Potenciais de Ação/efeitos dos fármacos
Disopiramida/farmacologia
Piperidinas/farmacologia
Piridinas/farmacologia
Quinidina/farmacologia
[Mh] Termos MeSH secundário: Arritmias Cardíacas/tratamento farmacológico
Arritmias Cardíacas/genética
Arritmias Cardíacas/patologia
Linhagem Celular
Disopiramida/uso terapêutico
Canal de Potássio ERG1/genética
Eletrocardiografia
Ventrículos do Coração/efeitos dos fármacos
Ventrículos do Coração/fisiopatologia
Seres Humanos
Modelos Biológicos
Piperidinas/uso terapêutico
Polimorfismo de Nucleotídeo Único
Piridinas/uso terapêutico
Quinidina/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ERG1 Potassium Channel); 0 (KCNH2 protein, human); 0 (Piperidines); 0 (Pyridines); 113558-89-7 (E 4031); GFO928U8MQ (Disopyramide); ITX08688JL (Quinidine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170919
[Lr] Data última revisão:
170919
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170621
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0179515


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[PMID]:28347660
[Au] Autor:Niwa T; Shizuku M; Yamano K
[Ad] Endereço:School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-ku, Okayama 703-8516, Japan. Electronic address: tniwa@shujitsu.ac.jp.
[Ti] Título:Effect of genetic polymorphism on the inhibition of dopamine formation from p-tyramine catalyzed by brain cytochrome P450 2D6.
[So] Source:Arch Biochem Biophys;620:23-27, 2017 Apr 15.
[Is] ISSN:1096-0384
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The inhibitory effects of steroid hormones, including glucocorticoids such as cortisol, and related compounds on dopamine formation from p-tyramine, catalyzed by cytochrome P450 (CYP) 2D6.2 (Arg296Cys, Ser486Thr) and CYP2D6.10 (Pro34Ser, Ser486Thr) were compared with the effects of those catalyzed by CYP2D6.1 (wild type), to investigate the effect of a CYP2D6 polymorphism on neuroactive amine metabolism in the brain. Inhibition constants (K ) or 50% inhibitory concentrations of six steroid hormones (cortisol, cortisone, corticosterone, dehydroepiandrosterone, progesterone, and pregnenolone) and quinidine and quinine-typical potent inhibitors of the human CYP2D6 and rat CYP2D subfamily, respectively-toward dopamine formation catalyzed by CYP2D6.1, CYP2D6.2, and CYP2D6.10 expressed in recombinant Escherichia coli were compared. Although most steroid hormones had no or minor inhibitory effects on the dopamine formation by all CYP2D6 variants, progesterone inhibited the metabolism and K value against CYP2D6.10 was approximately twice that for CYP2D6.1 and CYP2D6.2. Quinidine exhibited stronger inhibition than quinine; however, these two compounds inhibited the CYP2D6.10-mediated reaction more weakly than the CYP2D6.1 and CYP2D6.2 reactions. These results suggest that CYP2D6 polymorphism would affect drug interaction through dopamine formation in the brain.
[Mh] Termos MeSH primário: Citocromo P-450 CYP2D6/química
Citocromo P-450 CYP2D6/genética
Dopamina/química
Polimorfismo Genético
Tiramina/química
[Mh] Termos MeSH secundário: Animais
Citocromo P-450 CYP2D6/metabolismo
Inibidores do Citocromo P-450 CYP2D6/química
Dopamina/genética
Dopamina/metabolismo
Seres Humanos
Quinidina/química
Quinina/química
Ratos
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Tiramina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2D6 Inhibitors); 0 (Recombinant Proteins); A7V27PHC7A (Quinine); EC 1.14.14.1 (Cytochrome P-450 CYP2D6); ITX08688JL (Quinidine); VTD58H1Z2X (Dopamine); X8ZC7V0OX3 (Tyramine)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170428
[Lr] Data última revisão:
170428
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170329
[St] Status:MEDLINE


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[PMID]:28231318
[Au] Autor:Osadchii OE
[Ad] Endereço:Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
[Ti] Título:Effects of Na+ channel blockers on the restitution of refractory period, conduction time, and excitation wavelength in perfused guinea-pig heart.
[So] Source:PLoS One;12(2):e0172683, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Na+ channel blockers flecainide and quinidine can increase propensity to ventricular tachyarrhythmia, whereas lidocaine and mexiletine are recognized as safe antiarrhythmics. Clinically, ventricular fibrillation is often precipitated by transient tachycardia that reduces action potential duration, suggesting that a critical shortening of the excitation wavelength (EW) may contribute to the arrhythmic substrate. This study examined whether different INa blockers can produce contrasting effects on the rate adaptation of the EW, which would explain the difference in their safety profile. In perfused guinea-pig hearts, effective refractory periods (ERP), conduction times, and EW values were determined over a wide range of cardiac pacing intervals. All INa blockers tested were found to flatten the slope of ERP restitution, indicating antiarrhythmic tendency. However, with flecainide and quinidine, the beneficial changes in ERP were reversed owing to the use-dependent conduction slowing, thereby leading to significantly steepened restitution of the EW. In contrast, lidocaine and mexiletine had no effect on ventricular conduction, and therefore reduced the slope of the EW restitution, as expected from their effect on ERP. These findings suggest that the slope of the EW restitution is an important electrophysiological determinant which can discriminate INa blockers with proarrhythmic and antiarrhythmic profile.
[Mh] Termos MeSH primário: Flecainida/farmacologia
Sistema de Condução Cardíaco/efeitos dos fármacos
Coração/efeitos dos fármacos
Quinidina/farmacologia
Período Refratário Eletrofisiológico/efeitos dos fármacos
Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia
[Mh] Termos MeSH secundário: Potenciais de Ação/efeitos dos fármacos
Animais
Eletrocardiografia
Feminino
Cobaias
Frequência Cardíaca/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Voltage-Gated Sodium Channel Blockers); ITX08688JL (Quinidine); K94FTS1806 (Flecainide)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170224
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0172683


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[PMID]:28188270
[Au] Autor:Koepple C; Scherer D; Seyler C; Scholz E; Thomas D; Katus HA; Zitron E
[Ad] Endereço:Department of Cardiology, Medical University Hospital Heidelberg, Heidelberg, Germany (C.K., D.S., C.S., E.S., D.T., H.A.K., E.Z.); DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, University of Heidelberg, Heidelberg, Germany (C.S., E.S., D.T., H.A.K., E.Z.); and
[Ti] Título:Dual Mechanism for Inhibition of Inwardly Rectifying Kir2.x Channels by Quinidine Involving Direct Pore Block and PIP -interference.
[So] Source:J Pharmacol Exp Ther;361(2):209-218, 2017 May.
[Is] ISSN:1521-0103
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Class IA antiarrhythmic drug quinidine was one of the first clinically used compounds to terminate atrial fibrillation and acts as multichannel inhibitor with well-documented inhibitory effects on several cardiac potassium channels. In the mammalian heart, heteromeric assembly of Kir2.1-2.3 channels underlies I current. Although a low-affinity block of quinidine on Kir2.1 has already been described, a comparative analysis of effects on other Kir2.x channels has not been performed to date. Therefore, we analyzed the effects of quinidine on wild-type and mutant Kir2.x channels in the oocyte expression system. Quinidine exerted differential inhibitory effects on Kir2.x channels with the highest affinity toward Kir2.3 subunits. Onset of block was slow and solely reversible in Kir2.2 subunits. Quinidine inhibited Kir2.x currents in a voltage-independent manner. By means of comparative Ala-scanning mutagenesis, we further found that residues E224, F254, D259, and E299 are essential for quinidine block in Kir2.1 subunits. Analogously, quinidine mediated Kir2.3 inhibition by binding corresponding residues E216, D247, D251, and E291. In contrast, Kir2.2 current block merely involved corresponding residue D260. Using channel mutants with altered (phosphatidylinositol 4,5-bisphosphate PIP ) affinities, we were able to demonstrate that high PIP affinities (i.e., Kir2.3 I214L) correlate with low quinidine sensitivity. Inversely, mutant channels interacting only weakly with PIP (i.e., Kir2.1 K182Q, and L221I) are prone to a higher inhibitory effect. Thus, we conclude that inhibition of Kir2.x channels by quinidine is mediated by joint modes of action involving direct cytoplasmic pore block and an impaired channel stabilization via interference with PIP .
[Mh] Termos MeSH primário: Canais de Potássio Corretores do Fluxo de Internalização
Quinidina/farmacologia
[Mh] Termos MeSH secundário: Animais
Antiarrítmicos/farmacologia
Sítios de Ligação/fisiologia
Biofarmácia/métodos
Oócitos/metabolismo
Fosfatidilinositol 4,5-Difosfato/metabolismo
Canais de Potássio Corretores do Fluxo de Internalização/antagonistas & inibidores
Canais de Potássio Corretores do Fluxo de Internalização/metabolismo
Xenopus
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Arrhythmia Agents); 0 (Kir2.1 channel); 0 (Kir2.2 channel); 0 (Phosphatidylinositol 4,5-Diphosphate); 0 (Potassium Channels, Inwardly Rectifying); ITX08688JL (Quinidine)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170508
[Lr] Data última revisão:
170508
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170212
[St] Status:MEDLINE
[do] DOI:10.1124/jpet.116.238287


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[PMID]:28185296
[Au] Autor:Anani WQ; Smith GP; Irani M; Puca KE
[Ad] Endereço:BloodCenter of Wisconsin, Milwaukee, Wisconsin.
[Ti] Título:A report of cerebral malaria treated with automated red blood cell exchange.
[So] Source:Transfusion;57(4):985-988, 2017 Apr.
[Is] ISSN:1537-2995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Adjunctive automated whole blood or red blood cell exchange (RBCEx) can rapidly decrease malarial hyperparasitemia. Several case reports and series suggest improvement in clinical symptomatology; however, recent Centers of Disease Control and Prevention (CDC) recommendations concluded that RBCEx has no efficacy as an adjunctive therapy. We present a case of mental status changes secondary to cerebral malaria treated with automated RBCEx resulting in rapid and dramatic neurologic improvement. CASE REPORT: An 84-year-old Somali woman presented with a 3-day history of altered mental status, spiking fevers, chills, bilateral leg pain and weakness, and intermittent diarrhea. Her travel history included a recent trip to Kenya for 1 month without antimalarial chemoprophylaxis. During the hospital stay, her health declined, and she became obtunded. Physical examination revealed fever, tachypnea, hypertension, hypoxia, and no response to verbal or physical stimuli. Her hemoglobin decreased from 12.6 to 6.5 g/dL with 12% intraerythrocytic parasitemia by thin smear. Intraerythrocytic trophozoites and banana-shaped gametocytes were present consistent with Plasmodium falciparum. An emergent 1.5-volume RBC mass automated RBCEx and quinidine infusion decreased her parasitemia to 2%. The patient's mental status improved throughout the procedure, and after the 2½-hour procedure, the patient was alert, oriented, and speaking coherently. The patient continued to receive quinidine and artesunate 1 day later from CDC. CONCLUSION: Automated RBCEx transfusion reduced the parasite burden and restored neurologic functioning in a patient with cerebral malaria while awaiting definitive treatment with artesunate.
[Mh] Termos MeSH primário: Transfusão de Eritrócitos
Malária Cerebral
Malária Falciparum
Parasitemia
Plasmodium falciparum
Quinidina/administração & dosagem
[Mh] Termos MeSH secundário: Idoso de 80 Anos ou mais
Feminino
Seres Humanos
Malária Cerebral/sangue
Malária Cerebral/parasitologia
Malária Cerebral/terapia
Malária Falciparum/sangue
Malária Falciparum/parasitologia
Malária Falciparum/terapia
Parasitemia/sangue
Parasitemia/parasitologia
Parasitemia/terapia
[Pt] Tipo de publicação:CASE REPORTS
[Nm] Nome de substância:
ITX08688JL (Quinidine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170621
[Lr] Data última revisão:
170621
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170211
[St] Status:MEDLINE
[do] DOI:10.1111/trf.14013


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[PMID]:28178218
[Au] Autor:Bilonda MK; Mammino L
[Ad] Endereço:Department of Chemistry, University of Venda, Thohoyandou 0950, South Africa. mireillebilonda@yahoo.fr.
[Ti] Título:Intramolecular Hydrogen Bonds in Conformers of Quinine and Quinidine: An HF, MP2 and DFT Study.
[So] Source:Molecules;22(2), 2017 Feb 07.
[Is] ISSN:1420-3049
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Quinine is an alkaloid with powerful antimalarial activity, isolated from the bark of Peru's cinchona trees. Quinidine is an erythro diastereoisomer of quinine also exhibiting antimalarial activity. Conformational studies performed so far had never identified conformers with intramolecular hydrogen bonds (IHB). The current study shows the possibility of conformers with an IHB between the quinuclidine and quinoline moieties of these molecules. The study was performed at different levels of theory: Hartree Fock (HF) with the 6-31G(d,p) basis set, Density Functional Theory (DFT) with the B3LYP functional and the 6-31+G(d,p) basis set and Møller-Plesset Perturbation Theory (MP2) with the 6-31+G(d,p) basis set, to confirm the results. The results suggest that the stabilising effect of this IHB is weaker or comparable with respect to the stabilising effect of the preferred mutual orientation of the two moieties. Although the IHB-containing conformers may not be the lowest energy ones, their relative energy is sufficiently low for them to be included among the possible ones responsible for the compounds' antimalarial activity.
[Mh] Termos MeSH primário: Antimaláricos/química
Quinidina/química
Quinina/química
[Mh] Termos MeSH secundário: Estabilidade de Medicamentos
Ligações de Hidrogênio
Modelos Moleculares
Conformação Molecular
Teoria Quântica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antimalarials); A7V27PHC7A (Quinine); ITX08688JL (Quinidine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170605
[Lr] Data última revisão:
170605
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170209
[St] Status:MEDLINE



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