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1.
AAPS PharmSciTech ; 20(8): 310, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31520243

RESUMO

The production of 3D-printed dosage forms requires the preparation of high-quality filaments containing an active pharmaceutical ingredient (API). The objective of this research is to prepare filaments containing dronedarone hydrochloride, a drug used in the treatment of cardiac arrhythmias. Filaments and 3D-printed tablets were subjected to characterization methods in order to prove and ensure the stability of the API and preservation of the drug content. Blends containing different proportions of dronedarone hydrochloride (DNR), polyethylene glycol (PEG), and polyvinyl alcohol filament (PVA) were prepared in two forms: as a powder mixture and as a solid dispersion. Thermogravimetric analysis was conducted, and the thermal properties of the components and polymer blends were tested using differential scanning calorimetry. Hot melt extrusion at 170 °C was used to prepare the filaments, and the fused deposition modeling technique was employed to print tablets. Drug release profiles were obtained by in vitro tests. The results indicate that the mixture containing 10 wt.% of polyethylene glycol prepared as a solid dispersion exhibits the most straightforward structure and shows only the slightest deviation from the target filament diameter. The compact structure of the tablet obtained from the filament provides a uniform in vitro drug release over a 24-h period. It also shows the smallest aberration from the expected DNR content in the tablet. The paper demonstrates that a blend containing 10 wt.% of PEG, 10 wt.% of DNR, and 80 wt.% of PVA filament is the most appropriate formula for extrusion and tablet printing.


Assuntos
Antiarrítmicos/administração & dosagem , Arritmias Cardíacas/tratamento farmacológico , Dronedarona/administração & dosagem , Antiarrítmicos/química , Dronedarona/química , Composição de Medicamentos , Liberação Controlada de Fármacos , Polietilenoglicóis , Álcool de Polivinil , Impressão Tridimensional , Solubilidade , Comprimidos
2.
Curr Protein Pept Sci ; 20(10): 996-1003, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31389311

RESUMO

Abstract:Throughout the last decade, extensive efforts have been devoted to developing a percutaneous catheter ablation and implantable cardioverter-defibrillator technique for patients suffering from ventricular arrhythmia. Antiarrhythmic drug efficacy for preventing arrhythmias remains disappointing because of adverse cardiovascular effects. Allocryptopine is an isoquinoline alkaloid widely present in medicinal herbs. Studies have indicated that allocryptopine exhibits potential anti-arrhythmic actions in various animal models. The potential therapeutic benefit of allocryptopine in arrhythmia diseases is addressed in this study, focusing on multiple ion channel targets and reduced repolarization dispersion. The limitations of allocryptopine research are clear given a lack of parameters regarding toxicology and pharmacokinetics and clinical efficacy in patients with ventricular arrhythmias. Much remains to be revealed about the properties of allocryptopine.


Assuntos
Antiarrítmicos , Arritmias Cardíacas/tratamento farmacológico , Alcaloides de Berberina , Plantas Medicinais/química , Traqueófitas/química , Animais , Antiarrítmicos/química , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Alcaloides de Berberina/química , Alcaloides de Berberina/farmacologia , Alcaloides de Berberina/uso terapêutico , Humanos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico
3.
Pharm Nanotechnol ; 7(5): 375-388, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31376827

RESUMO

BACKGROUND: Dronedarone HCl (DRD), owing to its poor aqueous solubility and extensive presystemic metabolism shows low oral bioavailability of about 4% without food, which increases to approximately 15% when administered with a high fat meal. OBJECTIVE: Solid lipid nanoparticles (SLN) were designed with glyceryl monstearate (GMS) in order to improve oral bioavailability of DRD. METHODS: Hot homogenization followed by probe sonication was used to prepare SLN dispersions. Box-Behnken design was used to optimize manufacturing conditions. SLN were characterized for particle size, zeta potential, entrapment efficiency, physical state and in vitro drug release. Pharmacokinetics and intestinal uptake study of dronedarone HCl loaded solid lipid nanoparticles (DRD-SLN) in the presence and absence of endocytic uptake inhibitor, chlorpromazine (CPZ) was performed with conscious male Wistar rats. RESULTS: Optimized formulation of SLN showed particle size of 233 ± 42 nm and entrapment efficiency of 87.4 ± 1.29%. Results of pharmacokinetic studies revealed enhancement of bioavailability of DRD by 2.68 folds from SLN as compared to DRD suspension. Significantly reduced bioavailability of DRD-SLNs in the presence of chlorpromazine, demonstrated the role of endocytosis in uptake of SLN formulation. CONCLUSION: These results indicated that dronedarone HCl loaded SLN could potentially be exploited as a delivery system for improving oral bioavailability by minimizing first pass metabolism.


Assuntos
Antiarrítmicos/química , Dronedarona/química , Excipientes/química , Glicerídeos/química , Nanocápsulas/química , Animais , Antiarrítmicos/administração & dosagem , Antiarrítmicos/farmacocinética , Disponibilidade Biológica , Dronedarona/administração & dosagem , Dronedarona/farmacocinética , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Humanos , Masculino , Ratos Wistar , Solubilidade , Suspensões/química
4.
AAPS PharmSciTech ; 20(6): 226, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31214813

RESUMO

The objective of the present study was to develop a proliposomal formulation to increase the oral bioavailability of dronedarone hydrochloride (dronedarone HCl) by enhancing solubility, dissolution, and/or intestinal absorption. Proliposomes were prepared by using solvent evaporation method. In this process, different ratios of drug, phospholipids, such as soy phosphatidylcholine (SPC), Phospholipon 90H, hydrogenated egg phosphatidylcholine (HEPC), and dimyristoyl phosphatidylglycerol (DMPG), and cholesterol were used. Physical characterization and in vitro dissolution studies were evaluated for the prepared formulations. In vitro transport across the membrane was carried out using Caco-2 cells. Among all the formulations, the amount of drug released in dissolution was higher with DPF8 formulation (drug:DMPG Na:cholesterol:::1:2:0.2) compared to the pure drug. Also, Caco-2 cell permeability studies resulted in 2.6-fold increase in apparent permeability. Optimized formulation was evaluated in vivo in male Sprague-Dawley rats. After single oral administration of optimized formulation (DPF8), a relative bioavailability of 148.36% was achieved compared to the pure drug. Improved oral bioavailability of dronedarone could be provided by an optimized proliposomal formulation with enhanced solubility, permeability, and oral absorption.


Assuntos
Antiarrítmicos/química , Dronedarona/química , Lipossomos , Administração Oral , Animais , Antiarrítmicos/administração & dosagem , Antiarrítmicos/farmacocinética , Disponibilidade Biológica , Células CACO-2 , Colesterol , Dronedarona/administração & dosagem , Dronedarona/farmacocinética , Portadores de Fármacos , Composição de Medicamentos , Humanos , Masculino , Tamanho da Partícula , Permeabilidade , Fosfolipídeos , Ratos , Ratos Sprague-Dawley , Solubilidade
5.
Mater Sci Eng C Mater Biol Appl ; 100: 48-61, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30948084

RESUMO

Dronedarone is a new antiarrhythmic drug for the treatment of atrial fibrillation. This study investigated the complexation of dronedarone hydrochloride with ß­cyclodextrin (ß-CD) and 2­hydroxypropil­ß­CD (HP-ß-CD) using three different techniques. The complexes in the solid state were characterized by DSC, TGA, PXRD, FT-IR, SEM and 1H NMR, demonstrating the formation of the inclusion complexes and exhibiting different properties from the pure drug. Its aqueous solubility increased about 4.0-fold upon complexation with ß-CD and HP-ß-CD. The dissolution rate of the drug was notably improved in all tested physiological pH values from 1.2 to 6.8 in the presence of both cyclodextrins. Furthermore, an in vitro cytotoxic assay revealed that the inclusion complexes could reduce the cytotoxic effects of the drug on 3T3 cells. The overall results suggest that the inclusion complexes with ß-CD and HP-ß-CD may be potentially useful in the preparation of novel pharmaceutical formulations containing dronedarone hydrochloride.


Assuntos
Antiarrítmicos/química , Dronedarona/química , beta-Ciclodextrinas/química , 2-Hidroxipropil-beta-Ciclodextrina/química , Células 3T3 , Animais , Antiarrítmicos/síntese química , Antiarrítmicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Dronedarona/síntese química , Dronedarona/farmacologia , Composição de Medicamentos , Liofilização , Camundongos , Microscopia Eletrônica de Varredura , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Termogravimetria , Difração de Raios X
6.
Cell Physiol Biochem ; 52(5): 1223-1235, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31001961

RESUMO

BACKGROUND/AIMS: The two-pore-domain potassium channel TASK-1 regulates atrial action potential duration. Due to the atrium-specific expression of TASK-1 in the human heart and the functional upregulation of TASK-1 currents in atrial fibrillation (AF), TASK-1 represents a promising target for the treatment of AF. Therefore, detailed knowledge of the molecular determinants of TASK-1 inhibition may help to identify new drugs for the future therapy of AF. In the current study, the molecular determinants of TASK-1 inhibition by the potent and antiarrhythmic compound A293 (AVE1231) were studied in detail. METHODS: Alanine-scanning mutagenesis together with two-electrode voltage-clamp recordings were combined with in silico docking experiments. RESULTS: Here, we have identified Q126 located in the M2 segment together with L239 and N240 of the M4 segment as amino acids essential for the A293-mediated inhibition of TASK-1. These data indicate a binding site which is different to that of A1899 for which also residues of the pore signature sequence and the late M4 segments are essential. Using in silico docking experiments, we propose a binding site at the lower end of the cytosolic pore, located at the entry to lateral side fenestrations of TASK-1. Strikingly, TASK-1 inhibition by the low affinity antiarrhythmic TASK-1 blockers propafenone, amiodarone and carvedilol was also strongly diminished by mutations at this novel binding site. CONCLUSION: We have identified the A293 binding site in the central cavity of TASK-1 and propose that this site might represent a conserved site of action for many low affinity antiarrhythmic TASK-1 blockers.


Assuntos
Antiarrítmicos/química , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/química , Canais de Potássio de Domínios Poros em Tandem/antagonistas & inibidores , Canais de Potássio de Domínios Poros em Tandem/química , Substituição de Aminoácidos , Animais , Sítios de Ligação , Humanos , Mutagênese Sítio-Dirigida , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Canais de Potássio de Domínios Poros em Tandem/genética , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Xenopus laevis
7.
Bioorg Med Chem Lett ; 29(10): 1241-1245, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30879840

RESUMO

Atrial fibrillation (AF) is a major cause of stroke, heart failure, sudden death and cardiovascular morbidity. The Kv1.5 potassium channel conducts the IKur current and has been demonstrated to be predominantly expressed in atrial versus ventricular tissue. Blockade of Kv1.5 has been proven to be an effective approach to restoring and maintaining sinus rhythm in preclinical models of AF. In the clinical setting, however, the therapeutic value of this approach remains an open question. Herein, we present synthesis and optimization of a novel series of 1,2-bis(aryl)ethane-1,2-diamines with selectivity for Kv1.5 over other potassium ion channels. The effective refractory period in the right atrium (RAERP) in a rabbit PD model was investigated for a selection of potent and selective compounds with balanced DMPK properties. The most advanced compound (10) showed nanomolar potency in blocking Kv1.5 in human atrial myocytes and based on the PD data, the estimated dose to man is 700 mg/day. As previously reported, 10 efficiently converted AF to sinus rhythm in a dog disease model.


Assuntos
Antiarrítmicos/química , Fibrilação Atrial/tratamento farmacológico , Etilenodiaminas/química , Bloqueadores dos Canais de Potássio/química , Animais , Antiarrítmicos/farmacologia , Células CHO , Cricetulus , Modelos Animais de Doenças , Cães , Avaliação Pré-Clínica de Medicamentos , Etilenodiaminas/farmacologia , Átrios do Coração/efeitos dos fármacos , Humanos , Canal de Potássio Kv1.5/metabolismo , Estrutura Molecular , Miócitos Cardíacos/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Coelhos , Relação Estrutura-Atividade
8.
Proc Natl Acad Sci U S A ; 116(11): 4810-4815, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30792355

RESUMO

Ca2+ leak via ryanodine receptor type 2 (RyR2) can cause potentially fatal arrhythmias in a variety of heart diseases and has also been implicated in neurodegenerative and seizure disorders, making RyR2 an attractive therapeutic target for drug development. Here we synthesized and investigated the fungal natural product and known insect RyR antagonist (-)-verticilide and several congeners to determine their activity against mammalian RyR2. Although the cyclooligomeric depsipeptide natural product (-)-verticilide had no effect, its nonnatural enantiomer [ent-(+)-verticilide] significantly reduced RyR2-mediated spontaneous Ca2+ leak both in cardiomyocytes from wild-type mouse and from a gene-targeted mouse model of Ca2+ leak-induced arrhythmias (Casq2-/-). ent-(+)-verticilide selectively inhibited RyR2-mediated Ca2+ leak and exhibited higher potency and a distinct mechanism of action compared with the pan-RyR inhibitors dantrolene and tetracaine and the antiarrhythmic drug flecainide. ent-(+)-verticilide prevented arrhythmogenic membrane depolarizations in cardiomyocytes without significant effects on the cardiac action potential and attenuated ventricular arrhythmia in catecholamine-challenged Casq2-/- mice. These findings indicate that ent-(+)-verticilide is a potent and selective inhibitor of RyR2-mediated diastolic Ca2+ leak, making it a molecular tool to investigate the therapeutic potential of targeting RyR2 hyperactivity in heart and brain pathologies. The enantiomer-specific activity and straightforward chemical synthesis of (unnatural) ent-(+)-verticilide provides a compelling argument to prioritize ent-natural product synthesis. Despite their general absence in nature, the enantiomers of natural products may harbor unprecedented activity, thereby leading to new scaffolds for probe and therapeutic development.


Assuntos
Antiarrítmicos/química , Antiarrítmicos/farmacologia , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Cálcio/metabolismo , Depsipeptídeos/química , Depsipeptídeos/farmacologia , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Animais , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/fisiopatologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Depsipeptídeos/uso terapêutico , Dimerização , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Rianodina/metabolismo , Estereoisomerismo
9.
Proc Natl Acad Sci U S A ; 116(8): 2945-2954, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30728299

RESUMO

The human voltage-gated sodium channel, hNaV1.5, is responsible for the rapid upstroke of the cardiac action potential and is target for antiarrhythmic therapy. Despite the clinical relevance of hNaV1.5-targeting drugs, structure-based molecular mechanisms of promising or problematic drugs have not been investigated at atomic scale to inform drug design. Here, we used Rosetta structural modeling and docking as well as molecular dynamics simulations to study the interactions of antiarrhythmic and local anesthetic drugs with hNaV1.5. These calculations revealed several key drug binding sites formed within the pore lumen that can simultaneously accommodate up to two drug molecules. Molecular dynamics simulations identified a hydrophilic access pathway through the intracellular gate and a hydrophobic access pathway through a fenestration between DIII and DIV. Our results advance the understanding of molecular mechanisms of antiarrhythmic and local anesthetic drug interactions with hNaV1.5 and will be useful for rational design of novel therapeutics.


Assuntos
Antiarrítmicos/química , Simulação de Dinâmica Molecular , Canal de Sódio Disparado por Voltagem NAV1.5/química , Canais de Sódio/química , Sequência de Aminoácidos/genética , Antiarrítmicos/uso terapêutico , Sítios de Ligação , Interações Medicamentosas , Flecainida/química , Humanos , Lidocaína/química , Modelos Moleculares , Simulação de Acoplamento Molecular , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Ligação Proteica , Conformação Proteica/efeitos dos fármacos , Sódio/química , Canais de Sódio/genética
10.
J Am Soc Mass Spectrom ; 30(4): 639-646, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30617860

RESUMO

In drug discovery, it is important to identify phase I metabolic modifications as early as possible to screen for inactivation of drugs and/or activation of prodrugs. As the major class of reactions in phase I metabolism is oxidation reactions, oxidation of drugs with TiO2 photocatalysis can be used as a simple non-biological method to initially eliminate (pro)drug candidates with an undesired phase I oxidation metabolism. Analysis of reaction products is commonly achieved with mass spectrometry coupled to chromatography. However, sample throughput can be substantially increased by eliminating pretreatment steps and exploiting the potential of ambient ionization mass spectrometry (MS). Furthermore, online monitoring of reactions in a time-resolved way would identify sequential modification steps. Here, we introduce a novel (time-resolved) TiO2-photocatalysis laser ablation electrospray ionization (LAESI) MS method for the analysis of drug candidates. This method was proven to be compatible with both TiO2-coated glass slides as well as solutions containing suspended TiO2 nanoparticles, and the results were in excellent agreement with studies on biological oxidation of verapamil, buspirone, testosterone, andarine, and ostarine. Finally, a time-resolved LAESI MS setup was developed and initial results for verapamil showed excellent analytical stability for online photocatalyzed oxidation reactions within the set-up up to at least 1 h. Graphical Abstract.


Assuntos
Preparações Farmacêuticas/química , Espectrometria de Massas por Ionização por Electrospray/métodos , Titânio/química , Acetamidas/química , Aminofenóis/química , Antagonistas de Androgênios/química , Androgênios/química , Anilidas/química , Ansiolíticos/química , Antiarrítmicos/química , Buspirona/química , Catálise , Desenho de Equipamento , Humanos , Terapia a Laser/instrumentação , Terapia a Laser/métodos , Lasers , Luz , Oxirredução , Espectrometria de Massas por Ionização por Electrospray/instrumentação , Verapamil/química
11.
Xenobiotica ; 49(11): 1323-1331, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30596462

RESUMO

1. Propafenone, an antiarrhythmic drug, is a typical human cytochrome P450 (P450) 2D6 substrate used in preclinical studies. Here, propafenone oxidation by mammalian liver microsomes was investigated in vitro. 2. Liver microsomes from humans and marmosets preferentially mediated propafenone 5-hydroxylation, minipig, rat and mouse livers primarily mediated 4'-hydroxylation, but cynomolgus monkey and dog liver microsomes differently mediated N-despropylation. 3. Quinine, ketoconazole or anti-P450 2D antibodies suppressed propafenone 4'/5-hydroxylation in human and rat liver microsomes. Pretreatments with ß-naphthoflavone or dexamethasone increased N-despropylation in rat livers. 4. Recombinant rat P450 2D2 efficiently catalysed propafenone 4'-hydroxylation in a substrate inhibition manner, comparable to rat liver microsomes, while human P450 2D6 displayed propafenone 5-hydroxylation. Human and rat P450 1A, 2C and 3A enzymes mediated propafenone N-despropylation with high capacities. 5. Carbon-4' of propafenone docked favourably into the active site of P450 2D2 based on an in silico model; in contrast, carbon-5 of propafenone docked into human P450 2D6. 6. These results suggest that the major roles of individual P450 2D enzymes in regioselective hydroxylations of propafenone differ between human and rat livers, while the minor roles of P450 1A, 2C and 3A enzymes for propafenone N-despropylation are similar in livers of both species.


Assuntos
Hidrocarboneto de Aril Hidroxilases/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Microssomos Hepáticos/metabolismo , Propafenona/farmacocinética , Adulto , Idoso , Animais , Antiarrítmicos/química , Antiarrítmicos/metabolismo , Antiarrítmicos/farmacocinética , Hidrocarboneto de Aril Hidroxilases/química , Callithrix , Citocromo P-450 CYP2D6/química , Inibidores das Enzimas do Citocromo P-450/farmacologia , Cães , Feminino , Humanos , Hidroxilação , Macaca fascicularis , Masculino , Camundongos Endogâmicos , Microssomos Hepáticos/efeitos dos fármacos , Pessoa de Meia-Idade , Propafenona/química , Propafenona/metabolismo , Ratos Sprague-Dawley , Especificidade da Espécie , Suínos , Porco Miniatura
12.
Biomed Pharmacother ; 111: 427-435, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30594781

RESUMO

Decades of focus on selective ion channel blockade has been dismissed as an effective approach to antiarrhythmic drug development. In that context many older antiarrhythmic drugs lacking ion channel selectivity may serve as tools to explore mixed ion channel blockade producing antiarrhythmic activity. This study investigated the non-clinical electrophysiological and antiarrhythmic actions of bisaramil and penticainide using in vitro and in vivo methods. In isolated cardiac myocytes both drugs directly block sodium currents with IC50 values of 13µM (bisaramil) and 60µM (penticainide). Both drugs reduced heart rate but prolonged the P-R, QRS and Q-T intervals of the ECG (due to sodium and potassium channel blockade) in intact rats. They reduced cardiac conduction velocity in isolated rat hearts, increased the threshold currents for capture and fibrillation (indices of sodium channel blockade) and reduced the maximum following frequency as well as prolonged the effective refractory period (indices of potassium channel blockade) of electrically stimulated rat hearts. Both drugs reduced ventricular arrhythmias and eliminated mortality due to VF in ischemic rat hearts. The index of cardiac electrophysiological balance (iCEB) did not change significantly over the dose range evaluated; however, different drug effects resulted when changes in BP and HR were considered. While bisaramil is a more potent sodium channel blocker compared to penticainide, both produce a spectrum of activity against ventricular arrhythmias due to mixed cardiac ion channel blockade. Antiarrhythmic drugs exhibiting mixed ion channel blockade may serve as tools for development of safer mixed ion channel blocking antiarrhythmic drugs.


Assuntos
Antiarrítmicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Clorobenzenos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Propilaminas/farmacologia , Piridinas/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , Animais , Antiarrítmicos/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Células Cultivadas , Clorobenzenos/química , Relação Dose-Resposta a Droga , Frequência Cardíaca/fisiologia , Masculino , Técnicas de Cultura de Órgãos , Bloqueadores dos Canais de Potássio/química , Canais de Potássio/fisiologia , Propilaminas/química , Piridinas/química , Ratos , Ratos Sprague-Dawley , Bloqueadores dos Canais de Sódio/química , Canais de Sódio/fisiologia
13.
Xenobiotica ; 49(6): 734-739, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29962267

RESUMO

The aim of this study was to investigate the pharmacokinetic properties of dronedarone by using noncompartmental analysis and modeling approaches after intravenous and oral administration of dronedarone to rats. Twenty-eight male Sprague-Dawley rats were randomly divided into four groups, and dronedarone was administered intravenously (1 mg/kg) and orally (5, 10 and 40 mg/kg) based on a parallel design. Blood samples were collected before and 0.083 (intravenous administration only), 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12 and 24 h after drug administration. The plasma concentration of dronedarone was determined by using LC-MS/MS. The oral bioavailability of dronedarone was evaluated as approximately 16% in rats, similar to that in humans. The assessment of dose proportionality by using the power model showed that AUCinf increased in a dose-proportional manner, whereas AUC24h and Cmax exhibited a lack of dose proportionality over the dose range between 5 and 40 mg/kg. The two-compartment model, with first-order absorption and elimination rate constants, was sufficient to explain the pharmacokinetics of dronedarone with biexponential decay. These findings will help to understand the pharmacology of dronedarone to develop the new formulation and therapeutics optimization linked to pharmacokinetic/pharmacodynamic study.


Assuntos
Antiarrítmicos/farmacocinética , Dronedarona/farmacocinética , Administração Intravenosa , Administração Oral , Animais , Antiarrítmicos/administração & dosagem , Antiarrítmicos/química , Disponibilidade Biológica , Cromatografia Líquida , Dronedarona/administração & dosagem , Dronedarona/química , Masculino , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem
14.
Eur J Pharmacol ; 844: 241-252, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30571955

RESUMO

A series of amino-2-cyclohexyl ester derivatives were studied for their ion channel blocking and antiarrhythmic actions in the rat and a structure-activity analysis was conducted. The compounds are similar in chemical structure except for ionizable amine groups (pK values 6.1-8.9) and the positional arrangements of aromatic naphthyl moieties. Ventricular arrhythmias were produced in rats by coronary-artery occlusion or electrical stimulation. The electrophysiological effects of these compounds on rat heart sodium channels (Nav1.5) expressed in Xenopus laevis oocytes and transient outward potassium currents (Kv4.3) from isolated rat ventricular myocytes were examined. The compounds reduced the incidence of ischemia-related arrhythmias and increased current threshold for induction of ventricular fibrillo-flutter (VFt) dose-dependently. As pK increased compounds showed a diminished effectiveness against ischemia-induced arrhythmias, and were less selective for ischemia- versus electrically-induced arrhythmias. Where tested, compounds produced a concentration-dependent tonic block of Nav1.5 channels. An increased potency for inhibition of Nav1.5 occurred when the external pH (pHo) was reduced to 6.5. Some compounds inhibited Kv4.3 in a pH-independent manner. Overall, the differences in antiarrhythmic and ion channel blocking properties in this series of compounds can be explained by differences in chemical structure. Antiarrhythmic activity for the amino-2-cyclohexyl ester derivatives is likely a function of mixed ion channel blockade in ischemic myocardium. These studies show that drug inhibition of Nav1.5 occurred at lower concentrations than Kv4.3 and was more sensitive to changes in the ionizable amine groups rather than on positional arrangements of the naphthyl constituents. These results offer insight into antiarrhythmic mechanisms of drug-ion channel interactions.


Assuntos
Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/tratamento farmacológico , Bloqueadores dos Canais de Potássio/uso terapêutico , Bloqueadores dos Canais de Sódio/uso terapêutico , Animais , Antiarrítmicos/química , Antiarrítmicos/farmacologia , Ésteres/química , Ésteres/farmacologia , Ésteres/uso terapêutico , Coração/efeitos dos fármacos , Coração/fisiologia , Masculino , Isquemia Miocárdica/complicações , Oócitos/fisiologia , Bloqueadores dos Canais de Potássio/química , Bloqueadores dos Canais de Potássio/farmacologia , Ratos Sprague-Dawley , Bloqueadores dos Canais de Sódio/química , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/fisiologia , Relação Estrutura-Atividade , Xenopus laevis
15.
Eur J Med Chem ; 157: 1153-1163, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30189397

RESUMO

Arrhythmia means the heart is beating too fast, too slow, or with an irregular pattern. Due to the side effects and low bioavailability of many antiarrhythmic drugs, nano-encapsulation has been widely used for their targeted delivery. Lipid nanocapsules, nano liposomes, nano niosomes, solid lipid nanoparticles and polymeric nanoparticles are common nano-carriers used for this purpose. The aim of this article is to summarize some of nano systems used for the specific delivery of antiarrhythmic agents to target tissues. At first, nanotechnology and its applications in drug delivery are described in brief. Then, some information on arrhythmias and antiarrhythmic drugs are provided. Finally, the nano drug delivery systems are explained and examples of their applications in encapsulation of antiarrhythmic drugs are presented.


Assuntos
Antiarrítmicos/administração & dosagem , Arritmias Cardíacas/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Nanomedicina/métodos , Animais , Antiarrítmicos/química , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
16.
Circ Arrhythm Electrophysiol ; 11(5): e006408, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29748197

RESUMO

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia. Although treatment options for AF exist, many patients cannot be maintained in normal sinus rhythm. Amiodarone is an effective medication for AF but has limited clinical utility because of off-target tissue toxicity. METHODS: Here, we use a pig model of AF to test the efficacy of an amiodarone-containing polyethylene glycol-based hydrogel. The gel is placed directly on the atrial epicardium through the pericardial space in a minimally invasive procedure using a specially designed catheter. RESULTS: Implantation of amiodarone-containing gel significantly reduced the duration of sustained AF at 21 and 28 days; inducibility of AF was reduced 14 and 21 days post-delivery. Off-target organ drug levels in the liver, lungs, thyroid, and fat were significantly reduced in animals treated with epicardial amiodarone gel compared with systemic controls in small-animal distribution studies. CONCLUSIONS: The pericardium is an underutilized therapeutic site and may be a new treatment strategy for AF and other cardiovascular diseases.


Assuntos
Amiodarona/administração & dosagem , Antiarrítmicos/administração & dosagem , Fibrilação Atrial/prevenção & controle , Portadores de Fármacos , Frequência Cardíaca/efeitos dos fármacos , Pericárdio/efeitos dos fármacos , Polietilenoglicóis/química , Amiodarona/química , Amiodarona/toxicidade , Animais , Antiarrítmicos/química , Antiarrítmicos/toxicidade , Fibrilação Atrial/fisiopatologia , Modelos Animais de Doenças , Composição de Medicamentos , Implantes de Medicamento , Liberação Controlada de Fármacos , Hidrogéis , Masculino , Pericárdio/fisiopatologia , Ratos Sprague-Dawley , Sus scrofa , Fatores de Tempo
17.
Biochemistry ; 57(18): 2704-2710, 2018 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-29652491

RESUMO

Molecular dynamics simulations are employed to determine the inhibitory mechanisms of three drugs, 5-(4-phenoxybutoxy)psoralen (PAP-1), vernakalant, and flecainide, on the voltage-gated K+ channel Kv1.5, a target for the treatment of cardiac arrhythmia. At neutral pH, PAP-1 is neutral, whereas the other two molecules carry one positive charge. We show that PAP-1 forms stable dimers in water, primarily through hydrophobic interactions between aromatic rings. All three molecules bind to the cavity between the Ile508 and Val512 residues from the four subunits of the channel. Once bound, the drug molecules are flexible, with the average root-mean-square fluctuation being between 2 and 3 Å, which is larger than the radius of gyration of a bulky amino acid. The presence of a monomeric PAP-1 causes the permeating K+ ion to dehydrate, thereby creating a significant energy barrier. In contrast, vernakalant blocks the ion permeation primarily via an electrostatic mechanism and, therefore, must be in the protonated and charged form to be effective.


Assuntos
Antiarrítmicos/química , Arritmias Cardíacas/tratamento farmacológico , Canal de Potássio Kv1.5/química , Sequência de Aminoácidos/genética , Anisóis/química , Anisóis/farmacologia , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/genética , Sítios de Ligação , Cristalografia por Raios X , Ficusina/química , Ficusina/uso terapêutico , Flecainida/química , Flecainida/uso terapêutico , Humanos , Canal de Potássio Kv1.5/antagonistas & inibidores , Canal de Potássio Kv1.5/genética , Simulação de Dinâmica Molecular , Conformação Proteica/efeitos dos fármacos , Pirrolidinas/química , Pirrolidinas/farmacologia , Homologia de Sequência de Aminoácidos
20.
Mol Inform ; 37(6-7): e1700142, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29465167

RESUMO

The binding modes of many hERG ion channel blockers are well understood, but a notable exception is clofilium, a potent antiarrhythmic agent whose action relies on blocking the current mediated by hERG. From the previously hypothesized binding modes of clofilium to hERG, only two can explain most of the experimental results. In this study, computer simulations are performed in order to analyze the hypothesized binding modes and to identify the consensus one. This is accomplished by employing molecular dynamics (MD) simulations and interaction energy calculations. The results show an unexpected binding mode, in which the quaternary nitrogen is placed in the upper part of the inner cavity, interacting strongly with Ser624, while the chlorophenyl group is located in the lower part, in better agreement with previous experimental results. This novel binding position also explains the higher affinity of clofilium for the related hEag1 channel and was correlated with the possibility that potent hERG blockers interact in specific ways with the residues near the intracellular activation gate, offering a new explanation that could help predict the potency of other hERG-blocking compounds.


Assuntos
Antiarrítmicos/farmacologia , Canal de Potássio ERG1/química , Simulação de Acoplamento Molecular , Bloqueadores dos Canais de Potássio/farmacologia , Compostos de Amônio Quaternário/farmacologia , Antiarrítmicos/química , Sítios de Ligação , Canal de Potássio ERG1/antagonistas & inibidores , Canal de Potássio ERG1/metabolismo , Bloqueadores dos Canais de Potássio/química , Ligação Proteica , Compostos de Amônio Quaternário/química
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