RESUMO
Pathological cardiac remodeling is associated with cardiovascular disease and can lead to heart failure. Nuclear factor-kappa B (NF-κB) is upregulated in the hypertrophic heart. Moreover, the expression of the G-protein-coupled receptor kinase 2 (GRK2) is increased and linked to the progression of heart failure. The inhibitory effects of paroxetine on GRK2 have been established. However, its protective effect on IκBα/NFκB signaling has not been elucidated. This study investigated the cardioprotective effect of paroxetine in an animal model of cardiac hypertrophy (CH), focusing on its effect on GRK2-mediated NF-κB-regulated expression of prohypertrophic and profibrotic genes. Wistar albino rats were administered normal saline, paroxetine, or fluoxetine, followed by isoproterenol to induce CH. The cardioprotective effects of the treatments were determined by assessing cardiac injury, inflammatory biomarker levels, histopathological changes, and hypertrophic and fibrotic genes in cardiomyocytes. Paroxetine pre-treatment significantly decreased the HW/BW ratio (p < 0.001), and the expression of prohypertrophic and profibrotic genes Troponin-I (p < 0.001), BNP (p < 0.01), ANP (p < 0.001), hydroxyproline (p < 0.05), TGF-ß1 (p < 0.05), and αSMA (p < 0.01) as well as inflammatory markers. It also markedly decreased pIκBα, NFκB(p105) subunit expression (p < 0.05) and phosphorylation. The findings suggest that paroxetine prevents pathological cardiac remodeling by inhibiting the GRK2-mediated IκBα/NF-κB signaling pathway.
Assuntos
Insuficiência Cardíaca , NF-kappa B , Ratos , Animais , NF-kappa B/metabolismo , Paroxetina/farmacologia , Paroxetina/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , Isoproterenol/toxicidade , Quinase 2 de Receptor Acoplado a Proteína G/metabolismo , Remodelação Ventricular , Miócitos Cardíacos/metabolismo , Cardiomegalia/induzido quimicamente , Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismo , Insuficiência Cardíaca/metabolismo , Ratos Wistar , Expressão GênicaRESUMO
Venlafaxine, a serotonin-norepinephrine reuptake inhibitor (SNRI), is indicated for the treatment of major depressive disorder, social anxiety disorder, generalized anxiety disorder, and panic disorder. Venlafaxine is metabolized to the active metabolite desvenlafaxine mainly by CYP2D6. Genetic polymorphism of CYP2D6 and coadministration with other medications can significantly affect the pharmacokinetics and/or pharmacodynamics of venlafaxine and its active metabolite. This study aimed to establish the PBPK models of venlafaxine and its active metabolite related to CYP2D6 genetic polymorphism and to predict drug-drug interactions (DDIs) with clarithromycin and paroxetine in different CYP2D6 genotypes. Clinical pharmacogenomic data for venlafaxine and desvenlafaxine were collected to build the PBPK model. Physicochemical and absorption, distribution, metabolism, and excretion (ADME) characteristics of respective compounds were obtained from previously reported data, predicted by the PK-Sim® software, or optimized to capture the plasma concentration-time profiles. Model evaluation was performed by comparing the predicted pharmacokinetic parameters and plasma concentration-time profiles to the observed data. Predicted plasma concentration-time profiles of venlafaxine and its active metabolite were visually similar to the observed profiles and all predicted AUC and Cmax values for respective compounds were included in the twofold error range of observed values in non-genotyped populations and different CYP2D6 genotypes. When clarithromycin or clarithromycin plus paroxetine was concomitantly administered, predicted plasma concentration-time profiles of venlafaxine properly captured the observed profiles in two different CYP2D6 genotypes and all predicted DDI ratios for AUC and Cmax were included within the acceptance range. Consequently, the present model successfully captured the pharmacokinetic alterations of venlafaxine and its active metabolite according to CYP2D6 genetic polymorphism as well as the DDIs between venlafaxine and two CYP inhibitors. The present model can be used to predict the pharmacokinetics of venlafaxine and its active metabolite considering different races, ages, coadministered drugs, and CYP2D6 activity of individuals and it can contribute to individualized pharmacotherapy of venlafaxine.
Assuntos
Claritromicina , Citocromo P-450 CYP2D6 , Interações Medicamentosas , Genótipo , Modelos Biológicos , Paroxetina , Cloridrato de Venlafaxina , Cloridrato de Venlafaxina/farmacocinética , Cloridrato de Venlafaxina/administração & dosagem , Claritromicina/farmacocinética , Claritromicina/metabolismo , Humanos , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Paroxetina/farmacocinética , Paroxetina/metabolismo , Adulto , Masculino , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacocinética , Inibidores da Recaptação de Serotonina e Norepinefrina/administração & dosagem , Inibidores da Recaptação de Serotonina e Norepinefrina/metabolismo , Feminino , Polimorfismo Genético/genética , Adulto JovemRESUMO
El status cataplecticus es una situación excepcional, consistente en ataques continuados de cataplejía. Presentamos un caso clínico de una mujer de 42 años diagnosticada de síndrome de narcolepsia con cataplejía, bien controlada con modafinil y paroxetina, que presentó status cataplecticus tras la auto-retirada brusca de la medicación antidepresiva (AU)
Status cataplecticus is an exceptional situation, described as continuous cataplexy attacks. We report a 42-year-old woman with narcolepsy-cataplexy syndrome, well controled with modafinil and paroxetine, who developed status cataplecticus after abrupt self-withdrawal of the antidepressant medication (AU)