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1.
Int J Nanomedicine ; 16: 4713-4737, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34267519

RESUMO

Background: Amiodarone (AMD) is a widely used anti-arrhythmic drug, but its administration could be associated with varying degrees of pulmonary toxicity. In attempting to circumvent this issue, AMD-loaded polymeric nanoparticles (AMD-loaded NPs) had been designed. Materials and Methods: AMD was loaded in NPs by the nanoprecipitation method using two stabilizers: bovine serum albumin and Kolliphor® P 188. The physicochemical properties of the AMD-loaded NPs were determined. Among the prepared NPs, two ones were selected for further investigation of spectral and thermal analysis as well as morphological properties. Additionally, in vitro release patterns were studied and kinetically analyzed at different pH values. In vitro cytotoxicity of an optimized formula (NP4) was quantified using A549 and Hep-2 cell lines. In vivo assessment of the pulmonary toxicity on Sprague Dawley rats via histopathological and immunohistochemical evaluations was applied. Results: The developed NPs achieved a size not more than 190 nm with an encapsulation efficiency of more than 88%. Satisfactory values of loading capacity and yield were also attained. The spectral and thermal analysis demonstrated homogeneous entrapment of AMD inside the polymeric matrix of NPs. Morphology revealed uniform, core-shell structured, and sphere-shaped particles with a smooth surface. Furthermore, the AMD-loaded NPs exhibited a pH-dependent and diffusion-controlled release over a significant period without an initial burst effect. NP4 demonstrated a superior cytoprotective efficiency by diminishing cell death and significantly increasing the IC50 by more than threefold above the pure AMD. Also, NP4 ameliorated AMD-induced pulmonary damage in rats. Significant downregulation of inflammatory mediators and free radicle production were noticed in the NP4-treated rats. Conclusion: The AMD-loaded NPs could ameliorate the pulmonary injury induced by the pure drug moieties. Cytoprotective, anti-fibrotic, anti-inflammatory, and antioxidant properties were presented by the optimized NPs (NP4). Future studies may be built on these findings for diminishing AMD-induced off-target toxicities.


Assuntos
Amiodarona/química , Amiodarona/toxicidade , Portadores de Fármacos/química , Pulmão/efeitos dos fármacos , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Células A549 , Animais , Morte Celular/efeitos dos fármacos , Difusão , Células Hep G2 , Humanos , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley
2.
Mol Cell Biochem ; 476(9): 3433-3448, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33973131

RESUMO

Amiodarone (AMD) is a widely used antiarrhythmic drug prescribed to treat cardiac tachyarrhythmias; however, AMD has been reported to provoke pulmonary fibrosis (PF) and hepatotoxicity. This study aimed to investigate the influence of alpha lipoic acid (ALA) on AMD-induced PF and hepatotoxicity in male Wistar rats. AMD administration resulted in elevated lung contents of hydroxyproline (Hyp), malondialdehyde (MDA), and increased serum levels of transforming growth factor beta-1 (TGF-ß1), interferon-γ (IFN-γ), alanine amino transaminase (ALT), aspartate amino transaminase (AST), total cholesterol (TC), and glucose. On the other side, lung content of glutathione reduced (GSH) and serum levels of total anti-oxidant capacity (TAC) were significantly decreased. Histopathologically, AMD caused PF, produced a mild hepatic injury, and increased expression of alpha smooth muscle actin (α-SMA). Treatment with ALA produced a significant reversal of the oxidative stress, fibrosis, and inflammation parameters with reductions in α-SMA expressions, leading to amelioration of histopathological lesions. ALA might provide supportive therapy in AMD-receiving cardiovascular patients.


Assuntos
Amiodarona/toxicidade , Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Substâncias Protetoras/farmacologia , Fibrose Pulmonar/prevenção & controle , Ácido Tióctico/farmacologia , Alanina Transaminase/metabolismo , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citocinas/metabolismo , Glutationa/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Ratos , Ratos Wistar , Vasodilatadores/toxicidade
3.
J Toxicol Sci ; 46(3): 131-142, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33642519

RESUMO

Pluripotent stem cells (PSCs) possess unique characteristics that distinguish them from other cell types. Human embryonic stem (ES) cells are recently gaining attention as a powerful tool for human toxicity assessment without the use of experimental animals, and an embryonic stem cell test (EST) was introduced for this purpose. However, human PSCs have not been thoroughly investigated in terms of drug resistance or compared with other cell types or cell states, such as naïve state, to date. Aiming to close this gap in research knowledge, we assessed and compared several human PSC lines for their resistance to drug exposure. Firstly, we report that RIKEN-2A human induced pluripotent stem (iPS) cells possessed approximately the same sensitivity to selected drugs as KhES-3 human ES cells. Secondly, both ES and iPS cells were several times less resistant to drug exposure than other non-pluripotent cell types. Finally, we showed that iPS cells subjected to naïve-state induction procedures exhibited a sharp increase in drug sensitivity. Upon passage of these naïve-like cells in non-naïve PSC culture medium, their sensitivity to drug exposure decreased. We thus revealed differences in sensitivity to drug exposure among different types or states of PSCs and, importantly, indicated that naïve-state induction could increase this sensitivity.


Assuntos
Diferenciação Celular , Resistência a Medicamentos , Células-Tronco Embrionárias/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Amiodarona/toxicidade , Animais , Aspirina/toxicidade , Atorvastatina/toxicidade , Linhagem Celular , Clotrimazol/toxicidade , Resistência a Múltiplos Medicamentos , Células-Tronco Embrionárias/fisiologia , Humanos , Células-Tronco Pluripotentes Induzidas/fisiologia
4.
Arch Toxicol ; 95(4): 1433-1442, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33606068

RESUMO

Amiodarone is an antiarrhythmic agent inducing adverse effects on the nervous system, among others. We applied physiologically based pharmacokinetic (PBPK) modeling combined with benchmark dose modeling to predict, based on published in vitro data, the in vivo dose of amiodarone which may lead to adverse neurological effects in patients. We performed in vitro-in vivo extrapolation (IVIVE) from concentrations measured in the cell lysate of a rat brain 3D cell model using a validated human PBPK model. Among the observed in vitro effects, inhibition of choline acetyl transferase (ChAT) was selected as a marker for neurotoxicity. By reverse dosimetry, we transformed the in vitro concentration-effect relationship into in vivo effective human doses, using the calculated in vitro area under the curve (AUC) of amiodarone as the pharmacokinetic metric. The upper benchmark dose (BMDU) was calculated and compared with clinical doses eliciting neurological adverse effects in patients. The AUCs in the in vitro brain cell culture after 14-day repeated dosing of nominal concentration equal to 1.25 and 2.5 µM amiodarone were 1.00 and 1.99 µg*h/mL, respectively. The BMDU was 385.4 mg for intravenous converted to 593 mg for oral application using the bioavailability factor of 0.65 as reported in the literature. The predicted dose compares well with neurotoxic doses in patients supporting the hypothesis that impaired ChAT activity may be related to the molecular/cellular mechanisms of amiodarone neurotoxicity. Our study shows that predicting effects from in vitro data together with IVIVE can be used at the initial stage for the evaluation of potential adverse drug reactions and safety assessment in humans.


Assuntos
Amiodarona/toxicidade , Antiarrítmicos/toxicidade , Modelos Biológicos , Síndromes Neurotóxicas/etiologia , Amiodarona/administração & dosagem , Amiodarona/farmacocinética , Animais , Antiarrítmicos/administração & dosagem , Antiarrítmicos/farmacocinética , Área Sob a Curva , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Humanos , Técnicas In Vitro , Síndromes Neurotóxicas/fisiopatologia , Ratos , Distribuição Tecidual , Testes de Toxicidade
5.
Am J Respir Cell Mol Biol ; 64(4): 504-514, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33493427

RESUMO

Alveolar epithelial type II (AT2) cells secrete pulmonary surfactant via lamellar bodies (LBs). Abnormalities in LBs are associated with pulmonary disorders, including fibrosis. However, high-content screening (HCS) for LB abnormalities is limited by the lack of understanding of AT2 cell functions. In the present study, we have developed LB cells harboring LB-like organelles that secrete surfactant proteins. These cells were more similar to AT2 cells than to parental A549 cells. LB cells recapitulated amiodarone (AMD)-induced LB enlargement, similar to AT2 cells of patients exposed to AMD. To reverse AMD-induced LB abnormalities, we performed HCS of approved drugs and identified 2-hydroxypropyl-ß-cyclodextrin (HPßCD), a cyclic oligosaccharide, as a potential therapeutic agent. A transcriptome analysis revealed that HPßCD modulates lipid homeostasis. In addition, HPßCD inhibited AMD-induced LB abnormalities in human induced pluripotent stem cell-derived AT2 cells. Our results demonstrate that LB cells are useful for HCS and suggest that HPßCD is a candidate therapeutic agent for AMD-induced interstitial pneumonia.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/farmacologia , Células Epiteliais Alveolares/efeitos dos fármacos , Amiodarona/toxicidade , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Células A549 , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Ensaios de Triagem em Larga Escala , Homeostase , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Precursores de Proteínas/metabolismo , Proteína C Associada a Surfactante Pulmonar/metabolismo , Proteína D Associada a Surfactante Pulmonar/metabolismo , Proteínas Associadas a Surfactantes Pulmonares/metabolismo
6.
Ultrastruct Pathol ; 45(1): 49-58, 2021 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-33423596

RESUMO

Amiodarone (AMD) is one of the highly effective antiarrhythmic agents used for treating refractory arrhythmias. It is well known to have long-term administration side effects such as nephrotoxicity. The possible ameliorative effects of antioxidant grape seed extract; on the extent of tissue damage in AMD-induced nephrotoxicity has not been investigated before. Twenty-four albino rats were used in this study and divided into four groups (n = 6). The 1st group served as an untreated control group, under the same laboratory conditions, the 2nd group received (100 mg/kg/day) of grape seed extract (GSE), the 3rd group, AMD-treated group, received AMD (40 mg/kg/day) and the 4th group received both AMD and GSE in the same doses as the previous groups. AMD-treated group showed abnormal glomerular capillaries with wrinkling basement membranes damaged mesangial cells and distorted proximal tubules with plenty of lysosomes. Ultrastructural alterations were also observed in this group. This was also associated with a significant increase in biomarkers of kidney injury (creatinine), oxidative stress ((Decreased SOD and increased MDA) and biomarkers of inflammation IL-6) in comparison to the control group. Supplementation of GSE to AMD group for eight weeks counteracted these effects. It caused an improvement in histological and t ultrastructure changes of the renal tissues associated with decreased creatinine and biomarkers of oxidative stress and inflammation in comparison to AMD-treated group. We conclude that GSE protects against AMD-induced kidney injuries in rats, which is associated with the inhibition of biomarkers of inflammation and oxidative stress.


Assuntos
Amiodarona , Extrato de Sementes de Uva , Amiodarona/efeitos adversos , Amiodarona/toxicidade , Animais , Antioxidantes , Biomarcadores , Extrato de Sementes de Uva/farmacologia , Inflamação , Estresse Oxidativo , Ratos
7.
Aquat Toxicol ; 228: 105623, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32956954

RESUMO

Trace concentrations of a number of pharmaceutically active compounds have been detected in the aquatic environment in many countries, where they are thought to have the potential to exert adverse effects on non-target organisms. Amiodarone (AMD) is one such high-risk compound commonly used in general hospitals. AMD is known to alter normal thyroid hormone (TH) function, although little information is available regarding the specific mechanism by which this disruption occurs. Anuran tadpole metamorphosis is a TH-controlled developmental process and has proven to be useful as a screening tool for environmental pollutants suspected of disrupting TH functions. In the present study, our objective was to clarify the effects of AMD on Xenopus metamorphosis as well as to assess the bioconcentration of this pharmaceutical in the liver. We found that AMD suppressed spontaneous metamorphosis, including tail regression and hindlimb elongation in pro-metamorphic stage tadpoles, which is controlled by endogenous circulating TH, indicating that AMD is a TH antagonist. In transgenic X. laevis tadpoles carrying plasmid DNA containing TH-responsive element (TRE) and a 5'-upstream promoter region of the TH receptor (TR) ßA1 gene linked to a green fluorescent protein (EGFP) gene, triiodothyronine (T3) exposure induced a strong EGFP expression in the hind limbs, whereas the addition of AMD to T3 suppressed EGFP expression, suggesting that this drug interferes with the binding of T3 to TR, leading to the inhibition of TR-mediated gene expression. We also found AMD to be highly bioconcentrated in the liver of pro-metamorphic X. tropicalis tadpoles, and we monitored hepatic accumulation of this drug using mass spectrometry imaging (MSI). Our findings suggest that AMD imposes potential risk to aquatic wildlife by disrupting TH homeostasis, with further possibility of accumulating in organisms higher up in the food chain.


Assuntos
Amiodarona/toxicidade , Bioacumulação , Disruptores Endócrinos/toxicidade , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Larva/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Amiodarona/metabolismo , Animais , Disruptores Endócrinos/metabolismo , Membro Posterior/efeitos dos fármacos , Larva/genética , Larva/metabolismo , Receptores dos Hormônios Tireóideos/genética , Receptores dos Hormônios Tireóideos/metabolismo , Tri-Iodotironina/genética , Tri-Iodotironina/metabolismo , Poluentes Químicos da Água/metabolismo , Xenopus laevis
9.
Niger J Physiol Sci ; 34(1): 63-68, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31449273

RESUMO

Amiodarone, a drug that treats arrhythmias induces pulmonary toxicity through interplay between oxidative stress and inflammation. Quercetin, a flavonoid widely occurring in natural products possesses antioxidant and anti-inflammatory properties. The aim of the present study was to evaluate the effects of quercetin on pulmonary responses in rats after amiodarone intra-tracheal instillation. Eighteen female Wistar rats (150-250 g) were randomly assigned into three groups of six animals each namely; control, amiodarone (AMI) and amiodarone + Quercetin (AMI + Quercetin) groups. AMI group received 2 intra-tracheal instillations of amiodarone (6.25mg/kg in 0.3ml of water) on days 0 and 2 and 0.4ml of 2% DMSO (Dimethyl sulfoxide) orally from day 0 for 3 weeks. AMI + Quercetin group was administered 2 intratracheal instillations of amiodarone on days 0 and 2 and 20mg/kg body weight of quercetin in 2% DMSO from day 0 for 3 weeks. Thereafter, the animals were sacrificed and bronchoalveolar lavage fluid (BALF) was collected to determine total cell polymorphonuclear (PMN) cell and macrophage counts. Inflammation of the lung tissues was also assessed. Macrophage count of AMI + Quercetin group was significantly lowered (p<0.01) compared to AMI group. Inflammation rate of the AMI + Quercetin group was significantly reduced compared to AMI group (p<0.01). Quercetin treatment markedly suppressed amiodarone induced toxicity in the pulmonary tissues.


Assuntos
Amiodarona/administração & dosagem , Amiodarona/toxicidade , Antioxidantes/administração & dosagem , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Quercetina/administração & dosagem , Animais , Antiarrítmicos/administração & dosagem , Antiarrítmicos/toxicidade , Líquido da Lavagem Broncoalveolar , Feminino , Injeções Espinhais , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Fibrose Pulmonar/fisiopatologia , Ratos , Ratos Wistar
10.
Arch Toxicol ; 93(3): 615-621, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30604139

RESUMO

In vitro studies are increasingly proposed to replace in vivo toxicity testing of substances. We set out to apply physiologically based pharmacokinetic (PBPK) modeling to predict the in vivo dose of amiodarone that leads to the same concentration-time profile in the supernatant and the cell lysate of cultured primary human hepatic cells (PHH). A PBPK human model was constructed based on the structure and tissue distribution of amiodarone in a rat model and using physiological human parameters. The predicted concentration-time profile in plasma was in agreement with human experimental data with the unbound fraction of amiodarone in plasma crucially affecting the goodness-of-fit. Using the validated kinetic model, we subsequently described the in vitro concentration-time data of amiodarone in PHH culture. However, this could be only appropriately modeled under conditions of zero protein binding and the very low clearance of the in vitro system in PHH culture. However, these represent unphysiological conditions and, thus, the main difference between the in vivo and the in vitro systems. Our results reveal that, for meaningful quantitative extrapolation from in vitro to in vivo conditions in PBPK studies, it is essential to avoid non-intended differences between these conditions. Specifically, clearance and protein binding, as demonstrated in our analysis of amiodarone modeling, are important parameters to consider.


Assuntos
Amiodarona/toxicidade , Testes de Toxicidade/métodos , Vasodilatadores/toxicidade , Animais , Simulação por Computador , Hepatócitos , Humanos , Técnicas In Vitro , Cinética , Fígado , Modelos Biológicos , Ligação Proteica , Ratos , Distribuição Tecidual
11.
Toxicol Pathol ; 47(1): 26-34, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30373479

RESUMO

Cationic amphiphilic drugs (CADs) can induce phospholipidosis (PLD) in organs/tissues. Several ophthalmic pharmaceuticals containing CADs are marketed and used in children. To investigate the effect of PLD on the developing cornea, chloroquine and amiodarone, which are representative CADs, were applied topically to the eyes of juvenile rabbits, and the effects in juvenile rabbits were compared with those in young adult rabbits. Diffuse corneal cloudiness was observed in chloroquine- and amiodarone-treated eyes. Histopathologically, vacuolation was observed in the corneal epithelium and keratocytes. On ultrastructural examination, these vacuoles contained multilamellar inclusion bodies, which are a characteristic of PLD. The size of the vacuoles in the corneal epithelium was reduced in juveniles compared with young adults. Cytoplasmic lamellar bodies and exocytosis in the corneal endothelium were observed in young adult rabbits but not in juvenile rabbits. This study revealed that topical application of chloroquine or amiodarone induces corneal PLD in juvenile and young adult rabbits. Corneal endothelial changes occurred only in young adult rabbits, but ophthalmological changes were similar between juveniles and young adults. The results of the study suggest that the effects of corneal PLD were similar among age groups based on risk assessment.


Assuntos
Envelhecimento/metabolismo , Amiodarona/toxicidade , Cloroquina/toxicidade , Córnea/efeitos dos fármacos , Lipidoses/induzido quimicamente , Fosfolipídeos/metabolismo , Administração Oftálmica , Envelhecimento/patologia , Animais , Córnea/metabolismo , Córnea/ultraestrutura , Modelos Animais de Doenças , Feminino , Corpos de Inclusão/metabolismo , Instilação de Medicamentos , Lipidoses/metabolismo , Lipidoses/patologia , Masculino , Coelhos
12.
J Cardiovasc Pharmacol Ther ; 24(3): 288-297, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30497293

RESUMO

INTRODUCTION: Direct comparison of the effects of antiarrhythmic agents on myocardial performance may be useful in choosing between medications in critically ill patients. Studies directly comparing multiple antiarrhythmic medications are lacking. The use of an experimental heart preparation permits examination of myocardial performance under constant loading conditions. METHODS: Hearts of Sprague Dawley rats (n = 35, 402-507 g) were explanted and cannulated in working heart model with fixed preload and afterload. Each heart was then exposed to a 3-hour infusion of procainamide (20 µg/kg/min), esmolol (100 or 200 µg/kg/min), amiodarone (10 or 20 mg/kg/d), sotalol (80 mg/m2/d), or placebo infusions (n = 5 per dose). Cardiac output, contractility (dP/dTmax), diastolic performance (dP/dTmin), and heart rate were compared between groups over time by linear mixed modeling. RESULTS: Compared with placebo, sotalol decreased contractility by an average of 24% ( P < .001) over the infusion period, as did amiodarone (low dose by 13%, P = .029; high dose by 14%, P = .013). Compared with placebo, mean cardiac output was significantly lower in animals treated with sotalol (by 22%, P = .016) and esmolol 200 µg/kg/min (by 23%, P = .012). Over time, amiodarone decreased cardiac output (20 mg/kg/d, ß = -89 [-144, -33] µL/min2 decrease, P = .002) and also worsened diastolic function, decreasing dP/dTmin by ∼18% and 22% ( P = .032 and P = .011, low and high doses, respectively). Procainamide did not have a significant effect on any measures of systolic or diastolic performance. CONCLUSIONS: In isolated hearts, amiodarone and sotalol depressed myocardial contractility, cardiac output, and diastolic function. However, procainamide did not negatively affect myocardial performance and represents a favorable agent in settings of therapeutic equivalence.


Assuntos
Amiodarona/administração & dosagem , Antiarrítmicos/administração & dosagem , Débito Cardíaco/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Procainamida/administração & dosagem , Sotalol/administração & dosagem , Função Ventricular Esquerda/efeitos dos fármacos , Amiodarona/toxicidade , Animais , Antiarrítmicos/toxicidade , Relação Dose-Resposta a Droga , Infusões Intravenosas , Preparação de Coração Isolado , Procainamida/toxicidade , Ratos Sprague-Dawley , Medição de Risco , Sotalol/toxicidade
13.
Eur. j. anat ; 22(4): 323-333, jul. 2018. ilus, tab, graf
Artigo em Inglês | IBECS | ID: ibc-179096

RESUMO

Amiodarone is a highly effective anti-arrhythmic drug, used in the treatment of cardiac arrhythmias. However, it is of a limited use due its serious side effects especially lung toxicity. This study was designed to investigate the role of vitamin E in ameliorating amiodarone-induced lung toxicity in adult male albino rat. The study was carried out on 24 adult male albino rats, divided into 4 equal Groups: Group I (control), Group II (sham control), Group III (Amiodarone treated) and Group IV (Amiodarone and vitamin E treated). After the end of the experiment, the rats were sacrificed by cervical dislocation, then parts of the rat lungs of each Group were prepared for light microscopic, histochemical study, immune- histochemical and ultrastructural study. Fresh Lung sections were processed for electron microscopic study. The results revealed marked pathological alterations in the rat lungs of Group III: distortion in the pulmonary architecture, mononuclear cellular infiltration, presence of areas of consolidation with alveolar collapse, areas of emphysematous air spaces, marked degeneration of the pneumocytes and increased collagen fibers deposition and marked increase in iNOS immunoexpression. There were marked alterations in the level oxidative markers in the lung homogenates. The ultrastructural study confirmed these changes. Treatment with vitamin E in Group IV revealed noticeable improvement of the histological and ultrastructural architecture of the lung. There was marked improvement in the other parameters. The present study concluded that amiodarone has marked toxic effect on the lung of the adult male albino rat and vitamin E could partially protect the lung against such toxic effects


No disponible


Assuntos
Animais , Ratos , Amiodarona/toxicidade , Vitamina E/uso terapêutico , Pulmão/fisiopatologia , Amiodarona/efeitos adversos , Vasodilatadores/toxicidade , Pulmão/ultraestrutura , Albinismo , Estresse Oxidativo , Pulmão/anatomia & histologia
14.
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
15.
Lung ; 196(3): 321-327, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29516177

RESUMO

INTRODUCTION: A number of studies indicate that endothelin-1 (ET-1) may act as an inflammatory cell "gatekeeper," by regulating the influx of neutrophils following pulmonary injury. To further examine the role of ET-1 in modulating lung inflammation, hamsters were treated with an endothelin receptor antagonist (ERA), HJP272, either 1 h prior to intratracheal instillation of amiodarone (AM) or 24 h afterwards. METHODS: In both cases, the extent of lung injury and repair was determined by (1) histopathological changes; (2) neutrophil content in bronchoalveolar lavage fluid (BALF); (3) lung collagen content; (4) tumor necrosis factor receptor 1 expression by BALF macrophages; (5) BALF levels of (a) transforming growth factor beta-1, (b) stromal cell-derived factor 1 (commonly referred to as CXCL12), and (c) platelet-derived growth factor BB; (6) alveolar septal cell apoptosis. RESULTS: For each parameter, pretreatment with HJP272 resulted in a significant reduction compared to AM alone, whereas post-treatment was either ineffective or produced only a marginally significant change, suggesting that the course of lung inflammation and repair is programmed at a very early stage. CONCLUSIONS: This finding may explain why ERAs are not an effective treatment for human pulmonary fibrosis. Nevertheless, they may be useful as an adjunct to therapeutic regimens involving drugs that have fibrogenic potential.


Assuntos
Amiodarona/toxicidade , Antagonistas dos Receptores de Endotelina/farmacologia , Endotelina-1/antagonistas & inibidores , Hidroxiquinolinas/farmacologia , Pulmão/efeitos dos fármacos , Fibrose Pulmonar/induzido quimicamente , Vasodilatadores/toxicidade , Animais , Apoptose/efeitos dos fármacos , Becaplermina/efeitos dos fármacos , Becaplermina/metabolismo , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Quimiocina CXCL12/efeitos dos fármacos , Quimiocina CXCL12/metabolismo , Colágeno/efeitos dos fármacos , Colágeno/metabolismo , Feminino , Pulmão/metabolismo , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Mesocricetus , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Alvéolos Pulmonares/citologia , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/patologia , Receptores Tipo I de Fatores de Necrose Tumoral/efeitos dos fármacos , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Fator de Crescimento Transformador beta1/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo
16.
Environ Mol Mutagen ; 59(4): 278-289, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29399883

RESUMO

Dronedarone, an antiarrhythmic drug, has been marketed as an alternative to amiodarone. The use of dronedarone has been associated with severe liver injury; however, the mechanisms remain unclear. In this study, the possible mechanisms of dronedarone induced liver toxicity were characterized in HepG2 cells. Dronedarone decreased cells viability and induced apoptosis and DNA damage in a concentration- and time-dependent manner. Pretreatment of the HepG2 cells with apoptosis inhibitors (caspase-3, -8, and -9) or the necrosis inhibitor (Necrox-5), partially, but significantly, reduced the release of lactate dehydrogenase. Dronedarone caused the release of cytochrome c from mitochondria to cytosol, a prominent feature of apoptosis. In addition, the activation of caspase-2 was involved in dronedarone induced DNA damage and the activation of JNK and p38 signaling pathways. Inhibition of JNK and p38 by specific inhibitors attenuated dronedarone-induced cell death, apoptosis, and DNA damage. Additionally, suppression of caspase-2 decreased the activities of JNK and p38. Dronedarone triggered DNA damage was regulated by downregulation of topoisomerase IIα at both transcriptional and post-transcriptional levels. Taken together, our data show that DNA damage, apoptosis, and the activation of JNK and p38 contribute to dronedarone-induced cytotoxicity. Environ. Mol. Mutagen. 59:278-289, 2018. © 2018 Wiley Periodicals, Inc.


Assuntos
Amiodarona/análogos & derivados , Apoptose , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Hepatócitos/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Amiodarona/toxicidade , Regulação para Baixo , Dronedarona , Células Hep G2 , Hepatócitos/enzimologia , Humanos , Transdução de Sinais
17.
Br J Pharmacol ; 175(1): 125-139, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29057462

RESUMO

BACKGROUND AND PURPOSE: Amiodarone is one of the most effective anti-arrhythmic drugs available, but its clinical applications are limited by toxic side effects including optic toxicity. The purpose of this study was to investigate the toxic effect of amiodarone on D407 cells (a human retinal pigmented epithelial (RPE) cell line) and the mechanisms of the protective effect of insulin-like growth factor-1 (IGF-1). EXPERIMENTAL APPROACH: The involvement of the kinases, Akt and ERK, was analysed by Western blot. Intracellular accumulation of ROS was measured using fluorophotometric quantification. A pharmacological approach with inhibitors was used to investigate the pathways involved in the protective action of IGF-1. KEY RESULTS: Amiodarone concentration-dependently augmented the production of ROS, lipid peroxidation and apoptosis in D407 cells. IGF-1 time- and concentration-dependently reversed these effects of amiodarone and protected D407 cells from amiodarone-mediated toxicity. Amiodarone inhibited the pAkt but not pErk, and IGF-1 reversed this inhibitory effect of amiodarone. However, IGF-1 failed to suppress amiodarone-induced cytotoxicity in the presence of PI3K/Akt inhibitor LY294002 suggesting the direct involvement of the PI3K/Akt pathway. Furthermore, in vivo rat flash electroretinogram (FERG) recordings showed that IGF-1 reverses the amiodarone-induced decrease in a- and b-waves. The immunocytochemistry findings confirmed that vitreous IGF-1 injections promote the survival of RPE cells in rat retina treated with amiodarone. CONCLUSION AND IMPLICATIONS: IGF-1 can protect RPE cells from amiodarone-mediated injury via the PI3K/Akt pathway in vivo and in vitro. IGF-1 has potential as a protective drug for the prevention and treatment of amiodarone-induced optic toxicity.


Assuntos
Amiodarona/toxicidade , Fator de Crescimento Insulin-Like I/farmacologia , Estresse Oxidativo/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Citoproteção/efeitos dos fármacos , Citoproteção/fisiologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/patologia
18.
Toxicol Lett ; 284: 184-194, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29248575

RESUMO

Phospholipidosis is a metabolic disorder characterized by intracellular accumulation of phospholipids. It can be caused by short-term or chronic exposure to cationic amphiphilic drugs (CADs). These compounds bind to phospholipids, leading to inhibition of their degradation and consequently to their accumulation in lysosomes. Drug-induced phospholipidosis (DIPL) is frequently at the basis of discontinuation of drug development and post-market drug withdrawal. Therefore, reliable human-relevant in vitro models must be developed to speed up the identification of compounds that are potential inducers of phospholipidosis. Here, hepatic cells derived from human skin (hSKP-HPC) were evaluated as an in vitro model for DIPL. These cells were exposed over time to amiodarone, a CAD known to induce phospholipidosis in humans. Transmission electron microscopy revealed the formation of the typical lamellar inclusions in the cell cytoplasm. Increase of phospholipids was already detected after 24 h exposure to amiodarone, whereas a significant increase of neutral lipid vesicles could be observed after 72 h. At the transcriptional level, the modulation of genes involved in DIPL was detected. These results provide a valuable indication of the applicability of hSKP-HPC for the quick assessment of drug-induced phospholipidosis in vitro, early in the drug development process.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Hepatócitos/efeitos dos fármacos , Lipidoses/induzido quimicamente , Fosfolipídeos/metabolismo , Pele/citologia , Células-Tronco/citologia , Amiodarona/toxicidade , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Citometria de Fluxo , Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Hepatócitos/ultraestrutura , Humanos , Lipidoses/genética , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Masculino , Fosfolipídeos/genética
19.
Toxicol Sci ; 159(2): 402-412, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28962527

RESUMO

Amiodarone is a commonly used antiarrhythmic drug and can cause liver steatosis. We investigated the role of endoplasmic reticulum (ER) stress/unfolded protein response in the pathogenesis of amiodarone-induced steatosis. Amiodarone-induced liver injury was obtained by 1 intraperitoneal injection to wild-type (WT) or C/EBP homologous protein knock-out mice (Ddit3-/-). Amiodarone directly reduced intracellular ATP and Ca2+ in hepatocytes invitro, inducing ER stress and lipid accumulation. In vivo, amiodarone-driven liver damage and lipid accumulation was accompanied by activation of ER stress/unfolded protein response, as demonstrated by up-regulation of genes encoding key ER stress mediators and by phosphorylation of eIF2α. In contrast to WT mice, Ddit3-/- mice were protected from amiodarone-induced ER stress and lipid accumulation. Importantly, amiodarone-induced lipid accumulation was not mediated by de novo hepatic lipogenesis, increased adipose tissue lipolysis or increased hepatic uptake of triglycerides or free fatty acids. Rather, amiodarone strongly increased hepatic mRNA expression of lipid droplet proteins, particularly Cidea and Cidec, in WT, but less so in Ddit3-/- mice, suggesting a link between ER stress and increased triglyceride storage. Moreover, while insulin attenuated amiodarone-induced phosphorylation of hormone sensitive lipase (HSL) in WT, it did not affect pHSL in Ddit3-/-, indicating increased lipolysis and therefore reduced lipid accumulation in these mice. Finally, ER stress attenuation using 2 different pharmacological chaperones reduced lipid accumulation, accompanied by reduced mRNA expression of Cidec. In conclusion, amiodarone-induced ER stress drives liver steatosis and may be considered for therapeutic targeting.


Assuntos
Amiodarona/toxicidade , Antiarrítmicos/toxicidade , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Animais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Linhagem Celular Transformada , Ácidos Graxos não Esterificados/metabolismo , Fígado Gorduroso/induzido quimicamente , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Proteínas/genética , Esterol Esterase/metabolismo , Fator de Transcrição CHOP/genética , Triglicerídeos/metabolismo , Resposta a Proteínas não Dobradas , Regulação para Cima
20.
Toxicol In Vitro ; 45(Pt 2): 222-232, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28911986

RESUMO

In order to replace the use of animals in toxicity testing, there is a need to predict human in vivo toxic doses from concentrations that cause adverse effects in in vitro test systems. The virtual cell based assay (VCBA) has been developed to simulate intracellular concentrations as a function of time, and can be used to interpret in vitro concentration-response curves. In this study we refine and extend the VCBA model by including additional target-organ cell models and by simulating the fate and effects of chemicals at the organelle level. In particular, we describe the extension of the original VCBA to simulate chemical fate in liver (HepaRG) cells and cardiomyocytes (ICell cardiomyocytes), and we explore the effects of chemicals at the mitochondrial level. This includes a comparison of: a) in vitro results on cell viability and mitochondrial membrane potential (mmp) from two cell models (HepaRG cells and ICell cardiomyocytes); and b) VCBA simulations, including the cell and mitochondrial compartment, simulating the mmp for both cell types. This proof of concept study illustrates how the relationship between intra cellular, intra mitochondrial concentration, mmp and cell toxicity can be obtained by using the VCBA.


Assuntos
Hepatócitos/metabolismo , Mitocôndrias/metabolismo , Modelos Biológicos , Miócitos Cardíacos/metabolismo , Amiodarona/toxicidade , Alternativas aos Testes com Animais , Cafeína/toxicidade , Carbonil Cianeto p-Trifluormetoxifenil Hidrazona/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Simulação por Computador , Hepatócitos/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos
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