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1.
J Am Coll Cardiol ; 80(11): 1045-1056, 2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36075673

RESUMO

BACKGROUND: Recurrent ventricular tachycardia (VT) due to dilated cardiomyopathy (DCM) is difficult to treat, and long-term outcome data are limited. OBJECTIVES: The aim of this study was to identify predictors of mortality or heart transplantation (HTx) and VT recurrence. METHODS: Consecutive patients with DCM accepted for radiofrequency catheter ablation (RFCA) of VT at 9 centers were prospectively enrolled and followed. RESULTS: Of 281 consecutive patients (mean age 60 ± 13 years, 85% men, mean left ventricular ejection fraction [LVEF] 36% ± 12%), 35% had VT storm, 20% had incessant VT, and amiodarone was unsuccessful in 68%. During follow-up of 21 months (IQR: 6-30 months), 67 patients (24%) died or underwent HTx, and 138 (49%) had VT recurrence (45 within 30 days, defined as early); the 4-year rate of VT recurrence or mortality or HTx was 70%. Independent predictors of mortality or HTx were early VT recurrence (HR: 2.92; 95% CI: 1.37-6.21; P < 0.01), amiodarone at discharge (HR: 3.23; 95% CI: 1.43-7.33; P < 0.01), renal dysfunction (HR: 1.92; 95% CI: 1.01-3.64; P = 0.046), and LVEF (HR: 1.36; 95% CI: 1.0-1.84; P = 0.052). LVEF ≤32% identified patients at risk for mortality or HTx (area under the curve: 0.75). Mortality or HTx per 100 person-years was 40.4 events after early, compared with 14.2 events after later VT recurrence and 8.5 events with no VT recurrence after RFCA (P < 0.01 for both). Patients with early recurrence and LVEFs ≤32% had a 1-year rate of mortality or HTx of 55%. VT recurrence was predicted by prior implantable cardioverter-defibrillator shocks, basal anteroseptal VT origin, and procedural failure but not LVEF. CONCLUSIONS: Patients with DCM needing RFCA for VT are a high-risk group. Following RFCA, approximately one-half remain free of VT recurrence. Early VT recurrence with LVEF ≤32% identifies those at very high risk for mortality or HTx, and screening for mechanical support or HTx should be considered. Late VT recurrence after RFCA does not predict worse outcome.


Assuntos
Amiodarona , Cardiomiopatia Dilatada , Ablação por Cateter , Taquicardia Ventricular , Idoso , Amiodarona/uso terapêutico , Ablação por Cateter/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Volume Sistólico , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/terapia , Resultado do Tratamento , Função Ventricular Esquerda
2.
Heart Surg Forum ; 25(4): E564-E570, 2022 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-36052897

RESUMO

BACKGROUND: Atrial fibrillation (AF) is the most common form of dysrhythmia observed in the clinical field, causing multiple morbidities, such as thromboembolic complications. Hence, the maintenance of sinus rhythm is superior to rate control. This study tests the efficacy of single- and low-dose amiodarone on the persistence of AF after surgery before transfer to the intensive care unit. METHODS: A double-blinded, randomized controlled trial assessed 113 patients who underwent mitral valve surgery with preoperative chronic AF. Patients were divided into two groups: the control group (N = 55) who received 50 mL of 5% dextrose over 10 min after general anesthesia induction, and the amiodarone group (N = 58) who received 1 mg/kg of amiodarone diluted in 50 mL of 5% dextrose over 10 min shortly after anesthesia induction. RESULTS: The amiodarone group had a statistically significant successful conversion of preoperative AF to normal sinus rhythm in 40 patients (72.73%). The control group demonstrated spontaneous conversion from AF to a normal sinus rhythm in seven patients (12.73%). The sinus rhythm was maintained in 60% of patients (36), as four patients reverted to AF during the hospital stay despite the initial normal sinus rhythm after the operation. In contrast, 53 (96.36%) patients in the control group were discharged from the hospital with a controlled rate of AF. In addition, low-dose amiodarone caused a statistically significant reduction in heart rates at 10, 30, and 60 min after declamping, extended throughout the first 24 h with mean heart rates of 97.233±7.311, 99.509±8.482, and 97.940±7.715 bpm, respectively. In comparison, the control group had heart rates of 115.382±7.547, 115.055±13.919, and 113.618±8.765 bpm at these times. The mean postoperative heart rate at the end of the first 24 h was 97.793±7.189 bpm in the amiodarone group and 113.036±9.737 bpm in the control group. No mortality or need for mechanical support was recorded in either group. CONCLUSIONS: Single and low-dose intraoperative intravenous amiodarone during mitral valve surgery may be practical to aid in pharmacological cardioversion of patients with preoperative chronic AF presenting for mitral valve surgery.


Assuntos
Amiodarona , Fibrilação Atrial , Amiodarona/uso terapêutico , Antiarrítmicos/uso terapêutico , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Cardioversão Elétrica , Glucose/uso terapêutico , Humanos , Valva Mitral/cirurgia , Resultado do Tratamento
3.
Front Cell Infect Microbiol ; 12: 975931, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36093188

RESUMO

Chagas disease (CD), a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi, is an important public health problem mainly in Latin America, leading to approximately 12,000 annual deaths. Current etiological treatment for CD is limited to two nitro compounds, benznidazole (Bz) and nifurtimox (Nif), both presenting relevant limitations. Different approaches have been employed to establish more effective and safer schemes to treat T. cruzi infection, mostly based on drug repurposing and combination therapies. Amiodarone (AMD), an antiarrhythmic medicament of choice for patients with the chronic cardiac form of CD, is also recognized as a trypanocidal agent. Therefore, our aim is to investigate the combined treatment Bz + AMD on trypomastigote viability, control of T. cruzi intracellular form proliferation, and recovery of the infection-induced cytoskeleton alterations in cardiac cells. The combination of Bz + AMD did not improve the direct trypanocidal effect of AMD on the infective blood trypomastigote and replicative intracellular forms of the parasite. Otherwise, the treatment of T. cruzi-infected cardiac cells with Bz plus AMD attenuated the infection-triggered cytoskeleton damage of host cells and the cytotoxic effects of AMD. Thus, the combined treatment Bz + AMD may favor parasite control and hamper tissue damage.


Assuntos
Amiodarona , Doença de Chagas , Tripanossomicidas , Trypanosoma cruzi , Amiodarona/farmacologia , Amiodarona/uso terapêutico , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Citoesqueleto , Humanos , Nitroimidazóis , Tripanossomicidas/farmacologia
7.
Biol Pharm Bull ; 45(7): 948-954, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35786602

RESUMO

Some population pharmacokinetic models for amiodarone (AMD) did not incorporate N-desethylamiodarone (DEA) concentration. Glucocorticoids activate CYP3A4 activity, metabolizing AMD. In contrast, CYP3A4 activity may decrease under inflammation conditions. However, direct evidence for the role of glucocorticoid or inflammation on the pharmacokinetics of AMD and DEA is lacking. The pilot study aimed to address this gap using a population pharmacokinetic analysis of AMD and DEA. A retrospective cohort observational study in adult patients who underwent AMD treatment with trough concentration measurement was conducted at Tokyo Women's Medical University, Medical Center East from June 2015 to March 2019. Both structural models of AMD and DEA applied 1-compartment models, which included significant covariates using a stepwise forward selection and backward elimination method. The eligible 81 patients (C-reactive protein level: 0.26 [interquartile range; 0.09-1.92] mg/dL) had a total of 408 trough concentrations for both AMD and DEA. The median trough concentrations were 0.49 [0.31-0.81] µg/mL for AMD and 0.43 [0.28-0.71] µg/mL for DEA during a median follow-up period of 446 [147-1059] d. Three patients received low-dose oral glucocorticoid. The final model identified that AMD clearance was 7.9 L/h, and the apparent DEA clearance was 10.3 L/h. Co-administered glucocorticoids lowered apparent DEA clearance by 35%. These results indicate that co-administered glucocorticoids may increase DEA concentrations in patients without severe inflammation.


Assuntos
Amiodarona , Glucocorticoides , Adulto , Amiodarona/análogos & derivados , Antiarrítmicos , Citocromo P-450 CYP3A , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Projetos Piloto , Estudos Retrospectivos
8.
Clin Nucl Med ; 47(9): e582-e584, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35835112

RESUMO

ABSTRACT: 99m Tc-sestamibi thyroid scintigraphy (STS) can aid in differentiating between types 1 and 2 amiodarone-induced thyrotoxicosis (AIT). We present a consecutive case series of 4 men (aged 56-75 years) in whom both 99m Tc-STS and thyroid histology were consistent with a diagnosis of type 2 AIT, representing the first reported histopathologic correlation for this diagnostic test. Median amiodarone treatment duration was 26 months (range, 10-39 months), and amiodarone was discontinued a median of 3 months preoperatively (range, 2-4 months) in all 4 cases. 99m Tc-STS is a promising functional imaging modality, which has the potential to aid clinicians in the diagnostic workup and treatment of AIT.


Assuntos
Amiodarona , Hipertireoidismo , Tireotoxicose , Amiodarona/efeitos adversos , Antiarrítmicos/efeitos adversos , Humanos , Masculino , Cintilografia , Tecnécio Tc 99m Sestamibi , Tireotoxicose/induzido quimicamente , Tireotoxicose/diagnóstico por imagem
10.
J Diabetes Complications ; 36(7): 108227, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35717354

RESUMO

AIM: This post hoc analysis evaluated efficacy and safety of dronedarone in atrial fibrillation (AF) and atrial flutter (AFL) patients with/without diabetes. METHODS: Patients were categorized according to baseline diabetes status. Time-to-event analyses were performed using Kaplan-Meier method. Hazard-ratios were assessed using Cox models. RESULTS: 945/4628 (dronedarone = 482; placebo = 463) patients in ATHENA and 215/1237 (dronedarone = 148; placebo = 67) patients in EURIDIS/ADONIS studies had diabetes. In ATHENA, there were higher rates of CV hospitalization/death in patients with diabetes (39.5%) than without diabetes (34.7%). Incidence of first CV hospitalization/death was lower in patients with diabetes treated with dronedarone (35.1%) than placebo (44.1%), and time to this event was longer in those treated with dronedarone than placebo (log-rank p = 0.005). Median AF/AFL recurrence time was longer in patients treated with dronedarone than placebo in patients with diabetes (ATHENA: 722 vs 527 days, log-rank p = 0.004; EURIDIS/ADONIS: 100 vs 23 days, log-rank p = 0.15) or without diabetes (ATHENA: 741 vs 492 days, log-rank p < 0.0001; EURIDIS/ADONIS: 120 vs 59 days, log-rank p = 0.0002). Occurrence of any treatment-related adverse events with dronedarone was similar for patients with/without diabetes and was comparable to placebo. CONCLUSIONS: Dronedarone reduced incidence of CV hospitalization/death, AF/AFL recurrence and increased time to these events in AF/AFL patients with/without diabetes. TRIAL REGISTRATION: Not applicable, as it was a post hoc analysis. This article is based on previously conducted studies (ATHENA: NCT00174785, EURIDIS: NCT00259428, and ADONIS: NCT00259376).


Assuntos
Adonis , Amiodarona , Fibrilação Atrial , Diabetes Mellitus , Amiodarona/efeitos adversos , Antiarrítmicos/efeitos adversos , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/epidemiologia , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/epidemiologia , Dronedarona/efeitos adversos , Humanos
11.
J Am Heart Assoc ; 11(11): e023762, 2022 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-35656998

RESUMO

Background Atrial and ventricular arrhythmias are commonly encountered in patients with advanced heart failure, with amiodarone being the most commonly used antiarrhythmic drug in continuous-flow left ventricular assist device (CF-LVAD) recipients. The purpose of this study was to assess the impact of amiodarone use on long-term all-cause mortality in ptients with a CF-LVAD. Methods and Results A retrospective multicenter study of CF-LVAD was conducted at 5 centers including all CF-LVAD implants from 2007 to 2015. Patients were stratified based on pre-CF-LVAD implant amiodarone use. Additional use of amiodarone after CF-LVAD implantation was also evaluated. Primary outcome was all-cause mortality during long-term follow-up. Kaplan-Meier curves were used to assess survival outcomes. Multivariable Cox regression was used to identify predictors of outcomes. Propensity matching was done to address baseline differences. A total of 480 patients with a CF-LVAD (aged 58±13 years, 81% men) were included. Of these, 170 (35.4%) were on chronic amiodarone therapy at the time of CF-LVAD implant, and 310 (64.6%) were not on amiodarone. Rate of all-cause mortality over the follow-up period was 32.9% in the amiodarone group compared with 29.6% in those not on amiodarone (P=0.008). Similar results were noted in the propensity-matched group (log-rank, P=0.04). On multivariable Cox regression analysis, amiodarone use at baseline was independently associated with all-cause mortality (hazard ratio, 1.68 [95% CI, 1.1-2.5]; P=0.01). Conclusions Amiodarone use was associated with significantly increased rates of all-cause mortality in CF-LVAD recipients. Earlier interventions for arrhythmias to avoid long-term amiodarone exposure may improve long-term outcomes in CF-LVAD recipients and needs further study.


Assuntos
Amiodarona , Insuficiência Cardíaca , Coração Auxiliar , Amiodarona/efeitos adversos , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/terapia , Feminino , Coração Auxiliar/efeitos adversos , Humanos , Masculino , Estudos Retrospectivos , Resultado do Tratamento
12.
Medicine (Baltimore) ; 101(25): e29243, 2022 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-35758352

RESUMO

RATIONALE: Coronavirus disease 2019 (COVID-19) is a systemic disease with major clinical manifestations in the respiratory system. However, thyroid involvement has also been reported. We present a case of hypothyroidism with ventricular tachycardia following diagnosis with COVID-19. PATIENT CONCERNS: A 77-year-old man was admitted to the isolation ward due to COVID-19. After respiratory support and medical treatment, the patient was successfully weaned off the ventilator. However, an episode of short-run ventricular tachycardia was detected, and primary hypothyroidism was also diagnosed. DIAGNOSIS: Ventricular tachycardia was detected by electrocardiography. INTERVENTIONS: Intravenous amiodarone administration and oral levothyroxine replacement. OUTCOMES: No arrhythmia detected following treatment. LESSONS: Awareness of the association between hypothyroidism and COVID-19 is important in preventing possible complications.


Assuntos
Amiodarona , COVID-19 , Hipotireoidismo , Taquicardia Ventricular , Idoso , Amiodarona/uso terapêutico , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/complicações , COVID-19/complicações , Eletrocardiografia , Humanos , Hipotireoidismo/complicações , Hipotireoidismo/diagnóstico , Hipotireoidismo/tratamento farmacológico , Masculino , Taquicardia Ventricular/complicações , Taquicardia Ventricular/etiologia
13.
Artigo em Inglês | MEDLINE | ID: mdl-35682190

RESUMO

Patients with recurrence of atrial tachyarrhythmia after catheter ablation for atrial fibrillation or atrial flutter constitute a rapidly growing cohort, but study-driven treatment recommendations are lacking. The present study aimed to compare the cardioversion success of ibutilide and amiodarone in patients with post-ablation atrial tachyarrhythmia. We included all episodes of post-ablation atrial tachyarrhythmia in patients treated with either intravenous ibutilide or amiodarone at an academic emergency department from 2010 to 2018. The primary endpoint was the conversion to sinus rhythm. The conversion rates were stratified by arrhythmia type, and multivariable cluster-adjusted logistic regression was used to estimate the effect of ibutilide and amiodarone on cardioversion success, given as the odds ratio (OR) with 95% confidence intervals (95% CI). In total, 109 episodes of 72 patients were analyzed. The conversion rates were 37/49 (76%) for ibutilide and 16/60 (27%) for amiodarone. Compared to amiodarone, ibutilide was associated with higher odds of conversion (multivariable cluster-adjusted OR 5.6, 95% CI 1.3-24.3). The cardioversion success of ibutilide was the highest in atrial flutter (crude OR 19.5, 95% CI 3.4-112.5) and focal atrial tachycardia (crude OR 8.3, 95% CI 1.5-47.2), but it was less pronounced in atrial fibrillation (crude OR 4.5, 95% CI 1.2-17.2). Randomized trials are warranted to confirm our findings.


Assuntos
Amiodarona , Fibrilação Atrial , Flutter Atrial , Amiodarona/uso terapêutico , Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Flutter Atrial/tratamento farmacológico , Estudos de Coortes , Cardioversão Elétrica , Humanos , Sistema de Registros , Sulfonamidas , Taquicardia/tratamento farmacológico , Resultado do Tratamento
15.
Clin Rheumatol ; 41(9): 2875-2881, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35654917

RESUMO

Amiodarone can be used in a variety of arrhythmias. Given its widespread use, the probability of clinicians encountering its cutaneous adverse effects is high. A few cases of amiodarone-induced cutaneous vasculitis were reported in the literature, probably because it is underdiagnosed in clinical practice. Indeed, amiodarone-related cutaneous reactions may present a wide range of manifestations and are sometimes difficult to diagnose. Herein, we report a case with a sizeable necrotic ulcer on the left lower leg shortly after amiodarone exposure. A rigorous diagnostic study was performed before concluding the diagnosis of amiodarone-induced cutaneous vasculitis, which showed the histopathological features of leukocytoclastic vasculitis. The lesion was almost completely healed by the third month of discontinuation of amiodarone. We did a literature search and found seven cases which were reported as leukocytoclastic or lymphocytic vasculitis. We reviewed previous cases and presented our case in comparison to prior cases.


Assuntos
Amiodarona , Vasculite Leucocitoclástica Cutânea , Amiodarona/efeitos adversos , Arritmias Cardíacas , Humanos , Perna (Membro)/patologia , Pele/patologia , Vasculite Leucocitoclástica Cutânea/induzido quimicamente , Vasculite Leucocitoclástica Cutânea/diagnóstico , Vasculite Leucocitoclástica Cutânea/patologia
16.
Circ Arrhythm Electrophysiol ; 15(5): e007955, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35491871

RESUMO

Antiarrhythmic drugs (AAD) play an important role in the management of arrhythmias. Drug interactions involving AAD are common in clinical practice. As AADs have a narrow therapeutic window, both pharmacokinetic as well as pharmacodynamic interactions involving AAD can result in serious adverse drug reactions ranging from arrhythmia recurrence, failure of device-based therapy, and heart failure, to death. Pharmacokinetic drug interactions frequently involve the inhibition of key metabolic pathways, resulting in accumulation of a substrate drug. Additionally, over the past 2 decades, the P-gp (permeability glycoprotein) has been increasingly cited as a significant source of drug interactions. Pharmacodynamic drug interactions involving AADs commonly involve additive QT prolongation. Amiodarone, quinidine, and dofetilide are AADs with numerous and clinically significant drug interactions. Recent studies have also demonstrated increased morbidity and mortality with the use of digoxin and other AAD which interact with P-gp. QT prolongation is an important pharmacodynamic interaction involving mainly Vaughan-Williams class III AAD as many commonly used drug classes, such as macrolide antibiotics, fluoroquinolone antibiotics, antipsychotics, and antiemetics prolong the QT interval. Whenever possible, serious drug-drug interactions involving AAD should be avoided. If unavoidable, patients will require closer monitoring and the concomitant use of interacting agents should be minimized. Increasing awareness of drug interactions among clinicians will significantly improve patient safety for patients with arrhythmias.


Assuntos
Amiodarona , Síndrome do QT Longo , Amiodarona/uso terapêutico , Antiarrítmicos/efeitos adversos , Antibacterianos/uso terapêutico , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/tratamento farmacológico , Interações Medicamentosas , Humanos , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/tratamento farmacológico
18.
Eur J Pharm Sci ; 174: 106198, 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35504449

RESUMO

AIMS: The aims of this work are (i) to characterize the absorption properties of orally administered formulations at different dose levels, and (ii) to evaluate the impact of entero-hepatic circulation on the time-course of amiodarone (AM) in rats in order to optimize the development of new oral (OR) formulations. METHODS: Intravenous (IV) formulation consisted on a solution of a commercial injectable of AM chlorhydrate. OR formulations included the IV commercial formulation (Trangorex®) (Solution I), an aqueous supramicellar solution of AM chlorhydrate with Polysorbate at 5% (Solution II) and a suspension from Trangorex® tablets (Tablet). Data from 96 male Wistar rats, including 985 AM observations, were analyzed using NONMEM v7.4. RESULTS: The population pharmacokinetic (PK) model assumes linear absorption processes, showing ka of AM from Solution II (Polysorbate 80, 5%) and Solution I increased by 2.5- and 1.62-fold compared to Tablet formulation. OR bioavailability of AM from Tablet, Solution I and Solution II was 37%, 40%, and 50%, respectively. The structural model of AM disposition was adapted from a previously population PK model and expanded by incorporating entero-hepatic reabsorption (EHR) processes, which estimated a 12.3% biliary excretion of AM and complete re-absorption from lumen. CONCLUSIONS: The current population PK model of AM demonstrated the absorption rate enhancement when AM is formulated with supramicellar concentrations of Polysorbate 80. The study design allowed to characterize the EHR of AM and its contribution in the overall AM disposition.


Assuntos
Amiodarona , Administração Oral , Animais , Disponibilidade Biológica , Estudos Cross-Over , Circulação Êntero-Hepática , Cinética , Masculino , Polissorbatos , Ratos , Ratos Wistar , Comprimidos
19.
Toxicol Ind Health ; 38(5): 249-258, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35513769

RESUMO

Amiodarone (AMD) is an antiarrhythmic drug that induces idiosyncratic toxicity. Environmental pollutants, including heavy metals, could interact with its toxicity by affecting pharmacokinetics and pharmacodynamics. Other levels of interaction could exist in yeast, such as oxidative stress and the general stress response. In this study, we investigated the interaction of mercury chloride (HgCl2) and cadmium chloride (CdCl2) with AMD toxicity on Saccharomyces cerevisiae. Interaction type - synergistic, additive, or antagonistic - was determined by median drug effect analysis using "CompuSyn". HgCl2 potentiated AMD toxicity at high doses (≥ 71.4 µm, which yielded more than 60% inhibition). CdCl2 acted similarly at high doses (≥ 57.9 µm). An antagonistic effect appeared at lower doses with both heavy metals (≤ 49.4 µm for HgCl2 and AMD; ≤ 18.9 µm for CdCl2 and AMD). The threshold concentrations (HgCl2 or CdCl2 combined with AMD) that switched the interaction from antagonistic to additive, and then to synergistic, were decreased in the yeast strain mutant in catalase (CTT1), suggesting an important role for this enzyme. Moreover, mutation of the nutrient sensing receptor gene GPR1 caused the synergistic interaction of CdCl2, but not HgCl2, with AMD to occur at the lowest tested concentrations (1.2 µm). The reverse was obtained with the mutant strain in calcium-manganese transporter gene PMR1, where the synergistic interaction of HgCl2 with AMD occurred at concentrations (20.7 µm) lower than that of the wild type (71.4 µm). These results demonstrated a dose-dependent interaction between the two heavy metals with AMD toxicity, and the involvement of oxidative stress, calcium homeostasis, and nutrient sensing in the observed interaction.


Assuntos
Amiodarona , Mercúrio , Metais Pesados , Amiodarona/toxicidade , Cádmio/toxicidade , Cálcio , Mercúrio/toxicidade , Metais Pesados/toxicidade , Saccharomyces cerevisiae/genética
20.
Eur J Clin Pharmacol ; 78(8): 1311-1320, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35604424

RESUMO

PURPOSE: The diuretic effect of tolvaptan is largely blood level-dependent although it does exhibit interindividual differences according to cytochrome P450 (CYP) 3A5 genotype. This study aimed to investigate the pharmacokinetic relationship between plasma tolvaptan and its monohydroxylate enantiomers and the factors affecting their metabolism in heart failure patients. METHODS: Japanese heart failure patients (n = 88) receiving oral tolvaptan (median dosage 7.5 mg/day) were enrolled. Blood samples were collected prior to the dosing on day 6 or later after first administration to determine the plasma concentrations of tolvaptan and its monohydroxylate enantiomers. Gene polymorphisms of CYP3A5, carbonyl reductase (CBR) 1/3, and ATP-binding cassette subfamily B member (ABCB) 1 were analyzed for their impact on tolvaptan pharmacokinetics. Serum laboratory test values and concomitant use of amiodarone were evaluated as factors related to tolvaptan metabolism. RESULTS: The median of the sum of the 5S- and 5R-tolvaptan plasma concentrations was 48.9 (range, 15.3-100) ng/mL. CYP3A5 genotypes significantly affected the concentration ratio of all enantiomeric metabolites to tolvaptan, while the other metabolic-related gene polymorphisms had no influence. A negative correlation was found between serum albumin and the enantiomeric ratio of tolvaptan and monohydroxylate DM-4111. Concomitant use of amiodarone increased the plasma levels of whole tolvaptan but significantly decreased the metabolic ratios of 5R-tolvaptan. 5S-tolvaptan was selectively synthesized from ketone MOP-21826 by CBR1 with a substantially smaller reaction velocity compared to tolvaptan monohydroxylation by CYP3A4/5. CONCLUSION: This study clarified the racemic impact of CYP3A5 genotypes on tolvaptan metabolism. Amiodarone may stereoselectively interact with R-forms rather than S-forms of tolvaptan.


Assuntos
Amiodarona , Insuficiência Cardíaca , Amiodarona/uso terapêutico , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Genótipo , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/genética , Humanos , Imunossupressores/farmacocinética , Tolvaptan
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