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1.
Int J Clin Pharmacol Ther ; 60(12): 515-520, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36052653

RESUMO

BACKGROUND: The antiarrhythmic drug amiodarone has noncardiac adverse effects, leading to restrictive therapeutic plasma ranges. Despite the significant positive correlation between triglyceride and amiodarone levels, the effect of fluctuations in amiodarone levels in patients with hypertriglyceridemia on amiodarone therapy has not been fully characterized. This study is the first to report on the effect of hypertriglyceridemia on the efficacy and safety of amiodarone therapy. CASE PRESENTATION: The first patient was a 58-year-old man with hypertriglyceridemia who was diagnosed with ventricular fibrillation (patient #1). The second patient with hypertriglyceridemia was a 72-year-old man with sustained ventricular tachycardia (patient #2). Both patients received implantable cardioverter-defibrillator therapy. During the study period, amiodarone and N-desethylamiodarone concentrations were measured 12 times in patient #1 and 26 times in patient #2. Triglyceride concentrations in patient #1 and patient #2 ranged from 102 to 765 mg/dL and from 125 to 752 mg/dL, respectively. For both patients, amiodarone dosage was maintained at 100 mg/day, and the administration of concomitant drugs that could affect amiodarone pharmacokinetics was neither initiated nor discontinued. However, amiodarone concentrations fluctuated (patient #1, 0.52 - 1.86 µg/mL; patient #2, 0.73 - 2.82 µg/mL). Although amiodarone concentrations fluctuated, neither of the patients had defibrillation shocks to stop the abnormal rhythm via an implantable cardioverter-defibrillator, and laboratory data showed that thyroid-stimulating hormone, free thyroxine, KL-6, and surfactant protein-D remained close to normal. CONCLUSION: In patients with hypertriglyceridemia, it may be necessary for clinicians to pay more attention to the clinical symptoms along with fluctuations in amiodarone levels and accordingly adjust amiodarone dosage.


Assuntos
Amiodarona , Hipertrigliceridemia , Masculino , Humanos , Pessoa de Meia-Idade , Idoso , Amiodarona/uso terapêutico , Amiodarona/efeitos adversos , Antiarrítmicos/efeitos adversos , Fibrilação Ventricular/induzido quimicamente , Hipertrigliceridemia/tratamento farmacológico , Hipertrigliceridemia/induzido quimicamente , Triglicerídeos/uso terapêutico
2.
Int J Clin Pharmacol Ther ; 59(1): 63-70, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33026317

RESUMO

OBJECTIVE: Bepridil prolongs the QT interval and can induce torsade de pointes. Although increased bepridil concentration may be a primary cause of prolonged QT, the relationship between serum bepridil concentration and prolonged QT remains unclear. We investigated the relationship between serum bepridil concentration and the corrected QT (QTc) interval in patients treated with bepridil. MATERIALS AND METHODS: A retrospective study was performed at the National Cerebral and Cardiovascular Center in Japan. Patients with atrial fibrillation who were treated with bepridil from January 2014 to December 2015 were enrolled in the study. Serum bepridil concentrations and electrocardiogram data collected more than 21 days after the initiation of bepridil were used for analysis. RESULTS: A total of 60 patients were included in this study. There was a significant difference in mean QTc interval before and after initiation of bepridil (p < 0.0001). A significant relationship was observed between bepridil dose (p = 0.014) or serum bepridil concentration (p < 0.001) and QTc interval. Additionally, a significant relationship was observed between serum bepridil concentration and ΔQTc (p = 0.034). In the study, 4 patients developed QTc prolongation ≥ 500 ms after the initiation of bepridil. Serum bepridil concentration in this group was significantly higher compared with the group that did not display prolonged QTc (973 ± 651 vs. 526 ± 310 ng/mL, p = 0.01). CONCLUSION: This study revealed that the QTc interval was significantly associated with serum bepridil concentration. Serum bepridil concentration beyond a therapeutic range may be a critical risk factor for developing QTc prolongation.


Assuntos
Síndrome do QT Longo , Torsades de Pointes , Bepridil/efeitos adversos , Eletrocardiografia , Humanos , Japão , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/diagnóstico , Estudos Retrospectivos , Torsades de Pointes/induzido quimicamente , Torsades de Pointes/diagnóstico
3.
J Pharmacol Sci ; 140(3): 310-312, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31492577

RESUMO

We tested whether genetic deletion of Cav3.2 T-type Ca2+ channels abolishes hydrogen sulfide (H2S)-mediated pain signals in mice. In Cav3.2-expressing HEK293 cells, Na2S, an H2S donor, at 100 µM clearly increased Ba2+ currents, as assessed by whole-cell patch-clamp recordings. In wild-type C57BL/6 mice, intraplantar and intracolonic administration of Na2S evoked mechanical allodynia and visceral nociceptive behavior, respectively, which were abolished by TTA-A2, a T-type Ca2+ channel blocker. In Cav3.2-knockout mice of a C57BL/6 background, Na2S caused neither somatic allodynia nor colonic nociception. Our study thus provides definitive evidence for an essential role of Cav3.2 in H2S-dependent somatic and colonic pain.


Assuntos
Canais de Cálcio Tipo T/genética , Canais de Cálcio Tipo T/metabolismo , Sulfeto de Hidrogênio/farmacologia , Dor Nociceptiva/metabolismo , Transdução de Sinais/efeitos dos fármacos , Dor Visceral/metabolismo , Animais , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Linhagem Celular , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Wistar , Canal de Cátion TRPA1/metabolismo
4.
Eur J Clin Pharmacol ; 74(7): 885-894, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29781049

RESUMO

PURPOSE: This study aimed to investigate relationships between times in therapeutic range (TTR) or warfarin sensitivity indexes (WSI) and VKORC1-1639G>A and CYP2C9 polymorphisms in patients with left ventricular assist devices (LVAD). METHODS: Severe heart failure patients who received LVAD from January 1, 2013 to October 31, 2017 were recruited. Relationships between TTR or WSI and VKORC1-1639G>A and CYP2C9 gene polymorphisms were investigated immediately after LVAD implantation (period 1) and immediately prior to hospital discharge (period 2). RESULTS: Among 54 patients, 31 (72.1%) had VKORC1-1639AA and CYP2C9*1/*1 (AA group) polymorphisms and 12 (27.9%) had VKORC1-1639GA and CYP2C9*1/*1 (GA group) polymorphisms. During period 1, mean prothrombin time-international normalized ratio (PT-INR) values were significantly higher in the AA group than in the GA group (2.21 vs. 2.05, p < 0.0001). Mean WSI values were 1.68-fold greater in the AA group than in the GA group (1.14 vs. 0.68, p < 0.0001). In addition, times below the therapeutic range (TBTR) in the GA group were significantly greater than in the AA group during period 1 (39.8 vs. 28.3%, p = 0.032), and insufficient PT-INR was more frequent in the GA group than in the AA group. However, mean PT-INR values during period 2 did not differ and no significant differences in TTR, TATR, and TBTR values were identified. In subsequent multivariable logistic regression analyses, the VKORC1-1639GA allele was significantly associated with insufficient anticoagulation. CONCLUSION: Patients with the VKORC1-1639GA and CYP2C9*1/*1 alleles may receive insufficient anticoagulation therapy during the early stages after implantation of LVAD, and VKORC1-1639G>A and CYP2C9 genotyping may contribute to more appropriate anticoagulant therapy after implantation of LVAD.


Assuntos
Anticoagulantes/uso terapêutico , Citocromo P-450 CYP2C9/genética , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/terapia , Coração Auxiliar , Vitamina K Epóxido Redutases/genética , Varfarina/uso terapêutico , Adulto , Povo Asiático/genética , Feminino , Genótipo , Ventrículos do Coração , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Resultado do Tratamento
5.
Int J Clin Pharmacol Ther ; 54(10): 795-803, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27443663

RESUMO

OBJECTIVE: The purpose of this study was to evaluate the long-term impact of therapeutic drug monitoring (TDM) services on the risk of hypoglycemia in cibenzoline therapy. In addition, we evaluated the impact of changes in clinical setting or patient background on the risk of hypoglycemia in patients receiving cibenzoline. METHODS: TDM services for cibenzoline have been performed at the Japan National Cerebral and Cardiovascular Center since March 1998. A case-control study was performed from September 2012 to February 2013, and the calculated risk of hypoglycemia associated with cibenzoline use was compared with data from our previous studies, which were performed ~ 15 years ago. RESULTS: A significantly increased risk for hypoglycemia was observed for users of cibenzoline (adjusted OR: 2.6; 95% CI: 1.5 - 4.7). In an additional analysis, the calculated risk was slightly reduced (adjusted OR; 2.1, 95% CI; 1.1 - 3.8) and hypertrophic obstructive cardiomyopathy (HOCM) was identified as a possible risk factor for hypoglycemia (adjusted OR: 4.7, 95% CI: 1.8 - 12.3). There was a significant difference in the mean level of cibenzoline between outpatients with and without HOCM (360.5 ± 166.9 ng/mL vs. 276.4 ± 136.3 ng/mL). An inverse relationship was observed between the percentage of outpatients whose cibenzoline serum level had been measured and their risk of hypoglycemia. CONCLUSIONS: Consistent TDM services for cibenzoline have contributed to a reduced risk of hypoglycemia associated with cibenzoline therapy. Patients with HOCM have a higher risk of developing hypoglycemia. Clinicians should therefore carefully monitor serum glucose levels in patients with HOCM taking cibenzoline.
.


Assuntos
Antiarrítmicos/efeitos adversos , Monitoramento de Medicamentos/métodos , Hipoglicemia/induzido quimicamente , Imidazóis/efeitos adversos , Adulto , Idoso , Antiarrítmicos/farmacocinética , Antiarrítmicos/uso terapêutico , Cardiomiopatia Hipertrófica/tratamento farmacológico , Estudos de Casos e Controles , Feminino , Humanos , Hipoglicemia/epidemiologia , Imidazóis/farmacocinética , Imidazóis/uso terapêutico , Japão , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores de Tempo
6.
J Arrhythm ; 33(5): 434-439, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29021846

RESUMO

BACKGROUND: The periprocedural protocol for atrial fibrillation (AF) ablation commonly includes anticoagulation therapy. Apixaban, a direct oral anticoagulant, is currently approved for clinical use; however, little is known about the effects of residual apixaban concentration on bleeding complications during/after AF ablation. Therefore, we measured residual apixaban concentration by using mass spectrometry and examined the anticoagulant's residual effects on bleeding complications. METHODS: Fifty-eight patients (Mean age of 64.7±12.5 years; 31 males, 27 females) were enrolled and administered apixaban twice daily. We analyzed trough apixaban concentration, activated clotting time (ACT), heparin dose, and bleeding complications during/after AF ablation. Apixaban concentrations were directly measured using mass spectrometry. RESULTS: Bleeding complications were observed in 19 patients (delayed hemostasis at the puncture site, 16; hematuria, 3; hemosputum, 1). No patient required blood transfusion. The mean trough apixaban concentration was significantly lower in patients with bleeding complications than without (152.4±73.1 vs. 206.8±98.8 ng/mL respectively, P=0.037), while the heparin dose to achieve ACT>300 s was significantly higher in patients with bleeding complications (9368.4±2929.0 vs. 7987.2±2135.2 U/body respectively, P=0.046). Interestingly, a negative correlation was found between the trough apixaban concentration and the heparin dose to achieve ACT>300 s (P=0.033, R=-0.281). CONCLUSIONS: Low residual plasma apixaban is associated with a higher incidence of bleeding complications during/after AF ablation, potentially because of a greater heparin requirement during AF ablation.

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