Relationship between serum bepridil concentration and corrected QT interval.

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.

Drug interactions between tacrolimus and clotrimazole troche: a data mining approach followed by a pharmacokinetic study.

PURPOSE: This study investigated the effects of clotrimazole troche on the risk of transplant rejection and the pharmacokinetics of tacrolimus. METHODS: The data mining approach was used to investigate whether the use of clotrimazole increased the risk of transplant rejection in patients receiving tacrolimus therapy. Patient data were acquired from the US Food and Drug Administration's Adverse Event Reporting System (FAERS) from the first quarter of 2004 to the end of 2017. Next, we retrospectively investigated the effect of clotrimazole troche on tacrolimus pharmacokinetics in seven patients who underwent heart transplantation between March and December 2017. RESULTS: The FAERS subset data indicated a significant association between transplant rejection and tacrolimus with clotrimazole [reporting odds ratio 1.92, 95% two-sided confidence interval (95% CI) 1.43-2.58, information component 0.81, 95% CI 0.40-1.23]. The pharmacokinetic study demonstrated a significant correlation between trough concentration (C0) and area under the concentration-time curve of tacrolimus after discontinuation of clotrimazole (R2 = 0.60, P < 0.05) but not before its discontinuation. Furthermore, the median clearance/bioavailability of tacrolimus after discontinuation of clotrimazole was 2.2-fold greater than that before its discontinuation (0.27 vs. 0.59 L/h/kg, P < 0.05). The median C0 decreased from 10.7 ng/mL on the day after discontinuation of clotrimazole to 6.5 ng/mL at 1 day and 5.3 ng/mL at 2 days after its discontinuation. CONCLUSION: Immediate dose adjustments of tacrolimus may be beneficial to avoid transplant rejection when clotrimazole troche is added or discontinued.

Effects of clotrimazole on tacrolimus pharmacokinetics in patients with heart transplants with different CYP3A5 genotypes.

PURPOSE: This study aimed to investigate the effects of clotrimazole on the pharmacokinetics of tacrolimus in Japanese patients with heart transplants with different CYP3A5 genotypes. METHODS: Twenty-six patients who underwent heart transplantation between June 2012 and July 2017 were enrolled in this retrospective study. The CYP3A5 (rs776746; CYP3A5*3) genotype was determined after monitoring and analysing tacrolimus blood concentrations. The pharmacokinetic profile of tacrolimus was examined before and after the discontinuation of clotrimazole and in patients with different CYP3A5 genotypes. RESULTS: The CYP3A5*1/*1, *1/*3 and *3/*3 genotypes were detected in 2, 8 and 16 patients, respectively. After clotrimazole was discontinued, the CYP3A5 expresser (CYP3A5*1/*1 or *1/*3) group had a 3.3-fold median increase in apparent oral clearance of tacrolimus (0.27 vs. 0.89 L/h/kg, P = 0.002) compared with the CYP3A5 non-expresser (CYP3A5*3/*3) group with a 2.2-fold median increase (0.18 vs. 0.39 L/h/kg, P < 0.0001). Significant correlations were observed between C0 and area under the concentration-time curve (AUC0-12) of tacrolimus after the discontinuation of clotrimazole in the CYP3A5 expresser and non-expresser groups, respectively (R2 = 0.49 and 0.42, all P < 0.05), but not before the discontinuation of clotrimazole. CONCLUSION: The effects of clotrimazole on tacrolimus pharmacokinetics in the CYP3A5 expresser patients were significantly greater than those in the CYP3A5 non-expresser patients. In addition, clotrimazole disturbed the correlation between C0 and AUC0-12 of tacrolimus. Careful dose adjustment of tacrolimus based on CYP3A5 genotypes may be beneficial for the patients with heart transplants who are concomitantly treated with clotrimazole.

Effects of vitamin K epoxide reductase complex 1 gene polymorphisms on warfarin control in Japanese patients with left ventricular assist devices (LVAD).

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.

Effect of fluconazole on the pharmacokinetics of everolimus and tacrolimus in a heart transplant recipient: Case report.

OBJECTIVE: Everolimus is an inhibitor of the mammalian target of rapamycin (mTOR) and has been used in combination with calcineurin inhibitors (tacrolimus and cyclosporine) to prevent allograft rejection following organ transplantation. In heart transplant recipients, everolimus should be maintained at a target blood concentration of 3 - 8 ng/mL, in combination with reduced-dose calcineurin inhibitors and therefore, requires strict monitoring. Fluconazole, an azole antifungal agent, affects blood concentration of tacrolimus by inhibiting the cytochromes P450 (CYP) 3A4 and 3A5. Therefore, to avoid overexposure during everolimus-azole cotreatment, the dose of everolimus should be reduced. However, the mechanism of interaction between everolimus and fluconazole remains unclear. CASE REPORT: We report the case of a heart transplant recipient who experienced a 2.8-fold increase in everolimus clearance and a 3.5-fold increase in everolimus dosage, following withdrawal of fluconazole therapy. The clearance and dosage of tacrolimus increased 4.7- and 3.0-fold, respectively. CONCLUSION: The concentrations of everolimus and tacrolimus should be carefully monitored when administered concomitantly with fluconazole to heart transplant recipients. The patient in this case had a CYP3A5*1/*3 genotype, and CYP3A5 constituted the metabolic pathway. Therefore, concomitant use of fluconazole might have a relatively small impact on everolimus and tacrolimus pharmacokinetics in this case.
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Body mass index is a useful predictor of prognosis after left ventricular assist system implantation.

BACKGROUND: The obesity paradox has recently attracted considerable interest in the study of many diseases. In this investigation we examine the relationship between body mass index (BMI) and prognosis after left ventricular assist system (LVAS) implantation. METHODS: We measured the BMI of 64 patients 3 months after LVAS implantation for end-stage heart failure. The patients were classified according to BMI into Group A (BMI <16 kg/m(2)), Group B (BMI 16 to 18.4 kg/m(2)) or Group C (BMI > or =18.5 kg/m(2)). We compared the prognosis among these three groups after a mean follow-up period of 583 days. RESULTS: Seven patients were weaned from their LVAS, 24 received heart transplantation, 25 died on the transplant waiting list, and 8 remain on the list. Long-term (>1 year) mortality was significantly higher in Group A than in Groups B and C (59% vs 40% and 18%, respectively; p < 0.05). The incidence of sepsis was also significantly higher in Group A than in Groups B and C (68% vs 45% and 32%, respectively; p < 0.05). After multivariate adjustment, BMI <16 kg/m(2) (hazard ratio [HR] 14.9; 95% confidence interval [CI] 2.61 to 86.0; p < 0.01) and levels of C-reactive protein (HR 1.56; 95% CI 1.15 to 2.13; p < 0.01) were independent predictors of mortality. CONCLUSIONS: A lower BMI indicated a poor prognosis, as well as a higher incidence of a fatal complication, sepsis, after LVAS implantation. Control of BMI could be an effective way to improve management of patients with LVAS.

Binding affinity of bunazosin, dorzolamide, and timolol to synthetic melanin.

PURPOSE: The purpose of this study was to compare the binding affinity of bunazosin and dorzolamide to synthetic melanin relative to that of timolol. METHODS: Synthetic melanin was prepared from dopa by the action of tyrosinase. Timolol, dorzolamide, and bunazosin were incubated separately at a concentration of 10(-4) M in 2 ml of 0.066 M phosphate buffer containing 5 mg of synthetic melanin. After centrifugation, the absorbance of each free drug in the supernatant was measured at its optimum wavelength. The percentage of each drug bound to melanin was calculated directly from the change in absorbance relative to the initial value. RESULTS: The increase in the binding rates of all three drugs seemed to reach a plateau after 30 min. After incubating for 60 min, the binding rate of timolol was 22.2% +/- 4.9%, bunazosin 36.3% +/- 2.5%, and dorzolamide 8.5% +/- 1.9%. There were statistically significant differences between the binding rates of each drug. CONCLUSIONS: Under our study conditions, the order of binding affinity of these ocular hypotensive agents to synthetic melanin seems to be as follows: bunazosin>timolol>dorzolamide.