Effect of mammalian-target-of-rapamycin inhibitors on the cancer risk in patients receiving calcineurin inhibitors: Data mining of a spontaneous reporting database.

OBJECTIVE: Calcineurin inhibitors (CNIs), including cyclosporine and tacrolimus, are associated with an increased cancer risk. However, whether mammalian target of rapamycin inhibitors (mTORis), including sirolimus and everolimus, decrease the cancer risk in patients receiving CNIs remains uncertain. We aimed to determine whether mTORis are associated with a decreased cancer risk in patients receiving CNIs using data mining of a spontaneous adverse reaction database. MATERIALS AND METHODS: Disproportionality analysis was conducted using the U.S. Food and Drug Administration Adverse Event Reporting System database (2004 - 2019) with reporting odds ratio and information component being used to indicate a signal. RESULTS: Data subset analyses indicated that sirolimus and everolimus were not associated with a decreased cancer risk in patients receiving cyclosporine or tacrolimus but were associated with an increased risk of nonmelanoma skin cancer (NMSC) and Kaposi's sarcoma. CONCLUSION: mTORis are not associated with a decreased cancer risk but are associated with a further increase in the risk of NMSC and Kaposi's sarcoma in patients receiving CNIs. Further studies are necessary to clarify the mechanism underlying the association between mTORis and NMSC or Kaposi's sarcoma.

Pharmacokinetics and pharmacodynamics of amiodarone in patients with hypertriglyceridemia: Two case reports.

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.

Polypharmacy Is Associated With Amiodarone-Induced Hypothyroidism.

Background: Amiodarone is rich in iodine, so in clinical practice amiodarone-induced hypothyroidism (AIH) is a major side effect. This drug is used in patients with arrhythmias, especially atrial fibrillation, the most common sustained arrhythmia. Polypharmacy, which can result in complex drug-drug interactions, occurs in more than 70% of the patients with atrial fibrillation. Therefore, polypharmacy may be involved in the expression of AIH. In this study, we investigated the association between polypharmacy and AIH. Methods: We conducted a retrospective study using data from January 2006 to May 2020 collected from a large, organized database of prescriptions constructed by the Japan Medical Information Research Institute, Inc. (Tokyo, Japan). To investigate the association between number of prescribed drugs with amiodarone and AIH, we divided patients into two groups: polypharmacy (≥ 5 prescribed drugs) and non-polypharmacy (< 5 prescribed drugs). We then performed a sequence symmetry analysis on the two groups: incident thyroxine after incident amiodarone and incident thyroxine before incident amiodarone. Finally, we conducted a case-control study on two further groups: those prescribed thyroxine after incident amiodarone (AIH group; n=555) and those not prescribed thyroxine after incident amiodarone (non-AIH group; n=6,192). Results: Sequence symmetry analysis revealed a significant association between amiodarone and thyroxine in both the polypharmacy and non-polypharmacy groups. The ranges for the adjusted sequence ratio in the two groups were 12.0-16.7 and 7.3-9.0, respectively. The case-control study showed that ≥5 prescribed drugs at the first prescription of amiodarone were found to significantly increase the odds of AIH (odds ratio: 1.48, 95% confidence interval: 1.18-1.84). Conclusion: Polypharmacy was suggested as an independent risk factor for AIH. Careful assessment of the appropriateness of prescription is warranted.

Relationship between polypharmacy and adverse events.

A retrospective data analysis was performed to investigate the association between polypharmacy and adverse events using three different spontaneous adverse event reporting system databases. Multivariate logistic regression analyses were performed to investigate the association between the number of drugs and adverse events, including hepatic disorders, renal disorders, hypersensitivity, and extrapyramidal syndrome. The results showed that the risk of hepatic and renal disorders increased with the number of drugs. Thus, decreasing the number of drugs may reduce the risk of hepatic and renal disorders. Furthermore, attention should be given to specific drugs that may cause hypersensitivity and extrapyramidal syndrome.

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.

Association Between Antipsychotics and Osteoporosis Based on Real-World Data.

BACKGROUND: Osteoporosis, which is a major public health concern, has been known to reduce health-related quality of life. Some studies have suggested that antipsychotics could perhaps cause osteoporosis by increasing serum prolactin levels. However, the association between antipsychotics and the risk for developing osteoporosis has been controversial. OBJECTIVE: The present study aimed to assess the association between antipsychotic use and onset of osteoporosis in real-world settings. METHODS: A multimethod data-mining approach using different algorithms and databases was used. First, disproportionality analysis was conducted using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database (2004-2017) with reporting odds ratio (ROR) and information component (IC) being used to indicate a signal. Furthermore, a sequence symmetry analysis using data from a large Japanese administrative claims database (2005-2017; JMDC Inc, Japan) was conducted. Short-term intervals (ie, 12, 24, and 36 months) were set to investigate the association between antipsychotic use and onset of osteoporosis using the adjusted sequence ratio (SR) to indicate a signal. RESULTS: No potential association between osteoporosis and all antipsychotics was observed in the FAERS database, except for perphenazine, which exhibited significant signals using both ROR and IC. Moreover, no potential association between osteoporosis and antipsychotics was observed in the JMDC claims database, except for sulpiride and aripiprazole. None of the antipsychotics indicated significant signals using all analyzed items (ROR, IC, and adjusted SR). CONCLUSION AND RELEVANCE: Real-world data show no association between antipsychotic use and the onset of osteoporosis. Further pharmacoepidemiological studies are needed for causality assessment.

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.

Inverse Association between Metformin and Amiodarone-Associated Extracardiac Adverse Events.

Background: The association between metformin and amiodarone-induced adverse events was examined using spontaneous adverse event database. Additionally, the association between other antidiabetic drugs and amiodarone-induced adverse events were also examined. Methods: A total of 6,153,696 reports from the first quarter of 2004 through the fourth quarter of 2015 were downloaded from the US Food and Drug Administration adverse event reporting system. Reporting odds ratio (ROR) and information component (IC) were used to detect associations between antidiabetic drugs and amiodarone-associated adverse events. Additionally, subset data analysis was performed to investigate whether the use of antidiabetic drugs further increased or decreased the risk of adverse events in patients receiving amiodarone therapy. Next, the RORs were adjusted for coadministered antidiabetic drugs using logistic regression analysis. Results: By whole dataset analysis, significant inverse associations were found between metformin and interstitial lung disease (ROR 0.84, 95% confidence interval [CI] 0.79-0.90; IC -0.24, 95% CI -0.33 to -0.15). In the subset data analysis, metformin (ROR 0.62, 95%CI 0.43-0.89; IC -0.63, 95%CI -1.14 to -0.11), sulfonylureas (ROR 0.53, 95%CI 0.32-0.85; IC -0.85, 95%CI -1.53 to -0.17), and dipeptidyl peptidase-4 (DPP-4) inhibitors (ROR 0.25, 95%CI 0.08-0.78; IC -1.66, 95%CI -3.08 to -0.23) were inversely associated with hyperthyroidism. Additionally, metformin (ROR 0.43, 95%CI 0.33-0.57; IC -1.09, 95%CI -1.49 to -0.69), sulfonylureas (ROR 0.64, 95%CI 0.48-0.86; IC -0.59, 95%CI -1.00 to -0.17), and DPP-4 inhibitors (ROR 0.47, 95%CI 0.27-0.81; IC -0.99, 95%CI -1.76 to -0.22) were inversely associated with interstitial lung disease. In the logistic regression analyses, DPP-4 inhibitors (adjusted ROR 0.32, 95% CI 0.10-1.00) and metformin (adjusted ROR 0.46, 95% CI 0.34-0.62) were inversely associated with amiodarone-associated hyperthyroidism and interstitial lung disease, respectively. Conclusion: Metformin is a candidate drug to reduce the risk of amiodarone-induced hyperthyroidism and interstitial lung disease.

Association between oral anticoagulants and osteoporosis: Real-world data mining using a multi-methodological approach.

Introduction: Warfarin and direct oral anticoagulants (DOACs) have been widely used in antithrombotic therapy. Although warfarin use has been suspected to be associated with osteoporosis risk, several studies have shown otherwise. Conversely, a few reports have found an association between DOACs and osteoporosis. This study therefore clarifies the association between oral anticoagulants and osteoporosis by analyzing real-world data using different methodologies, algorithms, and databases. Methods: Real-world data from the US Food and Drug Administration Adverse Event Reporting System (FAERS; 2004-2016) and Japanese administrative claims database (2005-2017; JMDC Inc., Tokyo) were used. Reporting odds ratio (ROR) and information component (IC) were calculated through disproportionality analysis (DPA) using reports recorded in the FAERS. Sequence symmetry analysis (SSA) was employed to calculate the adjusted sequence ratio (SR) using the JMDC Claims Database. For the adjusted SR and ROR, a significant signal was detected when the lower limit of the two-sided 95% confidence interval (CI) was more than 1. For the IC, a significant signal was detected when the lower limit of the 95% CI was more than 0. Results: DPA for warfarin found significant signals for osteoporosis in ROR (1.43, 95% CI: 1.32-1.54) and IC (0.50, 95% CI: 0.39-0.61). SSA showed a significant association between warfarin use and osteoporosis or bisphosphonate use. Moreover, a significant association was observed in males and females, albeit only for warfarin. Conclusion: Multi-methodological data mining revealed that warfarin use, not DOACs, is significantly associated with osteoporosis regardless of sex difference.

Polypharmacy in three different spontaneous adverse drug event databases.

OBJECTIVE: Polypharmacy has become a major problem in medical care worldwide, including in Japan. The purpose of this study was to investigate the current situation of polypharmacy using different spontaneous adverse drug event report databases. MATERIALS AND METHODS: A retrospective data analysis was performed using reports from 2007 to 2015 from three different spontaneous adverse drug event report databases: the Japanese Adverse Drug Event Report (JADER) constructed by the Pharmaceuticals and Medical Devices Agency in Japan, the US Food and Drug Administration (FDA) Adverse Drug Event Reporting System (FAERS) constructed by the FDA in the United States, and the Canada Vigilance Adverse Reaction Online Database (CVARD) constructed by the government of Canada. Polypharmacy trends during the study period were investigated. RESULTS: The mean numbers of drugs per report in the JADER, FAERS, and CVARD databases during the study period were 6.62, 3.76, and 3.44, respectively. The mean number of drugs per report increased with age in all three databases, with a peak at ages 70 - 79 years in all three databases (7.0 drugs for JADER, 4.7 drugs for FAERS, and 4.2 drugs for CVARD). CONCLUSION: Adverse event reports were more likely to develop in the patients treated through polypharmacy. Polypharmacy in Japan should be improved to prevent adverse events. Additionally, the patients aged ≥ 80 years tended to develop adverse events even if the number of prescribed drugs was relatively small. Therefore, polypharmacy should be noted in these patients to prevent adverse events.

Association between malignancy and methotrexate and biological disease-modifying antirheumatic drugs in patients with rheumatoid arthritis
.

OBJECTIVE: This study was aimed at investigating the risk of malignancies in rheumatoid arthritis patients treated with methotrexate (MTX), and whether the addition of biological disease-modifying antirheumatic drugs (bDMARDs) further increases the risk of malignancies in patients receiving MTX therapy, by using data from a spontaneous adverse reaction database. MATERIALS: Patient data from the U.S. Food and Drug Administration's Adverse Event Reporting System (FAERS) from the first quarter of 2004 to the end of 2015 were analyzed. METHODS: A data subset analysis was performed to investigate whether the use of bDMARDs further increased the risk of malignancies in patients receiving MTX therapy. RESULTS: MTX showed significant associations with all malignancies except liver cancer. bDMARDs showed significant associations with stomach cancer, colorectal cancer, prostate cancer, ovarian cancer, malignant melanoma, and lung cancer. In addition, bDMARD use increased the risk of breast, ovarian, and lung cancers in rheumatoid arthritis patients receiving MTX therapy. CONCLUSION: MTX use was significantly associated with various malignancies. Moreover, concomitant use of bDMARDs further increased the risk of breast, ovarian, and lung cancers in MTX-treated patients with rheumatoid arthritis.

Influence of co-initiation of antiulcer drugs on persistence and adherence to low-dose aspirin: A retrospective cohort study using a Japanese claims database
.

OBJECTIVE: The purpose of this study was to examine whether co-initiation of antiulcer drugs (AUDs) and low-dose aspirin (LDA) therapy is beneficial for good adherence to LDA therapy. MATERIALS AND METHODS: A retrospective cohort study was conducted using the JMDC claims database. Patients for whom LDA therapy was newly initiated between January 2005 and April 2016 were selected from the JMDC database. The selected patients were divided into LDA and LDA+AUD groups and were followed up from the first prescription of LDA or LDA+AUD until the earliest of the following events: discontinuation or the end of the observation period. Unadjusted and multivariable Cox proportional hazards models controlling for all demographic and clinical characteristics were applied to examine whether the addition of an AUD to LDA improved adherence. A 1 : 1 propensity score matching analysis was conducted to balance confounders between the two groups. RESULTS: After the propensity score matching analysis, 4,089 patients were matched in each therapy group. The Kaplan-Meier curves for the rate of LDA continuation showed a sharp decline just after the initiation of LDA therapy. A significant difference was observed in the incidence of LDA therapy discontinuation between the LDA+AUD and LDA groups (HR: 0.87, 95% CI: 0.82 - 0.92), and the median duration of LDA therapy in the LDA+AUD and LDA groups were 18 and 11 months (log-rank test: p < 0.0001), respectively. CONCLUSION: The therapy persistence rate in the LDA+AUD group was significantly higher than that in the LDA group.

Relationship between serum calcium and creatinine in hematopoietic stem cell transplantation patients treated with foscarnet
.

OBJECTIVE: The relationship between serum creatinine and calcium (Ca) was investigated in hematopoietic stem cell transplantation (HSCT) patients treated with foscarnet. MATERIALS AND METHODS: A retrospective study was performed to investigate the development of foscarnet-induced renal dysfunction in patients who received HSCT from April 2010 to November 2018 at the Kindai University Nara Hospital. A total of 80 patients were identified from the medical records, and 42 patients who met the inclusion criteria were enrolled in this study. Renal dysfunction was classified according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. RESULTS: A significant inverse relationship was observed between serum creatinine and Ca levels (r = -0.372; p < 0.0001; y = -0.537x + 9.268). A separate analysis divided into renal dysfunction and non-renal dysfunction groups showed that there was a significant relationship between serum creatinine and Ca levels in the renal dysfunction group (r = -0.531; p < 0.0001; y = -0.617x + 9.239) but not in the non-renal dysfunction group (r = -0.011; p = 0.561; y = -0.023x + 8.934). The optimal cutoff for the minimum Ca level was calculated to be 8.1 mg/mL. CONCLUSION: A significant inverse relationship was observed between serum creatinine and Ca levels in HSCT patients with foscarnet-induced renal dysfunction. Foscarnet-induced renal dysfunction should be noted if Ca levels fall below 8.1 mg/dL. Monitoring Ca levels may be useful for detecting renal dysfunction at early stages in patients treated with foscarnet.

Polypharmacy in elderly patients in Japan: Analysis of Japanese real-world databases.

WHAT IS KNOWN AND OBJECTIVE: Polypharmacy is associated with an increased risk of adverse drug reactions (ADRs) and drug interactions, decreased adherence to medication and increased medical cost. Recently, polypharmacy has become a major problem in medical care in Japan as a result of the increase in the ageing population. The purpose of this study was to investigate the current situation of polypharmacy and the association between polypharmacy and adverse events. METHODS: A retrospective data analysis was performed using two different real-world data from 2007 to 2015 in Japan. The Japanese Adverse Drug Event Report (JADER), a public spontaneous adverse drug reaction database constructed by the Pharmaceuticals and Medical Devices Agency (PMDA), and a large prescription database constructed by a database vendor (Japan Medical Information Research Institute, Inc Japan [JMIRI]) were analysed. Trends of polypharmacy during the study period were investigated. RESULTS AND DISCUSSION: The mean number of drugs per report in the JADER database and per prescription in the JMIRI databases during the study period ranged from 4.8 to 5.6 and 3.5 to 3.7, respectively. The mean number of drugs increased with age in both the JADER and JMIRI databases, and the peak of the mean number of drugs was at 80-89 years (5.74 drugs) in the JADER database and at 90-99 years (4.97 drugs) in the JMIRI database. WHAT IS NEW AND CONCLUSIONS: The number of drugs increased until age 90 years or more, even though adverse events are more likely to occur after the age of 80 in Japan. Therefore, polypharmacy in the elderly should be focused on the patients aged ≥80 years rather than patients aged ≥65 years from the viewpoint of the prevention of adverse events.

Time-to-onset analysis of amiodarone-associated thyroid dysfunction.

WHAT IS KNOWN AND OBJECTIVE: Amiodarone (AMD) treatment is associated with a number of significant adverse effects including thyroid dysfunction. However, the relationship between the development of thyroid dysfunction and the dosage and treatment duration of AMD remains unclear. The purpose of this study was to examine the onset profiles of amiodarone-associated thyroid dysfunction using a spontaneous adverse drug reaction (ADR) reporting database. METHODS: Data were obtained from the US Food and Drug Administration Adverse Event Reporting System (FAERS). For signal detection of spontaneous ADRs, the reporting odds ratio (ROR) and information component (IC) were calculated. Cumulative incidences of hyperthyroidism and hypothyroidism were assessed using the Kaplan-Meier method, and time-to-onset profiles were analysed using the Weibull shape parameter (WSP) test. RESULTS AND DISCUSSION: The median time-to-onset of hyperthyroidism associated with AMD and other drugs was 720.0 (range: 225.5-1145.0) and 101.5 (range: 14.0-468.8) days, respectively. Patients treated with AMD showed a significantly longer time-to-onset of hyperthyroidism than those treated with other drugs (P < .001). The median time-to-onset of hypothyroidism associated with AMD and other drugs was 183.0 (range: 35.0-727.8) and 153.0 (range: 19.0-608.0) days, respectively. There was no significant difference in the time-to-onset of hypothyroidism between patients treated with AMD and those treated with other drugs (P = .13). For hyperthyroidism, the WSP test showed that AMD had a wear-out failure-type profile and other drugs had early failure-type profiles. For hypothyroidism, the WSP test showed that both AMD and other drugs had early failure-type profiles. WHAT IS NEW AND CONCLUSIONS: Amiodarone-associated hyperthyroidism had a different onset profile than hyperthyroidism associated with other drugs. Because the time-to-onset of AMD-associated hyperthyroidism is widely distributed, sustained and continuous attention is required to detect and treat hyperthyroidism during AMD treatment. In contrast, AMD-associated hypothyroidism had an onset profile that was similar to that of other drugs, suggesting that attention should be focused on the earlier stages of treatment.

Genetic deletion of Cav3.2 T-type calcium channels abolishes H2S-dependent somatic and visceral pain signaling in C57BL/6 mice.

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.

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.

Adherence to guidelines for antiulcer drug prescription in patients receiving low-dose aspirin therapy in Japan.

OBJECTIVE: Prevalence of guideline adherence for antiulcer drug prescription in patients receiving low-dose aspirin (LDA) therapy was examined and the association of risk factors with the adherence was assessed. MATERIALS AND METHODS: A retrospective cohort study using a population-based longitudinal healthcare database was conducted. Claims data between January 2005 and April 2016 were analyzed. A total of 3,079 patients were included in the study. The selected patients taking LDA were divided into two categories: those taking and those not taking antiulcer drugs in an inpatient setting. Additionally, they were classified into four groups according to the time antiulcer therapy was initiated. The risk factors for ulcer, such as history of gastrointestinal injuries; age ≥ 65 years; and concomitant use of anticoagulants, antiplatelets, oral corticosteroids, and nonsteroidal anti-inflammatory drugs except aspirin, were assessed. RESULTS: A total of 3,079 patients were included in the study. The rate of LDA patients using antiulcer drugs was 65.2%, with the strongest single factor associated with the use of antiulcer drugs being the concomitant use of corticosteroids. Among the LDA patients not taking antiulcer drugs, 66.8% had more than one risk factor. Irrespective of the use of concomitant treatment with antiulcer drug prior to hospital admission, 78.3% of the LDA patients continued their home regimen after hospital admission. CONCLUSION: Our results showed that the requirement of antiulcer therapy is not routinely evaluated at hospital admission, and antiulcer drugs for patients with ulcer risks are under-prescribed. Developing strategies to screen gastrointestinal risk factors at hospital admission is required to improve the guideline adherence for LDA-induced ulcer.

Risk of malignant lymphoma in patients with rheumatoid arthritis treated with biological disease-modifying antirheumatic drugs and methotrexate
.

OBJECTIVE: This study investigated whether using biological disease-modifying antirheumatic drugs (bDMARDs) further increases the risk of malignant lymphoma in patients with rheumatoid arthritis undergoing methotrexate therapy using spontaneous adverse reaction databases in different countries. MATERIALS AND METHODS: Patient data were acquired from the US Food and Drug Administration's Adverse Event Reporting System (FAERS), the Japanese Adverse Drug Event Report (JADER), and the Canada Vigilance Adverse Reaction Online Database (CVARD) from the first quarter of 2004 to the end of 2015. Data subset analysis was performed to investigate whether the use of bDMARDs further increased the risk of malignant lymphoma in patients receiving methotrexate therapy. RESULTS: The FAERS subset data indicated a significant association between Hodgkin lymphoma and methotrexate with infliximab (reporting odds ratio (ROR): 8.28. 95% CI: 5.70 - 12.02; information component (IC): 2.04, 95% CI: 1.59 - 2.49). In addition, signal scores suggested that methotrexate with infliximab (ROR: 3.26. 95% CI: 2.68 - 3.98; IC: 1.31, 95% CI: 1.04 - 1.58) was significantly associated with non-Hodgkin lymphoma (NHL). The CVARD subset data also indicated a significant association between NHL and methotrexate with infliximab (ROR: 22.82. 95% CI: 5.02 - 103.78; IC: 1.77, 95% CI: 0.13 - 3.41). However, the JADER subset data revealed no significant associations. CONCLUSION: The present study shows that using infliximab further increases the risk of malignant lymphoma in patients receiving methotrexate therapy.
.

Voriconazole trough concentration and hepatotoxicity in patients with low serum albumin
.

OBJECTIVE: We aimed to investigate the relationship between voriconazole (VRCZ) trough concentrations and hepatotoxicity and to evaluate whether the recommended trough concentration is adequate in our clinical setting. MATERIALS AND METHODS: A retrospective study was performed to investigate the relationship between serum VRCZ concentrations and the development of hepatotoxicity at the Kindai University Nara Hospital. Patients treated with VRCZ from March 2010 to January 2018 were identified from the medical records. A total of 42 patients (mean age of 61.9 ± 16.9 years; 33 males and 9 females) were enrolled in this study. RESULTS: Hepatotoxicity developed in 28.6% (12/42) of patients treated with VRCZ, and 91.7% (11/12) of these patients developed hepatotoxicity within 3 weeks after initiating the treatment. Significantly increased aspartate aminotransferase (AST; p < 0.001), alkaline phosphatase (ALP; p < 0.001), and alanine aminotransferase (p = 0.001) levels were observed after the initiation of VRCZ therapy. In addition, significant positive correlations between AST and VRCZ trough concentrations (p = 0.017) and between ALP and VRCZ trough concentrations (p = 0.012) were observed. VRCZ trough concentration was identified as a significant independent risk factor for hepatotoxicity (adjusted odds ratio: 1.611, 95% confidence interval: 1.131 - 2.579, p = 0.006), and the cutoff serum trough concentration was calculated to be 4.2 µg/mL. CONCLUSION: VRCZ-induced hepatotoxicity should be noted in the early stages of therapy. A sustained VRCZ trough concentration of ~ < 4.2 µg/mL is recommended to prevent hepatotoxicity in patients with low serum albumin levels.