Predictors of olaparib discontinuation owing to adverse drug events in patients with ovarian, peritoneal, or fallopian tube cancer: a retrospective observational study.

We investigated predictors of olaparib discontinuation owing to adverse effects. Patients with ovarian, peritoneal, or fallopian tube cancers treated with olaparib at Osaka Medical and Pharmaceutical University Hospital between April 2018 and September 2022 were included in this study. The exclusion criteria were as follows: discontinuation of treatment due to disease progression, use of anaemia medications, and use of cytochrome P450 (CYP3A4) inhibitors. The follow-up period was 90 d. Of the 46 eligible patients, 21 patients discontinued olaparib, including 15 patients with grade 3 or higher anaemia, eight patients with grade 3 or higher neutropenia, and four patients with non-haematological toxicity (including multiple onset). Multivariate logistic regression analysis showed that grade 4 neutropenia and anaemia progression to grades 2-3 due to chemotherapy administered before olaparib administration were predictors of olaparib discontinuation. The severity of neutropenia and anaemia due to chemotherapy before olaparib administration may be a potential marker for its discontinuation.

Association between sodium-glucose cotransporter 2 inhibitors and pancreatic cancer in the Japanese working-age population.

OBJECTIVE: Pancreatic cancer-related mortality is increasing worldwide, and prevention methods and effective novel therapies are required. In pancreatic cancer, sodium-glucose cotransporters (SGLT) are involved in glucose uptake. This study aimed to clarify the association between SGLT2 inhibitors and pancreatic cancer development. MATERIALS AND METHODS: A nested case-control study was conducted using the JMDC administrative claims database (January 2005 to June 2020). Patients newly diagnosed with type 2 diabetes mellitus (T2DM) were included, and cases were defined as patients who developed pancreatic cancer. Patients with outcomes were randomly matched to a maximum of 20 controls according to age (± 5 years), sex, and calendar date (month and year) of the first T2DM diagnosis through risk set sampling. RESULTS: Of the 181,107 T2DM patients, 363 cases and 7,043 controls were selected with 14 and 457 patients prescribed SGLT2 inhibitors, respectively. Cumulative administration of SGLT2 inhibitors for > 180 days was significantly inversely associated with the development of pancreatic cancer (adjusted odds ratio: 0.58, 95% confidence interval: 0.31 - 0.99). CONCLUSION: SGLT2 inhibitors may reduce the risk of developing pancreatic cancer in T2DM patients. The number of patients over 65 years of age was small in this study due to the nature of the data source. Further studies with larger sample sizes including older patients are needed.

Association between statin use and open-angle glaucoma: a nested case-control study using the Japanese claims database.

The association between statins and open-angle glaucoma (OAG) remains controversial. This study investigated the relationship between statins and OAG in Japanese patients with dyslipidemia using the Japanese administrative claims database. A nested case-control study using two models was conducted using the JMDC claims database (01/2005-01/2020). The onset of OAG: index date was defined as the diagnosis of glaucoma, prescription of anti-glaucoma drugs, or surgery of glaucoma. For each case, a maximum of 10 age-, sex-, and calendar year/month-matched controls were randomly selected by risk-set sampling with replacement. The number of statin prescriptions during the exposure assessment period, which was identified as the 12-month (model 1) or 24-month (model 2) periods prior to the index date, was used as an indicator for statin exposure. Adjusted odds ratios (aORs) and 95% confidence interval (CI) were estimated using conditional logistic regression analyses. We identified 375,373 patients with newly diagnosed dyslipidemia. Of these, 6180 cases and 61,792 controls (model 1) and 4153 cases and 41,522 controls (model 2) were selected. Statin use was not identified as a significant risk factor for OAG (model 1: aOR 0.98, 95% CI 0.93-1.03, model 2: aOR 0.97, 95% CI 0.91-1.04). Compared with nonexposure, short-term exposure (< 2 years) to statins was not related to an increased risk of OAG in the Japanese working-age population with dyslipidemia.

Platelet count and dose, but not comorbidities, predict severe neutropenia in cabazitaxel-treated prostate cancer patients: A retrospective observational study.

OBJECTIVE: To determine the safety of cabazitaxel and predictors of severe neutropenia caused by cabazitaxel in a patient population that includes those with comorbidities. MATERIALS AND METHODS: Of 42 prostate cancer patients treated with cabazitaxel at Osaka Medical and Pharmaceutical University Hospital between September 2014 and June 2022, 33 were included in this study, whereas 6 patients who were outpatients and 3 who were discharged early within 7 days upon patient request were excluded. Logistic regression analysis was used to examine predictors of severe neutropenia. RESULTS: Of the 33 eligible patients, 24 had comorbidities, with hypertension being the most common (n = 19), followed by dyslipidemia (n = 14) and diabetes (n = 11). There was no statistically significant difference in the rate of severe neutropenia due to any of the comorbidities, depending on the presence or absence of the comorbidity. However, the rate of severe neutropenia was significantly higher in patients with baseline platelet levels < 22.4×104/µL and those receiving cabazitaxel doses > 34 mg/body. In the final model adjusted for age, body mass index, C-reactive protein, and monocyte count, lower baseline platelet levels and higher doses of cabazitaxel were also predictors of the development of severe neutropenia. CONCLUSION: Comorbidities such as hypertension, dyslipidemia, diabetes mellitus, cerebrovascular disease, chronic kidney disease, liver dysfunction, and cardiac disease did not affect the incidence of severe neutropenia in patients receiving cabazitaxel. The baseline platelet count and the dose of cabazitaxel were also suggested to be markers for the development of severe neutropenia.

[Utilization of Big Data with a Focus on Administrative Claims Database].

With the development of information technology, patient information is stored as electronic data, and huge amounts of such data are collected every day. Such a collection compiled over the course of clinical practice is called real-world data and is expected to be used for evaluating drug efficacy and safety. Real-world data such as health insurance association-based administrative claims databases, pharmacy-based dispensing databases, and spontaneous reporting system databases are mainly used in pharmaceutical research. Among them, claims databases are used for various observational studies such as studies on nationwide prescription trends, pharmacovigilance studies, and studies on rare diseases due to their large sample size. Although the nature of omics data is different from that of real-world data, it has become accessible on cloud platforms and are being used to broaden the scope of research in recent years. In this paper, we introduce a method for generating and further testing hypotheses through integrated analysis of real-world data and omics data, with a focus on administrative claims databases.

Association between hemorrhage and direct oral anticoagulants in combination with verapamil: Analysis of Japanese Adverse Drug Event Report database and electronic medical record data.

OBJECTIVE: The aim of this study was to investigate the risk of hemorrhage in concomitant therapy with direct oral anticoagulants (DOACs) and class IV antiarrhythmic drugs. MATERIALS AND METHODS: First, disproportionality analysis (DPA) was performed using the Japanese Adverse Drug Event Report (JADER) database to investigate the risk of hemorrhage with DOACs. Second, a cohort study was performed using electronic medical record data to confirm the results of the JADER analysis. RESULTS: In the JADER analysis, hemorrhage was significantly associated with treatment with edoxaban and verapamil (reporting odds ratio = 1.66; 95% confidence interval (CI) = 1.04 - 2.67). The cohort study revealed that hemorrhage incidence significantly differed between the verapamil-treated group and the bepridil-treated group, with a higher risk for hemorrhage in the verapamil group (log-rank test: p < 0.001). The multivariate Cox proportional hazards model also showed that the verapamil and DOAC combination was significantly associated with hemorrhage events compared with the bepridil and DOAC combination (hazard ratio (HR): 2.87, 95% CI: 1.17 - 7.07, p = 0.022). Furthermore, creatinine clearance (Ccr) ≥ 50 mL/min was significantly associated with hemorrhage events (HR: 2.72, 95% CI: 1.03 - 7.18, p = 0.043), and verapamil was significantly associated with hemorrhage in patients with Ccr ≥ 50 mL/min (HR: 3.58, 95% CI: 1.36 - 9.39, p = 0.010) but not in patients with Ccr < 50 mL/min. CONCLUSION: Verapamil increases the risk of hemorrhage in patients on DOACs. Dose adjustment of DOACs based on renal function may prevent hemorrhage when verapamil is concomitantly administered.

Trends in tolvaptan prescription and the association between hypernatremia and aging in tolvaptan-treated patients in Japan: Real-world data mining using Japanese databases.

OBJECTIVE: To identify the trends in tolvaptan prescription and the association between aging and tolvaptan-induced hypernatremia. MATERIALS AND METHODS: A health insurance claims database and a spontaneous adverse drug reaction database were used. RESULTS: Of all patients who had been prescribed tolvaptan, the proportion of patients aged 60 - 79 years and ≥ 80 years was consistent at ~ 40%. Moreover, the prescription frequency of tolvaptan increased over time for patients in the same age groups. The adjusted reporting odds ratio of tolvaptan-induced hypernatremia was 5.54 (95% confidence interval, 3.31 - 9.25) in patients aged ≥ 60 years from among all patients and 2.09 (95% confidence interval, 1.59 - 2.75) in those aged ≥ 80 years from among those aged ≥ 60 years. CONCLUSION: It may be necessary to be aware of hypernatremia in elderly patients who are expected to have increased prescriptions of tolvaptan.

Association of Statin Adherence With the Development of Nonalcoholic Fatty Liver Disease: A Nested Case-Control Study Using a Japanese Claims Database.

BACKGROUND: Statins are expected to have beneficial effects on nonalcoholic fatty liver disease (NAFLD); however, evidence remains insufficient. OBJECTIVE: In this study, we aim to investigate the association between statin adherence and NAFLD development. METHODS: We conducted a nested case-control study of statin users using the Japan Medical Data Center administrative claims database (January 2005 to January 2020). Individuals who developed NAFLD were designated as cases. For each case, we randomly selected a maximum of 10 controls using risk set sampling. Good adherence was defined as the proportion of days covered (PDC) of ≥0.80. Higher intensity was defined as the median or higher of a cumulative defined daily dose (cDDD) per day covered by statin prescription. Conditional logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: In this study, 253 383 patients with the first statin prescription were identified. Of them, 7080 were selected and matched to 70 734 controls. The medians of PDC and intensity were 0.88 (interquartile range [IQR], 0.61-0.96) and 0.32 (IQR, 0.25-0.50) cDDD/day, respectively. Good adherence was significantly associated with a reduced risk of NAFLD development (adjusted OR, 0.82; 95% CI, 0.78-0.86). Higher intensity was not significantly associated with a reduced risk of NAFLD development (adjusted OR, 1.02; 95% CI, 0.97-1.08). CONCLUSION AND RELEVANCE: Good adherence to statins is associated with a reduced risk of NAFLD development, regardless of the statin intensity. Appropriate statin therapy could reduce the risk of NAFLD development.

Effect of storage temperature on the dispersibility of commercially available 0.1% fluorometholone ophthalmic suspension.

In this study, we focused on the storage conditions and investigated the effects of low-temperature storage (10°C) on the dispersibility of active components in three formulations of fluorometholone (FLU) suspension eye-drops (one original drug and two generic drugs, P1-P3). For all three eye-drop products, before shaking by hand, white sediment anticipated to be the principal active component was seen at the vial base. In the ordinary-temperature storage group, the FLU contents per drop after shaking by hand were 0.076% in P1, 0.023% in P2, and 0.100% in P3, and the content in P2 was significantly lower than that in P1 and P3. In contrast, almost no dispersion was observed in the low-temperature group. The results after sufficient shaking of these samples with a vortex, in contrast, were such that the FLU contents per drop were 0.063% in P1, 0.086% in P2, and 0.088% in P3; the content in P1 was significantly lower than that in P2 and P3, and there was no difference between P2 and P3. Moreover, we evaluated the dispersibility according to the evaluation "Vs / (ρg - ρf) g." In both the low- and ordinary-temperature storage groups, the value of Vs / (ρg - ρf) g, proportional to the terminal velocity, decreased in the following order: P3 > P1 ≫ P2, and each value in the ordinary-temperature was higher than that in low temperature. The zeta potential decreased in the following order: P2 > P3 ≫ P1. In conclusion, when FLU suspension eye drops are stored at low temperatures until use, such as in a refrigerator, ordinary shaking does not help achieve dispersion to the specified concentration, and even with vigorous shaking with some formulations, the specified concentration cannot be achieved.

Adverse event profiles of microscopic colitis in the Japanese Adverse Drug Event Report (JADER) database.

Microscopic colitis (MC) is a chronic inflammatory bowel disease that is characterized by nonbloody watery diarrhea. The epidemiology in Japan differs from that in Europe and the United States, but little information is available from epidemiological surveys of MC in Japan. This study aimed to provide a new hypothesis regarding the factors associated with MC by using the Japanese Adverse Drug Event Report (JADER) database. "Colitis microscopic" (preferred term code: 10056979) cases entered into the JADER database between 2004 and 2021 were analyzed. Of the 246,997 cases in the JADER database, 161 cases were observed to be associated with MC. A Weibull analysis revealed that the median onset duration of MC (interquartile range) was 72.5 (36.0‒125.5) days in lansoprazole users and 116.0 (60.3‒1089.0) days in aspirin users. A multiple logistic regression analysis revealed that MC was significantly associated with the female sex, as well as ages ≥ 60 years and drugs including lansoprazole, aspirin, and nicorandil. A subset analysis revealed that MC was positively associated with obesity in female cases. Our study cannot demonstrate a causal inference between MC and each drug; however, the findings suggest that MC was associated with nicorandil as well as with lansoprazole and aspirin.

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.

Impact of Medication Adherence on the Association Between Oral Anticoagulant Use and Risk of Dementia: A Retrospective Cohort Study using the Japanese Claims Database.

BACKGROUND: Atrial fibrillation (AF) is a major risk factor for the development of stroke and silent cerebral infarct (SCI). Additionally, AF is independently associated with neurological disorders, including cognitive impairment and dementia. Although oral anticoagulants (OACs) are used to reduce the risk of development of stroke and SCI in patients with AF, it is unclear whether OACs reduce the risk of dementia. OBJECTIVE: This study aimed to investigate the association between OAC use and dementia in relatively young patients with AF. Moreover, the impact of medication adherence on the association between OAC use and the risk of dementia was examined. PATIENTS AND METHODS: This retrospective cohort study was conducted using a large claims database-Japan Medical Data Center, Inc. (JMDC)-from which newly diagnosed patients with AF younger than 75 years of age were identified. We analyzed medication adherence using the medication possession ratio (MPR). The dementia risk was compared between the OAC and non-OAC groups using Cox proportional hazards regression analysis and the Kaplan-Meier method after propensity score matching. Similarly, the MPR-classified and non-OAC groups were also compared. RESULTS: OAC administration was not associated with the risk of dementia in the entire cohort (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.40-1.08; p = 0.098); however, OAC administration in patients with an MPR ≥90% was significantly associated with a lower risk of dementia (HR 0.45, 95% CI 0.25-0.81; p = 0.008). Meanwhile, direct OAC (DOAC) and warfarin (WF) administration was not associated with the risk of dementia regardless of MPR. Kaplan-Meier analysis revealed a significant difference in the incidence of dementia between the MPR ≥ 90% OAC and non-OAC groups (log-rank test: p = 0.006). However, no difference was observed in the incidence of dementia between the MPR ≥ 90% WF and non-OAC groups, or between the MPR ≥ 90% DOAC and non-OAC groups. CONCLUSIONS: OAC administration was not associated with the risk of dementia in relatively young patients with AF; however, when limited to patients with an MPR ≥ 90%, OAC administration reduced the risk of dementia. Our results suggest that the association between OAC use and dementia should be evaluated while considering medication adherence.

Identification of Remaining Life Expectancy Less Than Two Weeks by C-Reactive Protein/Albumin Ratio, Prognostic Nutritional Index, Fibrosis-4 Index, and Albumin-Bilirubin Score in Terminal Cancer Patients.

Background: Accurate prognosis in terminal cancer patients is useful to improve their quality of life and also to decide the cessation of fluid administration. Nonetheless, few prognostic indicators are available for prediction of such a short-term life expectancy. Objectives: The present study aimed at evaluating the efficacy of C-reactive protein (CRP)/albumin (CRP/Alb) ratio, prognostic nutritional index (PNI), fibrosis-4 (FIB-4) index, and albumin-bilirubin (ALBI) score in identifying terminal cancer patients who have a life expectancy less than two weeks. Design: Retrospective study. Setting/Subjects: Of 483 patients who died between April 2019 and March 2020 at a single center in Japan, 102 who met the inclusion criteria were enrolled in this study. Measurements: CRP/Alb, PNI, FIB-4, and ALBI were calculated from the laboratory data collected 1-13, 14-27, 28-83, and 168-365 days before death and subjected to statistical analyses. Results: CRP/Alb, PNI, FIB-4, and ALBI values were significantly associated with the time before death during terminal 365 days. CRP/Alb ≥4.4, PNI <30, FIB-4 ≥ 9.4, and ALBI ≥ -1.26 were significantly associated with the transition from the first half to the second half of terminal four weeks. Of those prognostic indicators, three and four combinations provided significantly reliable estimation of a life expectancy less than two weeks. Conclusions: CRP/Alb, PNI, FIB-4, ALBI, and their combinations are considered to help identify cancer patients who have a life expectancy less than two weeks, which is useful to make appropriate end-stage treatment decisions, for example, cessation of artificial hydration therapy.

Treatment strategy of oxaliplatin-induced peripheral neuropathy: a retrospective, nationwide study.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse event of cancer treatment; however, no drug is recommended for the prevention of CIPN. In Japan, several drugs such as Gosha-Jinki-Gan and duloxetine are frequently administered as a treatment for CIPN. The aim of this study was to elucidate prescription patterns of drugs administered for CIPN caused by oxaliplatin and the association between these drugs and the duration of oxaliplatin treatment. METHODS: We conducted a retrospective nationwide study using the JMDC administrative claims database (January 2005-June 2020; JMDC Inc., Japan). Patients newly treated with oxaliplatin were identified, and prescription patterns of CIPN medication including Gosha-Jinki-Gan, pregabalin, duloxetine, mecobalamin, and mirogabalin were investigated. The primary outcome was the duration of oxaliplatin treatment. Multivariable logistic regression analysis was performed to examine the association between CIPN medication and duration of oxaliplatin treatment. RESULTS: A total of 4,739 patients who newly received oxaliplatin were identified. Of these, 759 (16.0%) had received CIPN medication. Duloxetine was administered in 99 (2.1%) patients. Multivariable logistic regression analysis revealed that CIPN medication was significantly associated with the prolonged duration of oxaliplatin treatment (odds ratio: 2.35, [95% confidence interval: 1.99-2.77]). CONCLUSION: Real-world data demonstrated that the administration rate of CIPN medication was higher in patients who received oxaliplatin treatment for over 6 months.

Repurposing haloperidol for the treatment of rheumatoid arthritis: an integrative approach using data mining techniques.

INTRODUCTION: Treatment of rheumatoid arthritis (RA) has advanced with the introduction of biological disease-modifying antirheumatic drugs. However, more than 20% of patients with RA still have moderate or severe disease activity. Hence, novel antirheumatic drugs are required. Recently, drug repurposing, a process of identifying new indications for existing drugs, has received great attention. Furthermore, a few reports have shown that antipsychotics are capable of affecting several cytokines that are also modulated by existing antirheumatic drugs. Therefore, we investigated the association between antipsychotics and RA by data mining using real-world data and bioinformatics databases. METHODS: Disproportionality and sequence symmetry analyses were employed to identify the associations between the investigational drugs and RA using the US Food and Drug Administration Adverse Event Reporting System (2004-2016) and JMDC administrative claims database (January 2005-April 2017; JMDC Inc., Tokyo, Japan), respectively. The reporting odds ratio (ROR) and information component (IC) were used in the disproportionality analysis to indicate a signal. The adjusted sequence ratio (SR) was used in the sequence symmetry analysis to indicate a signal. The bioinformatics analysis suite, BaseSpace Correlation Engine (Illumina, CA, USA) was employed to explore the molecular mechanisms associated with the potential candidates identified by the drug-repurposing approach. RESULTS: A potential inverse association between the antipsychotic haloperidol and RA, which exhibited significant inverse signals with ROR, IC, and adjusted SR, was found. Furthermore, the results suggested that haloperidol may exert antirheumatic effects by modulating various signaling pathways, including cytokine and chemokine signaling, major histocompatibility complex class-II antigen presentation, and Toll-like receptor cascade pathways. CONCLUSION: Our drug-repurposing approach using data mining techniques identified haloperidol as a potential antirheumatic drug candidate.

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.

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.

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.