Exploring the Mechanisms Underlying Drug-Induced Fractures Using the Japanese Adverse Drug Event Reporting Database

Fractures occur when bones become fragile and are subjected to external forces as occurring during falls. The use of drugs that increase bone fragility or fall risk increases the risk of fracture. This study investigates drug-induced fractures reported in the Japanese Adverse Drug Event Report (JADER) database in patients using 4892 drugs. Atypical femur fracture was the most frequently reported fracture, and 58 other fractures were also reported. Using Volcano plots and multiple logistic regression analysis, we identified the risk factors for drug-induced fractures as being female, of older age, higher body mass index, and using one of 90 drugs. The drug groups significantly associated with drug-induced fractures included bone resorption inhibitors, antiviral drugs, dopaminergic drugs, corticosteroids, and sleep sedatives. Principal component analysis was used to examine the relationship between the use of specific drugs and the site of drug-induced fracture. Bone resorption inhibitors and corticosteroids were associated with atypical femur fractures, jaw fractures, and ulna fractures through an osteoclast-mediated process. Other drugs were found to increase fracture risk via non-osteoclast-mediated mechanisms. These findings suggest that many drugs can result in drug-induced fractures through a variety of mechanisms.

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Evaluation of the Expression Profile of Antibiotic-Induced Thrombocytopenia Using the Japanese Adverse Drug Event Report Database

International Journal of Toxicology ◽

10.1177/10915818211048151 ◽

2021 ◽

pp. 109158182110481

Author(s):

Yuki Asai ◽

Takanori Yamamoto ◽

Yasuharu Abe

Keyword(s):

Adverse Drug Event ◽

Shape Parameter ◽

Expression Profiles ◽

Oral Treatment ◽

Multiple Logistic Regression Analysis ◽

Drug Event ◽

Reporting Odds Ratio ◽

Event Report ◽

Drug Induced ◽

Male Sex

Drug-induced thrombocytopenia (DITP) can be triggered by antibiotics; however, the details remain unclear. Here, we evaluated the expression profiles of DITP using the Japanese Adverse Drug Event Report (JADER) database. We analyzed reports of DITP between April 2004 and January 2021 from the JADER database. The reporting odds ratio (ROR) and 95% confidence interval (CI) were used to detect DITP signals. Factors thought to affect DITP, such as male sex and an age of at least 60 years, were added as covariates. We evaluated the time-to-onset profile and hazard type using the Weibull shape parameter. The JADER database contained 1,048,576 reports. Twelve of 60 antibiotics showed signals for DITP; the RORs (95% CIs) for ampicillin/sulbactam, ceftazidime, cefozopran, ciprofloxacin, fluconazole, fos-fluconazole, linezolid, pazufloxacin, piperacillin/tazobactam, teicoplanin, trimethoprim/sulfamethoxazole, and voriconazole were 1.75 (1.41-2.16), 1.77 (1.42-2.18), 1.35 (1.06-1.72), 2.56 (2.19-2.98), 1.93 (1.67-2.23), 2.08 (1.76-2.46), 5.29 (2.73-9.60), 1.92 (1.51-2.41), 1.54 (1.05-2.19), 1.47 (1.16-1.84), 1.92 (1.73-2.14), and 2.32 (1.59-3.30), respectively. In multiple logistic regression analysis, 7 and 6 antibiotics were detected for the factors age and male sex, respectively. The median times-to-onset of DITP for ciprofloxacin (oral treatment), fluconazole, linezolid, piperacillin/tazobactam, and trimethoprim/sulfamethoxazole were 91, 91, 11.5, 10, and 9 days, respectively. Furthermore, the 95% CI of the Weibull shape parameter β for these antibiotics was above and excluded 1, indicating that the antibiotics were the wear out failure type. We revealed the expression profiles of DITP following treatment with 12 antibiotics.

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Comprehensive Analysis of Antibiotic-induced Agranulocytosis Using the Japanese Adverse Drug Event Report Database

10.22541/au.161839221.10007524/v1 ◽

2021 ◽

Author(s):

Yuki Asai ◽

Takanori Yamamoto ◽

Yasuharu Abe

Keyword(s):

Confidence Intervals ◽

Adverse Drug Event ◽

Shape Parameter ◽

Comprehensive Analysis ◽

Drug Event ◽

Event Report ◽

Odds Ratios ◽

Drug Induced ◽

Failure Type

Although infrequent, drug-induced agranulocytosis can be stimulated by antibiotics. Here, we analyzed the Japanese Adverse Drug Event Report database to identify profiles of antibiotic-induced agranulocytosis. Ten of 60 antibiotics showed signals for agranulocytosis; the reporting odds ratios (95% confidence intervals) for ampicillin/sulbactam, amikacin, cefmetazole, cefozopran, clindamycin, ciprofloxacin, imipenem/cilastatin, kanamycin, teicoplanin, and vancomycin were 2.65 (1.79–3.80), 2.49 (1.91–4.34), 4.48 (2.27–6.92), 2.77 (1.88–3.95), 1.64 (1.04–2.47), 2.01 (1.40–2.82), 2.78 (2.11–3.60), 6.05 (2.16–13.7), 2.05 (1.31–3.07), and 3.54 (2.73–4.54), respectively. The median times-to-onset of agranulocytosis for ampicillin/sulbactam, cefmetazole, cefozopran, clindamycin, imipenem/cilastatin, kanamycin, teicoplanin, and vancomycin were 20, 6, 10, 16, 12, 3, 18, and 13 days, respectively. The 95% confidence intervals of the Weibull shape parameter β for these antibiotics were over and excluded 1, indicating that the antibiotics were the wear out failure type. These findings provided insights into the characteristics of antibiotic-induced agranulocytosis.

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Comprehensive Study of the Risk Factors for Medication-Related Osteonecrosis of the Jaw Based on the Japanese Adverse Drug Event Report Database

Pharmaceuticals ◽

10.3390/ph13120467 ◽

2020 ◽

Vol 13 (12) ◽

pp. 467

Author(s):

Shinya Toriumi ◽

Akinobu Kobayashi ◽

Yoshihiro Uesawa

Keyword(s):

Risk Factors ◽

Side Effects ◽

Adverse Drug Event ◽

Femoral Fractures ◽

Principal Component ◽

Osteonecrosis Of The Jaw ◽

Drug Event ◽

Event Report ◽

Atypical Femoral Fractures ◽

Antiresorptive Agents

Medication-related osteonecrosis of the jaw (MRONJ) is associated with many drugs, including bisphosphonates (BPs). BPs are associated with atypical femoral fractures and osteonecrosis of the external auditory canal. Thus, many drugs are reported to cause adverse effects on bone. This study aimed to investigate the effects of drugs and patient backgrounds regarding osteonecrosis-related side effects, including MRONJ. This study used a large voluntary reporting database, namely, the Japanese Adverse Drug Event Report database. First, we searched for risk factors related to MRONJ using volcano plots and logistic regression analysis. Next, we searched for bone-necrosis-related side effects using principal component and cluster analysis. Factors that were significantly associated with MRONJ included eight types of BPs and denosumab, prednisolone, sunitinib, eldecalcitol, raloxifene, letrozole, doxifluridine, exemestane, radium chloride, medroxyprogesterone, female, elderly, and short stature. Furthermore, antiresorptive agents (i.e., BPs and denosumab) tended to induce MRONJ and atypical femoral fractures by affecting osteoclasts. We believe these findings will help medical personnel manage the side effects of many medications.

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Analysis of Drug-Induced Gastrointestinal Obstruction and Perforation Using the Japanese Adverse Drug Event Report Database

Frontiers in Pharmacology ◽

10.3389/fphar.2021.692292 ◽

2021 ◽

Vol 12 ◽

Author(s):

Riko Satake ◽

Kiyoka Matsumoto ◽

Mizuki Tanaka ◽

Ririka Mukai ◽

Kazuyo Shimada ◽

...

Keyword(s):

Prescription Drugs ◽

Adverse Drug Event ◽

Barium Sulfate ◽

Gastrointestinal Perforation ◽

Drug Event ◽

Event Report ◽

Drug Induced ◽

X Ray ◽

Gastrointestinal Obstruction ◽

Time To Onset

Drug-induced gastrointestinal obstruction (DIGO) and gastrointestinal perforation (DIGP) may be the result of gastrointestinal hypomotility and severe constipation, which may lead to potentially fatal complications of bowel ischemia, sepsis and perforation. We evaluated the onset profile of DIGs (DIGO and DIGP) associated with prescription drugs by analyzing data in the Japanese Adverse Drug Event Report (JADER) database. We selected 161 DIG-related drugs and categorized them into 19 classes based on the Anatomical Therapeutic Chemical (ATC) Classification System. Finally, we focused on 58 drugs and conducted subsequent analyses for the time-to-onset and outcomes. We extracted 79 preferred terms (PTs) with the strings “ileus,” “stenosis,” “obstruction,” “obstructive,” “impaction,” “perforation,” “perforated,” “hypomotility,” and “intussusception” from the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs) of SMQ20000104: gastrointestinal perforation, ulcer, hemorrhage, obstruction non-specific findings/procedures; SMQ20000105: gastrointestinal obstruction; and SMQ20000107: gastrointestinal perforation. Among the 667, 729 reports in the JADER database submitted between April 2004 and November 2020, we identified 11,351 occurrences of DIGs. The reporting odds ratios (RORs) (95% confidence interval) of “barium sulfate containing X-ray media,” “drugs for treatment of hyperkalemia and hyperphosphatemia,” and “oral bowel cleanser” were 142.0 (127.1–158.6), 25.8 (23.1–28.8), and 29.7 (24.8–35.6), respectively. The median number of days (interquartile range) until the onset of an adverse event caused by each drug category was as follows: barium sulfate containing X-ray contrast media [2.0 (1.0–3.0)], diazepines, oxazepines, thiazepines, and oxepines [8.0 (8.0–18.5)], drugs for treatment of hyperkalemia and hyperphosphatemia [29.0 (8.0–55.0)], non-selective monoamine reuptake inhibitors [19.0 (7.0–47.5)], and oral bowel cleanser [0.0 (0.0–0.0)]. Depending on the drug, the time to onset of side effects ranged from days to several months. Our results highlighted the need to perform detailed monitoring of each drug for possible association with DIGs, which might otherwise have fatal consequences.

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Risk Assessment for Anti-Infectives-Related Acute Kidney Injury Using the Japanese Adverse Drug Event Report Database

10.21203/rs.3.rs-41018/v1 ◽

2020 ◽

Author(s):

Satoshi Nakao ◽

Shiori Hasegawa ◽

Ryogo Umetsu ◽

Kazuyo Shimada ◽

Ririka Mukai ◽

...

Keyword(s):

Acute Kidney Injury ◽

Adverse Drug Event ◽

Association Rule ◽

Association Rule Mining ◽

Kidney Injury ◽

Drug Event ◽

Event Report ◽

Rule Mining ◽

Drug Induced ◽

Medical Dictionary

Abstract Background: Acute kidney injury (AKI) is associated with significant increases in short- and long-term morbidity and mortality. Drug-induced AKI is a major concern in the present healthcare system. Our spontaneous reporting system (SRS) analysis assessed links between AKIs, along with patients’ age, as healthcare-associated risks and administered anti-infectives. We also generated anti-infectives-related AKI-onset profiles.Method: We calculated adjusted reporting odds ratios (RORs) for reports of anti-infectives-related AKIs (per Medical Dictionary for Regulatory Activities) in the Japanese Adverse Drug Event Report database and evaluated associations between anti-infectives and age by association rule mining. We evaluated time-to-onset data and hazard types using the Weibull parameter.Results: Among 534,688 reports (submission period: April 2004–June 2018), there were 21,727 AKI events. Anti-infective treatments including glycopeptide antibacterials, fluoroquinolones, third-generation cephalosporins, triazole derivatives, and carbapenems were associated with 596, 494, 341, 315, and 313 AKI incidences, respectively. Adjusted RORs of anti-infectives-related AKIs increased among older patients and were higher in anti-infective combination therapies [anti-infectives, ≥ 2; ROR, 2.75 (2.56–2.95)] than in monotherapies [ROR, 1.52 (1.45–1.61)]. In association rule mining, the number of anti-infectives and age were associated with anti-infectives-related AKI lift values (as consequent). Moreover, 48.1% of AKIs occurred within 5 days (median, 5.0 days) of anti-infective therapy initiation.Conclusion: Thus, adjusted RORs derived from our new SRS analysis indicate potential AKI risks linked to age and number of administered anti-infectives.

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Risk Analysis of Drug-induced Acute Pancreatitis Using Japanese Adverse Drug Event Report Database

Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences) ◽

10.5649/jjphcs.45.441 ◽

2019 ◽

Vol 45 (8) ◽

pp. 441-450

Author(s):

Yufumi Taira ◽

Shigeru Oiso ◽

Hiroko Kariyazono

Keyword(s):

Acute Pancreatitis ◽

Risk Analysis ◽

Adverse Drug Event ◽

Drug Event ◽

Event Report ◽

Drug Induced

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Drug-induced hyperglycemia in the Japanese Adverse Drug Event Report database: association of evelolimus use with diabetes

Endocrine Journal ◽

10.1507/endocrj.ej18-0553 ◽

2019 ◽

Vol 66 (6) ◽

pp. 571-574 ◽

Cited By ~ 4

Author(s):

Hiromi Konishi ◽

Jun Shirakawa ◽

Masanori Arai ◽

Yasuo Terauchi

Keyword(s):

Adverse Drug Event ◽

Drug Event ◽

Event Report ◽

Drug Induced

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3. Evaluation of Drug Induced Severe Eruption Cases in the Japanese Adverse Drug Event Report Database and Commonality of the Reported Drugs

Japanese Journal of Pharmacoepidemiology/Yakuzai ekigaku ◽

10.3820/jjpe.19.31 ◽

2014 ◽

Vol 19 (1) ◽

pp. 31-37 ◽

Cited By ~ 2

Author(s):

Katsuhiko SAWADA ◽

Tadashi HIROOKA

Keyword(s):

Adverse Drug Event ◽

Drug Event ◽

Event Report ◽

Drug Induced

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Adverse drug event and medication extraction in electronic health records via a cascading architecture with different sequence labeling models and word embeddings

Journal of the American Medical Informatics Association ◽

10.1093/jamia/ocz120 ◽

2019 ◽

Vol 27 (1) ◽

pp. 47-55 ◽

Cited By ~ 6

Author(s):

Hong-Jie Dai ◽

Chu-Hsien Su ◽

Chi-Shin Wu

Keyword(s):

Neural Network ◽

Adverse Drug Event ◽

Conditional Random Fields ◽

Principal Component ◽

Medical Intervention ◽

Drug Event ◽

Word Embeddings ◽

Word Representation ◽

Clinical Records ◽

Medical Concepts

Abstract Objective An adverse drug event (ADE) refers to an injury resulting from medical intervention related to a drug including harm caused by drugs or from the usage of drugs. Extracting ADEs from clinical records can help physicians associate adverse events to targeted drugs. Materials and Methods We proposed a cascading architecture to recognize medical concepts including ADEs, drug names, and entities related to drugs. The architecture includes a preprocessing method and an ensemble of conditional random fields (CRFs) and neural network–based models to respectively address the challenges of surrogate string and overlapping annotation boundaries observed in the employed ADEs and medication extraction (ADME) corpus. The effectiveness of applying different pretrained and postprocessed word embeddings for the ADME task was also studied. Results The empirical results showed that both CRFs and neural network–based models provide promising solution for the ADME task. The neural network–based models particularly outperformed CRFs in concept types involving narrative descriptions. Our best run achieved an overall micro F-score of 0.919 on the employed corpus. Our results also suggested that the Global Vectors for word representation embedding in general domain provides a very strong baseline, which can be further improved by applying the principal component analysis to generate more isotropic vectors. Conclusions We have demonstrated that the proposed cascading architecture can handle the problem of overlapped annotations and further improve the overall recall and F-scores because the architecture enables the developed models to exploit more context information and forms an ensemble for creating a stronger recognizer.

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