Predictive value of serum high-mobility group box 1 levels for checkpoint inhibitor pneumonitis.

BACKGROUND AND OBJECTIVE: Checkpoint inhibitor pneumonitis (CIP), caused by the anti-programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) antibody, can be a fatal adverse event in cancer patients. However, no predictive biomarkers for CIP have been identified. Because high-mobility group box 1 (HMGB1) can aggravate lung injury and potentially increase the immune response, it was investigated as a predictive blood marker. METHODS: Blood samples, prospectively stored before anti-PD-1/PD-L1 monotherapy between December 2015 and October 2020, were obtained at two university hospitals from 87 and 43 non-small cell lung cancer (NSCLC) patients (discovery and validation cohorts, respectively). We retrospectively evaluated the association of serum HMGB1 levels with the incidence of CIP developed within 3 months of initiating anti-PD-1/PD-L1 therapy. RESULTS: CIP was observed in 9 (10.3%) and 6 (14.0%) patients in the discovery and validation cohorts, respectively. In each cohort, serum HMGB1 levels were significantly and reproducibly higher in patients with CIP. In the discovery cohort, an HMGB1 cut-off level of 11.24 ng/ml was identified by receiver operating characteristic analysis. CIP incidence in the HMGB1high subgroup was significantly higher than that in the HMGB1low subgroup in the discovery (41.2% vs. 2.9%) and validation cohorts (36.4% vs. 6.3%). In an exploratory pooled analysis, three patients died of grade 5 CIP; a 19.29 ng/ml HMGB1 cut-off level detected grade 5 CIP with 100% sensitivity and 96.85% specificity. CONCLUSION: Our results suggest that HMGB1 may be a potential blood marker to predict the development and severity of CIP in NSCLC patients.

Systematic surveillance of immune-related adverse events in clinical practice and impact of subsequent steroid medication on survival outcomes.

BACKGROUND: Recent advances in immune-checkpoint inhibitors (ICIs) have highlighted the need for effective management of immune-related adverse events (irAEs). This study aimed to conduct a systematic surveillance of real-world development of irAEs for understanding their characteristics and examine the prognostic impact of steroid use for these events. METHODS: We retrospectively investigated cancer patients treated with ICIs between 2014 and 2021 and collected information about irAEs throughout their development, management, and clinical outcomes. RESULTS: Overall, 458 patients (45.4%) developed 670 irAEs. The prevalence of irAEs varied by cancer type, but it was increased in regimens with longer treatment durations. Severe irAEs were more common in the nivolumab + ipilimumab and pembrolizumab + axitinib regimens. Patients who received steroids for irAEs at a dosage of < 2 mg/kg had comparable prognosis to those who did not receive steroids; however, patients who received methylprednisolone pulse therapy, primarily for severe pneumonitis and hepatitis, had shorter overall survival than those who did not receive steroids (7.8 versus 23.4 months, p = 0.016). Furthermore, methylprednisolone pulse therapy for irAEs was a poor prognostic factor in multivariate analysis (hazard ratio: 2.19, 95% confidence interval: 1.34-2.86, p < 0.001). CONCLUSION: Steroid treatment for irAE does not affect prognosis and should thus be used promptly to control inflammation. However, pulse therapy for severe cases is a poor prognostic factor, and early detection remains the key to managing such irAEs. The irAE characteristics in each regimen should be clarified to establish and provide more sophisticated irAE management, and the current findings will be beneficial to this goal.

Early Detection of Cardiac Amyloidosis in Transthyretin Mutation Carriers.

Diagnostic strategies for symptomatic transthyretin (ATTR) cardiac amyloidosis showing typical morphological features such as increased ventricular wall thickness and myocardial injury such as an elevation in serum troponin T level have been established, but those for subclinical cardiac amyloidosis are limited. In the era when effective therapies to suppress/delay progression of ATTR cardiac amyloidosis are available, early detection of cardiac involvement plays a crucial role in appropriate decision-making for treatment in TTR mutation carriers who have a family history of heart failure and death due to ATTR amyloidosis. Findings of three cases with known pathogenic transthyretin (TTR) mutations (p.Ser70Arg, p.Phe53Val, and p.Val50Met) and family histories of death for amyloidosis were presented. Two cases were asymptomatic, and a case carrying p.Phe53Val had gastrointestinal symptoms and autonomic neuropathy. Levels of plasma N-terminal fragment of pro-B-type natriuretic peptide and troponin T were within normal ranges in all cases, but results of cardiac magnetic resonance (CMR) and bone scintigraphy clearly revealed the presence of cardiac involvement in all cases, even in a case without echocardiographic abnormalities including left ventricular hypertrophy and relative apical sparing of longitudinal strain shown by two-dimensional speckle-tracking echocardiography. Electrocardiography revealed modest abnormalities including reduced R wave amplitude in V2 and a trend toward left axis deviation in all cases. In conclusion, CMR, bone scintigraphy, and electrocardiography are useful for early detection of ATTR cardiac amyloidosis in TTR mutation carriers. The role of comprehensive cardiac assessment in the early detection of cardiac amyloidosis in TTR mutation carriers is discussed.

Pseudohypoxic brain swelling and secondary hydrocephalus with pseudomeningocele after lumbar surgery: a case report.

BACKGROUND: Postoperative intracranial complications are rare in spine surgery not including cranial procedures. We describe an uncommon case of pseudohypoxic brain swelling (PHBS) and secondary hydrocephalus after transforaminal lumbar interbody fusion (TLIF) presenting as impaired consciousness and repeated seizures. CASE PRESENTATION: A 65-year-old man underwent L4-5 TLIF for lumbar spondylolisthesis and began experiencing generalized seizures immediately postoperatively. Computed tomography (CT) revealed diffuse cerebral edema-like hypoxic ischemic encephalopathy. He was transported to our hospital, at which time epidural drainage was halted and anti-edema therapy was commenced. His impaired consciousness improved. However, he suffered secondary hydrocephalus due to continuous bleeding from a dural defect and spinal epidural fluid collection 3 months later. Following the completion of dural repair and insertion of a ventriculoperitoneal shunt, his neurologic symptoms and neuroimaging findings improved significantly. CONCLUSIONS: PHBS can be considered in patients with unexpected neurological deterioration following lumbar spine surgery even with the absence of documented durotomy. This might be due to postoperative intracranial hypotension-associated venous congestion, and to be distinguished from the more common postoperative cerebral ischemic events-caused by arterial or venous occlusions-or anesthetics complications.

Analysis of immune-related adverse events caused by immune checkpoint inhibitors using the Japanese Adverse Drug Event Report database.

PURPOSE: The aim of our study was to characterize the clinical features of immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) in a real-world setting using the Japanese Adverse Drug Event Report (JADER) database. METHODS: The irAEs were defined using the preferred terms of the Medical Dictionary for Regulatory Activities. irAEs were categorized as follows: adrenal insufficiency, colitis, eye diseases, hematological disorder, hepatitis, hyperthyroidism, hypopituitarism, hypothyroidism, myasthenia gravis, myocarditis, nephritis/renal dysfunction, pneumonitis, rash, and type 1 diabetes mellitus. We used several indices such as reporting odds ratio (ROR) to assess disproportionality in pharmacovigilance data, time-to-onset analysis using Weibull shape parameters, and the association rule mining technique to evaluate possible risk factors between variables in the spontaneous reporting system database. RESULTS: The JADER database contained 534 688 reports from April 2004 to June 2018. The RORs of pneumonitis including interstitial lung disease for nivolumab, pembrolizumab, and ipilimumab were 7.02 (95% confidence interval: 6.55-7.52), 9.08 (8.28-9.97), and 1.74 (1.27-2.38), respectively. The median onsets (quartiles, 25-75%) of myocarditis caused by nivolumab and pembrolizumab were 28.0 (15.5-60.5) and 18.0 (13.0-44.5) days, respectively. Co-therapy with nivolumab and ipilimumab may be associated with irAEs in several categories as per the association rule mining analysis. CONCLUSION: Our results demonstrated a potential risk of irAEs associated with ICIs, based on RORs and time-to-onset analysis. Furthermore, our findings indicated that patients receiving nivolumab and ipilimumab as co-therapy should be carefully monitored.

Trends Associated with Hemorrhoids in Japan: Data Mining of Medical Information Datasets and the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) Open Data Japan.

Hemorrhoids are a common anorectal disease. Epidemiological studies on medication trends and risk factors using information from real-world databases are rare. Our objective was to analyze the relationship between hemorrhoid treatment prescription trends and several risk factors using the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) Open Data Japan and related medical information datasets. We calculated the standardized prescription ratio (SPR) based on the 2nd NDB Open Data Japan from 2015. The correlation coefficients between the SPR of antihemorrhoidals and those of "antispasmodics," "antiarrhythmic agents," "antidiarrheals, intestinal regulators," "purgatives and clysters," "hypnotics and sedatives, antianxietics," "psychotropic agents," and "opium alkaloids preparations" were 0.7474, 0.7366, 0.7184, 0.6501, 0.6320, 0.4571, and 0.4542, respectively. The correlation coefficient between the SPR of antihemorrhoidals and those of "average annual temperature," "percentage of people who were smokers," and "percentage of people who drank regularly" were -0.7204, 0.6002, and 0.3537, respectively. The results of cluster analysis revealed that Hokkaido and Tohoku regions tended to have low average annual temperature values and high percentage of people who were smokers and had comparatively high SPRs of "antispasmodics," "antiarrhythmic agents," "antidiarrheals, intestinal regulators," "purgatives and clysters," "hypnotics and sedatives, antianxietics," "psychotropic agents," and "opium alkaloids preparations." Antihemorrhoidals are frequently used in Hokkaido and Tohoku, Japan; thus, it is important for these prefectural governments to focus on these factors when taking measures regarding health promotion.

Evaluation of anti-infective-related Clostridium difficile-associated colitis using the Japanese Adverse Drug Event Report database.

Clostridium difficile-associated colitis (CDAC) may cause gastrointestinal illness, ranging in severity from mild diarrhea to fulminant colitis and even mortality. The purpose of this study was to evaluate anti-infective-related CDAC profiles using the Japanese Adverse Drug Event Report (JADER) database. Methods: We selected case reports of adverse events of CDAC as specified in the Medical Dictionary for Regulatory Activities. The association between the number of administered anti-infectives and aging was evaluated using reporting odds ratio (ROR) and adjusted for covariates using multiple-logistic regression. We also evaluated anti-infective-related CDAC-onset profiles using Weibull shape parameter. Results: The JADER database contained 534 688 reports from April 2004 to June 2018. There were 1222 anti-infective related CDAC events. The top five anti-infectives were as follows: third-generation cephalosporins (Anatomical Therapeutic Chemical (ATC) code: J01DD, 313 cases), fluoroquinolones (ATC code: J01MA, 201 cases), macrolides (ATC code: J01FA, 146 cases), carbapenems (ATC code: J01DH, 143 cases), and penicillins with extended spectrum (ATC code: J01CA, 103 cases). The adjusted RORs (95% confidence interval) in individuals using 1, 2, and ≥ 3 anti-infectives were 8.88 (7.05-11.18), 9.77 (6.89-13.86), and 18.39 (11.85-28.54), respectively. Moreover, 47.2% of CDACs occurred within 7 days of anti-infective therapy initiation. The adjusted ROR of interaction terms of ≥ 70 years × 1 drug was 21.81 (14.56-32.68). Conclusion: Our results suggest that the number of administered anti-infectives and patient age are associated with CDAC. These data may be particularly beneficial to prescribers and would contribute to improving the management of CDAC.

Adverse reaction profiles of hemorrhagic adverse reactions caused by direct oral anticoagulants analyzed using the Food and Drug Administration Adverse Event Reporting System (FAERS) database and the Japanese Adverse Drug Event Report (JADER) database.

Direct oral anticoagulants (DOACs) are used in anticoagulant therapy. The purpose of this study was to evaluate the association of DOAC-induced gastrointestinal (GI) and nervous system hemorrhage using the FDA's Adverse Event Reporting System (FAERS) database and the Japanese Adverse Drug Event Report (JADER) database. We identified and analyzed the reports of hemorrhagic reactions between 2004 and 2016 from the FAERS and JADER databases, and calculated the adjusted reported odds ratio (ROR) using the multiple logistic regression method. Additionally, we used the time-to-onset analysis. In the FAERS database, the adjusted ROR of apixaban, rivaroxaban, and dabigatran for GI hemorrhage was 6.79 (5.84-7.91), 19.58 (18.85-20.34), and 14.51 (13.58-15.51), respectively. In the JADER database, the adjusted ROR of apixaban, rivaroxaban, edoxaban, and dabigatran for GI hemorrhage was 11.80 (9.50-14.64), 11.03 (9.18-13.26), 10.17 (6.95-14.88), and 9.85 (7.23-13.42), respectively. We found that the association of GI hemorrhage with DOACs was affected by sex (female). Additionally, 30% of GI hemorrhage was observed after 30 days. Hemorrhagic reactions of both GI and nervous systems were observed in both the spontaneous reporting system databases. We recommend that female patients who experience symptoms related to GI hemorrhage should be closely monitored and advised to adhere to an appropriate care plan. Additionally, our results show that patients should be closely monitored for hemorrhage even after a month.

Evaluation of pregabalin-induced adverse events related to falls using the FDA adverse event reporting system and Japanese Adverse Drug Event Report databases.

WHAT IS KNOWN AND OBJECTIVE: Pregabalin is used for neuropathic and postherpetic pain and generalized anxiety. The aim of this study was to obtain the onset profiles of adverse events (AE) related to falls (AEFs) such as "somnolence," "dizziness," "loss of consciousness" and "fall" onset and several clinical factor combinations such as age and administered dose, using spontaneous reporting system (SRS) analysis such as the US Food and Drug Administration Adverse Event Reporting System (FAERS) database and the Japanese Adverse Drug Event Report (JADER) database. METHODS: We used the reporting odds ratio (ROR) to analyse the association between pregabalin and AEFs. Additionally, we used the time-to-onset analysis. RESULTS AND DISCUSSION: The crude RORs of AEFs such as somnolence and dizziness were higher than one for both the databases. The adjusted RORs for AEFs in the ≥60 years age group compared to those in the <60 years age group for the FAERS and JADER databases were 1.46 (95% CI = 1.39-1.53; P < 0.0001) and 2.58 (95% CI = 2.06-3.27; P < 0.0001), respectively. In the JADER database, the median and quartile range for AEFs with pregabalin, at ≤75 and ≥100 mg/d, were 2.0 (0.0-5.0) and 2.0 (1.0-4.3) days, respectively. Additionally, 57.2% of AEFs (four preferred terms) were observed within 2 days after administration. WHAT IS NEW AND CONCLUSIONS: This study is the first to evaluate the relationship between pregabalin and AEFs using the SRS analysis strategy. The risk of AEFs in the ≥60 years age group might increase compared to that in the <60 years age group. AEFs occurred almost within 1 week after pregabalin administration, and the median for AEF onset was 2 days. Our results show that patients should be closely monitored for AEFs for 1 week from the start of pregabalin administration.

Vonoprazan- vs proton-pump inhibitor-based first-line 7-day triple therapy for clarithromycin-susceptible Helicobacter pylori: A multicenter, prospective, randomized trial.

BACKGROUND: The eradication rate of vonoprazan-based first-line triple therapy (combined with clarithromycin and amoxicillin) (V-AC) was reported to be 97.6% in patients with clarithromycin (CAM)-susceptible Helicobacter pylori in a phase III study, whereas our real-world, prospective, multicenter cohort study yielded an eradication rate <90%. OBJECTIVE: To validate the eradication rate of V-AC using CAM-susceptible testing in a multicenter, prospective, randomized trial. METHODS: We included 147 treatment-naïve H. pylori-positive patients [41 with CAM-resistant infections and 106 with CAM-susceptible infections]. The CAM-susceptible group patients were randomized to either the V-AC group (vonoprazan 20 mg bid, amoxicillin 750 mg bid, and clarithromycin 200 or 400 mg bid) or PPI-AC group (lansoprazole 30 mg, rabeprazole 10 mg, or esomeprazole 20 mg bid; amoxicillin 750 mg bid; and clarithromycin 200 or 400 mg bid). All CAM-resistant H. pylori were eradicated by V-AC, as measured by the urea breath test around 8 weeks after eradication. Safety was evaluated by patient questionnaires. RESULTS: The intention-to-treat and per-protocol eradication rates of V-AC in the CAM-susceptible H. pylori-infected patients were 87.3% (95% confidence interval 75.5%-94.7%) and 88.9% (77.4%-95.8%). The respective eradication rates of PPI-AC were 76.5% (62.5%-87.2%) and 86.7% (73.2%-94.9%). No significant difference was observed between the V-AC and PPI-AC regimes in terms of the intention-to-treat (P = .21) or per-protocol (P = .77) analyses. The questionnaire scores did not differ significantly between the groups. Both the intention-to-treat and per-protocol eradication rates of V-AC in the CAM-resistant patients were 82.9% (67.9%-92.8%). CONCLUSION: The eradication rate of V-AC treatment in the CAM-susceptible H. pylori-infected patients was <90%, as was that by PPI-AC, thus V-AC is not ideal regimen in CAM-susceptible H. pylori. However, the 82.9% eradication rate of V-AC in the CAM-resistant infections may indicate the potential of V-AC with modified dose, dosing interval, and treatment duration. (UMIN000016337).

Evaluation of Drug-Induced Photosensitivity Using the Japanese Adverse Drug Event Report (JADER) Database.

Drug-induced photosensitivity (DIP) refers to the development of cutaneous disorders caused by the combined effects of different medications and light. The aim of this study was to obtain new information on drug risk comparisons and on DIP onset profiles, including seasonal variations, for clinically used prescription drugs. We analyzed reports of DIP recorded in the Japanese Adverse Drug Event Report (JADER) database using a reporting odds ratio (ROR). We also used Weibull proportional-hazards models for each drug to examine the patterns of DIP. The JADER database contains 430587 reports recorded from April 2004 to November 2016. The ROR values (95% confidence interval [CI]) of losartan/hydrochlorothiazide (HCTZ), valsartan/HCTZ, and ketoprofen were 214.5 (162.1-283.9), 104.7 (66.3-165.5), and 117.9 (76.6-181.5), respectively. For time-to-onset analysis, the median durations (interquartile range) for DIP caused by losartan/HCTZ, valsartan/HCTZ, and ketoprofen were 56 (41-78), 49 (38-88), and 8 (2-14) days, respectively. The lower limit of the 95% CI for the Weibull shape parameter ß value for losartan/HCTZ was greater than 1. More than half of the reports of DIP onset following the administration of ketoprofen were recorded within 10 d of treatment initiation. The seasonal variation of photosensitivity reactions was shown to follow an annual sinusoidal pattern with a peak in April and May. Based on the results, losartan/HCTZ, valsartan/HCTZ, and ketoprofen should be used carefully in clinical practice to avoid DIP.

Conservative management of spontaneous spinal epidural hematoma: A case report with favorable prognosis.

Sudden spinal epidural hematoma (SSEH) is relatively rare. Sudden pain from the neck to the back and subsequent extremity paralysis necessitate immediate head and cervical magnetic resonance imaging or computed tomography, keeping SSEH in mind. Although surgery is recommended for progressive paralysis, conservative treatment is indicated for mildly symptomatic cases.

Identification of Drugs and Patient Profiles at Risk for Severe Skin Injuries Due to Extravasation: Analysis of a Spontaneous Reporting System.

This study aimed to identify risk factors and combinations thereof that are associated with severe skin injuries due to the extravasation of injectable drugs. A cross-sectional study using the Japanese Adverse Drug Event Report database was conducted according to the RECORD-PE checklist. Adverse event reports related to necrosis, ulcers, or erosions due to extravasation were considered "with severe skin injury," and others were considered "without severe skin injury." Approximately 255 cases "with" and 260 cases "without" severe skin injury were identified. The relationship between the incidence of severe skin injury and age, sex, drugs, and primary disease was evaluated using the χ2 test. Association rule mining was used to evaluate the correlation between each combination of factors and skin injury. Nine factors were identified as independent risk factors for severe skin injury, including age (<10 or ≥70 years), peripheral parenteral nutrition use, and mental disorders. The association rule mining results suggested that a combination of specific patient backgrounds and drug use was associated with the incidence of necrosis or ulcers. The findings of this study reiterate that nurses might consider closely observing patients with the risk factors identified in this study for the prevention and early detection of extravasation-related skin injuries.

Relationships between acute generalized eruptive pustulosis, age, sex, primary disease, and prescription medications: Further analysis of the Japanese Adverse Drug Event Report database.

Background: Acute generalized eruptive pustulosis (AGEP) is a rare, but serious, drug-related adverse event. This study aimed to determine the relationships between AGEP and age, sex, primary disease, and prescription medications using a database of adverse drug events, namely, the Japanese Adverse Drug Event Report (JADER) database. Methods: In this retrospective observational study, we analyzed AGEP reports extracted from the JADER database based on the preferred term for AGEP (code 10048799). We evaluated the effects of causative drugs, underlying diseases, age, and sex. The association between AGEP and prescription drugs was analyzed using the reporting odds ratio and adjusted for covariates using multiple logistic regression. Association rule mining was performed to evaluate the correlation between each combination of factors and AGEP. Results: Between April 2004 and March 2023, 823,662 reports, including 869 reports on AGEP, were entered in the JADER database. The highest percentage of reports in each age group was in males aged <10 years, and clarithromycin was the most used drug in males aged <10 years. Nasopharyngitis was the most common reason for use, and Kawasaki disease was reported as a reason for use among males under 10 years of age, but not among females. Conclusions: In boys aged <10 years, attention should be paid to the occurrence of AGEP when prescribing clarithromycin and treating Kawasaki disease.

Survey of community and hospital pharmacist involvement in outpatient chemotherapy using Japanese health information data.

In this study, information on injectable anticancer drug use and additional fee for enhanced collaboration (AEC) and additional fee for specific drug management guidance 2 (ASD2) claims from the NDB Open Data Japan (NODJ) dataset and the number of patients with cancer according to sex and age from the National Cancer Registry (NCR) dataset were integrated and evaluated to determine the current status and challenges in pharmacist interventions for patients receiving cancer treatment. The NODJ data, including receipt data billed from 2020 to 2021, were obtained from the Ministry of Health, Labour and Welfare website. The use of injectable anticancer drugs decreased relative to the number of cancer patients aged ≥ 75 years compared to those aged < 75 years. Regarding injectable anticancer drug use, the number of AEC claims was similar between men and women, but the number of ASD2 claims was lower in men than in women. The number of times community pharmacists claimed their ASD2 was approximately 5% of the number of times hospital pharmacists claimed their AEC. This study revealed that several patients did not receive sufficient guidance from community pharmacists compared to hospital pharmacists, suggesting a potential insufficiency in the collaboration between the two groups.

Analysis of drug-induced interstitial lung disease caused by herbal medicine using the Japanese Adverse Drug Event Report database.

BACKGROUND: Drug-induced interstitial lung disease (DIILD) is a severe adverse event leading to morbidity and mortality. This study evaluated the adverse event indicators of DIILD and time-to-onset profiles following the daily intake of herbal drugs (Scutellariae radix ["ogon" in Japanese], Bupleuri radix ["saiko" in Japanese], and Pinelliae tuber ["hange" in Japanese]) using the Japanese Adverse Drug Event Report database. DIILD was defined in accordance with the Medical Dictionary for Regulatory Activities. METHODS: The Japanese Adverse Drug Event Report database contained 830,079 reports published between April 2004 and April 2023. The association between herbal medicines and DILLD was evaluated using the pharmacovigilance index as the reporting odds ratio (ROR), logistic regression models, propensity score-matching techniques, and Weibull shape parameters. RESULTS: The adjusted RORs using multivariate logistic regression models for Scutellariae radix (daily intake), Pinelliae tuber (daily intake), sex (male), age (≥ 60 years), Scutellariae radix (daily intake)*age (≥ 60 years), and Scutellariae radix (daily intake)* Pinelliae tuber (daily intake) were 1.47 (1.36 - 1.59), 1.05 (1.01 - 1.10), 1.45 (1.34 - 1.57), 1.92 (1.74 - 2.11), 3.35 (3.12 - 3.60), and 1.49 (1.46 - 1.53), respectively. DIILD onset profiles were evaluated using the Weibull shape parameter. A logistic plot of daily intake and onset of DIILD was drawn. ROR signals were detected in 32 of 54 herbal medicines, including Scutellariae radix, Bupleuri radix, and Pinelliae tuber. The median duration (days) (interquartile range) to DIILD onset was 36.0 (27.0-63.0) for Saikokaryukotsuboreito, 35.0 (21.0-55.0) for Saireito, and 31.0 (13.5-67.5) for Shosaikoto. The Weibull shape parameter beta (95% confidence interval) values for Saikokaryukotsuboreito, Saireito, and Shosaikoto were 1.36 (1.08-1.67), 1.36 (1.20-1.52), and 1.31 (0.98-1.68), respectively. CONCLUSIONS: DIILD demonstrated a dose-dependent to crude drugs. Clinicians should strive for the early detection of DIILD and avoid the inadvertent administration of herbal medicines.

Promoting generic drug usage in Japan: correlation between generic drug usage and monthly personal income.

BACKGROUND: To reduce pharmacy-related medical expenses, it is necessary to cut drug costs, potentially by increasing generic drug usage. This study analyzes the correlation between generic drug usage and monthly personal income by examining prescriptions for individual drugs. METHODS: We conducted a cross-sectional study based on the data set from the National Database of Health Insurance Claims and Specific Health Checkups of Japan Open Data Japan and the Basic Survey on Wage Structure. We calculated the correlation coefficient between the usage rate of generic drugs in each prefecture of Japan and monthly personal incomes. We then analyzed the correlation coefficients based on the therapeutic categories of medicinal drugs; the contingency table was visualized as a mosaic plot. To compare the proportions between multiple categories, the chi-squared test was applied as a statistical significance test that was used in the analysis of n × m contingency tables. We worked with the null hypothesis that there were no differences between classes in the population. RESULTS: Regarding the correlation coefficient between the usage rate of generic drugs and monthly personal incomes, the proportion of negative correlation coefficients for outpatient out-of-hospital and outpatient in-hospital prescriptions was over 70%, while that for inpatient prescriptions was 46.9%. The proportion of medicinal drugs exhibiting a negative correlation between the rates of generic drug usage and monthly personal incomes for outpatient out-of-hospital prescriptions and outpatient in-hospital prescriptions was higher than that of inpatient prescriptions. The proportion of statistically correlated medicinal drugs among inpatient prescriptions was lower than that among outpatient out-of-hospital and outpatient in-hospital prescriptions. The proportions of significant negative correlations for outpatient out-of-hospital, outpatient in-hospital, and inpatient prescriptions were 30.6%, 22.7%, and 3.5%, respectively. It was also observed that the rate of generic prescription usage for outpatient out-of-hospital and in-hospital prescriptions increased as monthly personal incomes decreased. In outpatients, the therapeutic categories with strong negative correlations were vasodilators and hyperlipidemia drugs. CONCLUSIONS: Our results may help to increase the usage rate of generic drugs in different prefectures by providing useful information for promoting them throughout Japan.

Progressive multifocal leukoencephalopathy analyzed using the Japanese Adverse Drug Event Report database.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) has been reported as the development of drugs with immunomodulatory properties, such as anticancer, immunosuppressive, and biological agents, has accelerated. To clarify an incidence profile of drug-associated PML in real-world clinical practice, we analyzed reported patients with PML using the Japanese Adverse Drug Event Report (JADER) database. METHODS: We analyzed PML reports extracted from the JADER database based on the preferred term of "progressive multifocal leukoencephalopathy" from between 2004 and 2021. This was a retrospective, observational study. We evaluated the effects of causative drugs, underlying diseases, and the age of the patients on the annual number of PML reports. RESULTS: The JADER database contained 773,966 reports published between April 2004 and March 2022, from which we identified 361 PML events. These PML events may include multiple counts of the same case reported by different pathways and patients diagnosed with probable or possible PML. The number of PML reports and reporting ratios have gradually increased over the past decade. The annual number of PML reports associated with biologics, immunosuppressants, and antineoplastic drugs showed an increasing trend. Females aged ≥30 years showed an increase in PML reports; in contrast, there the number of reports for males aged ≥50 years increased. CONCLUSIONS: The number of PML reports and reporting ratios have gradually increased in the past decade in Japan, and it considered that it was related to change in the treatment of malignancies and autoimmune diseases, and the increasing use of biologics, immunosuppressive agents, and antineoplastic agents.

Evaluation of neuroleptic malignant syndrome induced by antipsychotic drugs using spontaneous reporting system.

Adverse events (AEs) of antipsychotic drugs include neuroleptic malignant syndrome (NMS), which presents complex clinical symptoms, resulting in a fatal outcome. In this study, the association between antipsychotic drugs and NMS was comprehensively evaluated by cluster and association analyses using the Japanese Adverse Drug Event Report (JADER) database. The analyses were performed using 20 typical antipsychotics (TAPs) alongside 9 atypical antipsychotics (AAPs). The Standardised MedDRA Queries (SMQ) database was used to analyze NMS (SMQ code: 20000044). Reporting odds ratios (RORs) were used for AE signal detection. The relationship between antipsychotic drugs and AEs for NMS was investigated by performing hierarchical cluster analysis using Ward's method. Between April 2004 and September 2021, the total number of JADER reports was 705,294. RORs (95 % confidence interval) of NMS for haloperidol, chlorpromazine, risperidone, and aripiprazole were 12.1 (11.1-13.3), 6.3 (5.7-7.0), 6.2 (5.8-6.6), and 4.7 (4.4-5.1), respectively. Three clusters were formed, with characteristics as follows: Cluster 1 consisted of only TAPs, such as bromperidol and fluphenazine, whilst having a high reporting rate of hypotension, tachycardia, dyskinesia, and dystonia. Cluster 2 consisted of all AAPs alongside several TAPs, such as haloperidol and chlorpromazine, with higher reporting rates of disturbance of consciousness, extrapyramidal disorders (excluding dyskinesia and dystonia), and serotonin syndrome. Cluster 3 consisted of only perphenazine, whilst having a higher reporting rate of coma, leukocytosis, and Parkinsonism. The results of this study may therefore aid in the management of NMS using antipsychotic drugs.

Profiles and Outcomes of Skin Injuries Caused by Injectable Drug Extravasation: An Analysis of the Japanese Adverse Drug Event Report Database.

Extravasation occurs when injectable drugs leak out of the blood vessels, damaging the surrounding tissues and causing a variety of skin injuries. This study aimed to comprehensively analyze extravasation risk, skin injury profiles, and outcomes for suspect drugs from the Japanese Adverse Drug Event Report (JADER) database. Adverse events were defined according to the Medical Dictionary for Regulatory Activities/Japanese version; the term extravasation (Standardized MedDRA Query Code: 20000136) was used in this analysis. The names of adverse events were entered as unified preferred terms and redefined to evaluate skin injury profiles. In addition, skin injury outcomes were divided into 2 broad categories: "improvement" and "no improvement." Reporting odds ratios were used to detect signals for adverse events. A total of 656 cases of extravasation-related adverse events were reported between April 2004 and January 2022. Signals for extravasation-related adverse events were detected from 11 drugs. Then, their respective skin injury profiles and outcomes were determined. These results suggest a relationship between adverse events associated with extravasation and 11 drugs and identify the characteristics of each skin injury and their outcomes. These findings will contribute to improving the quality of infusion management in clinical practice.