A simulation study on model-informed precision dosing of amikacin for achieving target area under the concentration-time curve.

AIMS: Amikacin requires therapeutic drug monitoring for optimum efficacy; however, the optimal model-informed precision dosing strategy for the area under the concentration-time curve (AUC) of amikacin is uncertain. This simulation study aimed to determine the efficient blood sampling points using the Bayesian forecasting approach for early achievement of the target AUC range for amikacin in critically ill patients. METHODS: We generated a virtual population of 3000 individuals using 2 validated population pharmacokinetic models identified using a systematic literature search. AUC for each blood sampling point was evaluated using the probability of achieving a ratio of estimated/reference AUC at steady state in the 0.8-1.2 range. RESULTS: On day 1, the 1-point samplings for population pharmacokinetic models showed a priori probabilities of 26.3 and 45.6%, which increased to 47.3 and 94.4% at 23 and 15 h, respectively. Using 2-point sampling at the peak (3 and 4 h) and trough (24 h) on day 1, these probabilities further increased to 72.3 and 99.5%, respectively. These probabilities were comparable on days 2 and 3, regardless of 3 and 6 sampling points or estimated glomerular filtration rate. These results indicated the higher predictive accuracy of 2-point sampling than 1-point sampling on day 1 for amikacin AUC estimation. Moreover, 2-point sampling was a more reasonable approach than rich sampling. CONCLUSIONS: This study contributes to the development of an efficient model-informed precision dosing strategy for early targeting of amikacin AUC in critically ill patients.

Risk of infection from glucocorticoid and methotrexate interaction in patients with rheumatoid arthritis using biologics: A retrospective cohort study.

AIMS: This retrospective cohort study aimed to evaluate the effect of the interaction between methotrexate and glucocorticoids on the risk of developing bacterial infections in patients with rheumatoid arthritis (RA) using biological disease-modifying antirheumatic drugs (bDMARDs). METHODS: We used the 2005-2018 JMDC claims database, a nationwide claims database in Japan. From the database of 7 175 048 patients, study patients were obtained by applying the following exclusion criteria: no use of bDMARDs; without information on the date of prescription; without RA as a disease; other than the new users of bDMARDs; and age <18 years. The exposures were glucocorticoids and methotrexate, and the outcome was bacterial infection. The interaction effects were examined using multivariate Cox regression analysis. Bacterial infections were identified according to antibiotic prescription and International Statistical Classification of Diseases and Related Health Problems, 10th revision codes. RESULTS: A total of 2837 RA patients were identified, with a median age of 50 years. The incidence of infection was 16.8% (95% confidence interval: 15.5-18.3). The interaction term for the doses of glucocorticoids and methotrexate was significant. Additionally, a higher dose of glucocorticoid was a significant risk factor for developing bacterial infections on the side of high doses of methotrexate. The incidence of bacterial infections tended to increase significantly with increasing methotrexate doses coprescribed with glucocorticoids ≥5 mg or glucocorticoid doses coprescribed with methotrexate ≥8 mg. CONCLUSION: Our results indicate a potential association between methotrexate dose and bacterial infections during bDMARDs administration with glucocorticoids in patients with RA.

Preventive effect of dexamethasone premedication on the development of infusion-related reaction in breast cancer patients receiving trastuzumab.

AIM: To clarify the incidence and risk factors of infusion-related reactions (IRRs) caused by trastuzumab in breast cancer patients and verify the preventive effects of dexamethasone. METHODS: All breast cancer patients newly treated with trastuzumab at the Osaka Medical and Pharmaceutical University Hospital from 1 January 2017 to 31 December 2020 were included. The electronic medical records were retrospectively reviewed. The outcome measure was the occurrence of IRRs of grade 1 or higher during trastuzumab infusion. Only dexamethasone and anticancer drugs administered concomitantly before trastuzumab were used as explanatory variables. RESULTS: The 176 patients included in the study received 2320 infusions. Fifty-eight patients (33.0%) experienced IRRs, and IRRs occurred in 80 (3.4%) of the total 2320 infusions. Owing to the hierarchical structure of the data, the independence of the observed values was evaluated using the intraclass correlation coefficient. Multivariate multilevel logistic regression analysis showed that premedication with dexamethasone lowered the risk of trastuzumab-induced IRRs (mg, per 1 unit, odds ratio [OR] = 0.61, 95% confidence interval [95% CI] 0.43-0.85, P = .003). In addition, preoperative status (OR = 38.9, 95% CI 5.4-278.7, P < .001) and high-dose trastuzumab (mg/kg, per 1 unit, OR = 60.6, 95% CI 20.1-182.9, P < .001) were independent risk factors for IRRs. CONCLUSION: The results of this study suggest that premedication with dexamethasone exhibits preventive effects on trastuzumab-induced IRRs in breast cancer patients. Future studies are needed to determine the optimal dose of dexamethasone to prevent IRRs and the impact of dexamethasone on the efficacy of trastuzumab in breast cancer.

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.

Liquid Enteral Nutrients Alter the Pharmacokinetics of Orally Administered Carbamazepine in Rats.

The interaction between enteral nutrients (ENs) and drugs co-administered through a nasogastric (NG) tube reportedly affects the absorption and resultant plasma concentrations of the respective drugs. However, the gastrointestinal absorption of carbamazepine (CBZ), an antiepileptic drug, co-administered with liquid ENs through an NG tube has not been clarified. In this study, we measured the recovery rate (%) of CBZ (Tegretol® powder) passed through an NG tube when co-administered with distilled water or ENs (F2α®, Racol® NF, Ensure Liquid®, and Renalen® LP) of different compositions, frequently used in Japan. We also measured the plasma CBZ level in 26 rats after oral co-administration of CBZ with liquid ENs. The CBZ recovery rate was close to 100% in rats of all EN groups after passage through the NG tube. Furthermore, CBZ area under the plasma concentration-time curve from time zero to 9 h (AUC0→9h) of the Ensure liquid® group decreased compared with that of control group (P < 0.05) and Renalen® LP group (P < 0.01). However, the AUC0→9h of CBZ remained unchanged when co-administered with Ensure liquid® 2 h after initial CBZ administration. In conclusion, the co-administration of CBZ with Ensure Liquid® caused a reduction in the absorption of CBZ from the gastrointestinal tract, without adsorption on the NG tube. The administration of Ensure Liquid® 2 h after CBZ is a way to prevent a decrease in plasma CBZ concentration. Our findings suggest that carefully monitoring the plasma levels of CBZ is necessary in co-administation with Ensure liquid® to prevent the unintended effects of the interaction between CBZ and liquid EN.

Observational study to determine the optimal dose of daptomycin based on pharmacokinetic/pharmacodynamic analysis.

High doses of daptomycin (DAP) (>6 mg/kg/day) have been preliminarily recommended in recent practical guidelines for methicillin-resistant Staphylococcus aureus infection, to achieve better clinical effects. While such doses can elevate the plasma trough concentration (Cmin) of DAP, there is an associated risk of creatine phosphokinase (CPK) elevation warranting further investigation. In the current study relationships between DAP Cmin and CPK elevation were investigated, and optimal DAP doses were determined. Plasma DAP concentrations were measured in 20 patients. Logistic regression analysis was performed to assess relationships between DAP Cmin and CPK elevation, then a population pharmacokinetic model of DAP was developed. To determine an optimal DAP dose a Monte Carlo simulation (MCS) was performed to minimize the risk of CPK elevation and maximize the probability of successful treatment. In logistic regression analysis DAP Cmin was significantly associated with CPK elevation (odds ratio 1.21, p = 0.048). With respect to dose-dependent increases in the probability of CPK elevation and exposure to DAP, MCS estimated an optimal DAP dose of 4-6 mg/kg/day, corresponding to a minimum inhibitory concentration (MIC) of ≤0.5 µg/mL. For an MIC of 1 µg/mL, MCS estimated an optimal DAP dose of 10 mg/kg/day. However, the probability of CPK elevation associated with high doses of DAP was higher than that associated with the approved doses. In cases where high doses of DAP are administered, close CPK monitoring is required and therapeutic drug monitoring of DAP may be desirable.

[Influence of the Site of Port Insertion on the Flow Velocity of 5-FU Continuous Intravenous Injection by Using a Compression-Type Portable Continuous Infuser for Colorectal Cancer Patients].

For the continuous intravenous injection off luorouracil (5-FU) over 46 hours in a chemotherapeutic regimen for colorectal cancer, a compression-type portable continuous infuser is used. However, there is an error in the flow velocity. Errors in the dose or time of administration completion may influence the efficacy and safety of 5-FU. Therefore, it is necessary to reduce the error in the flow velocity. The type of diluent, air temperature, and concentration of 5-FU are reportedly factors influencing the flow velocity. However, no study has examined the influence of the site of port insertion. In this study, we investigated factors associated with the flow velocity of 5-FU continuously and intravenously injected by using an infuser in patients with colorectal cancer, among whom the site of port insertion differed. The results showed that the site of port insertion influenced the flow velocity during the continuous intravenous injection of 5-FU using an infuser. It is important to reduce the error in the flow velocity by considering the site of port insertion in addition to the concentration of 5-FU and the air temperature.

Incidence of serious infections in the working-age Japanese adult population with rheumatoid arthritis treated with tumor necrosis factor-α inhibitors and interleukin-6 inhibitors: A nationwide retrospective cohort study.

AIM: This retrospective cohort study aimed to compare the risk of serious infections in patients with rheumatoid arthritis (RA) treated with tumor necrosis factor-α inhibitors (TNFαi) and interleukin-6 inhibitors (IL-6i), with no prior use of biological disease-modifying antirheumatic drugs (bDMARDs). METHODS: We employed the nationwide insurance claims database encompassing the years 2005 to 2018 in Japan. The inclusion criteria specified patients who were prescribed any type of bDMARDs, including TNFαi and IL-6i. The following exclusion criteria were applied: missing prescription dates, RA not diagnosed, below 16 years of age, bDMARDs prescribed within 6 months of registration, RA diagnosed post-bDMARDs prescription, and incidence of serious infections within 2 weeks before bDMARDs therapy. We applied stabilized inverse probability weights and utilized a Cox regression model to estimate the risk of serious infections associated with TNFαi and IL-6i. RESULTS: The cohort of 2493 patients with RA was categorized into a TNFαi group and an IL-6i group of 2018 and 475 participants, respectively. The median follow-up duration (interquartile range) was 347 (147-820) days in the TNFαi group and 369 (149-838) days in the IL-6i group. In the inverse probability-weighted cohort, the incidence rates (95% confidence interval) of serious infections were 2.13 (1.65-2.71) and 3.25 (2.15-4.69) per 100 person-years for the TNFαi and IL-6i groups, respectively. The hazard ratio (95% confidence interval) comparing the TNFαi group to the IL-6i group was 0.66 (0.36-1.20, p = 0.168). DISCUSSION: The results underscore the lack of evidence to preferentially favor either TNFαi or IL-6i as later-line therapy in the management of bDMARDs-naive RA to mitigate the risk of serious infections.

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.

[Serotonin syndrome in a patient with small cell lung cancer].

The patient was a 67-year-old male who had been treated for several years with 150 mg fluvoxamine maleate due to depression. He visited our hospital with primary symptoms of swelling of the right upper extremity and dyspnea in August, XXXX. As a result of examinations, he was diagnosed with stage IIIB extended small cell lung cancer(T4N3M0). One course of carboplatin/etoposide(CBDCA/VP-16)therapy was started on October 1. Since the tumor size was reduced, thoracic effusion disappeared, and superior vena cava syndrome was alleviated, the therapy was changed to cisplatin/irinotecan (CDDP/CPT-11)on October 23, and the 3rd course was initiated on November 22. Anxiety and tremor appeared on the 4th day of the 3rd course and because they were exacerbated, and myoclonus appeared, a diagnosis of serotonin syndrome was made on the 38th day, and the administration of fluvoxamine maleate was discontinued. The symptoms were alleviated after the discontinuation, and the 4th course could be implemented. In this patient, serotonin syndrome was considered to have been induced by serotonin secretion promoted by the CDDP administration, and by serotonin in the brain increasing abnormally due to the SSRI.

[Effectiveness of intervention by the infection control team for cancer patients with a positive blood culture].

Cancer patients at a high risk of acquiring infectious diseases should be maintained in a facility where good infection control practices are followed. At our hospital, the infection control team(ICT)provides expertise, education, and support to the staff, helping them maintain proper standards, thereby minimizing the risks of infection. The ICT(established in 2004)has implemented infection control programs by employing an appropriate number of staff members after the revision of medical treatment fees in 2011. Our intervention program includes 2 general policies, namely, ordering and collection of blood cultures and intervention for the medical care of patients with positive blood cultures. In this study, we evaluated the effectiveness of our intervention for cancer patients with a positive blood culture. During the surveillance period(April 2011 to July 2012), 42 positive cases were determined to be infectious. ICT intervention was required in 37 cases. Our suggestions were accepted in 92%(34/37)of the cases, and improved outcome was estimated in 65%(22/34)of the cases. The results of our study contribute to the scientific bases on which routine clinical practices could be promoted in the future.

Disproportionality analysis of acetaminophen-induced hepatic disorders with and without immune checkpoint inhibitors.

BACKGROUND: Although acetaminophen is recommended for the treatment of mild-to-moderate cancer pain, acetaminophen-induced hepatic disorders pose an important clinical challenge. Concomitant prescription of immune checkpoint inhibitors (ICIs) may further increase the risk of hepatic disorders in patients taking acetaminophen; however, there are few clinical studies that confirm this. AIM: To evaluate the risk of hepatic disorders in patients taking concomitant acetaminophen and ICIs using a disproportionality analysis from the Japanese Adverse Drug Event Report database. METHOD: Acetaminophen users aged ≥ 20 years were included; factors that can affect the risk of acetaminophen-induced hepatic disorders were collated. Similar data on the widely used analgesic, loxoprofen, were used for comparison. RESULTS: Among 233,594 patients surveyed, 10,403 were prescribed acetaminophen, and among them, 1,245 patients developed hepatic disorders. The disproportionality of hepatic disorders was observed in acetaminophen users regardless of concomitant ICI use (without ICI: reporting odds ratio [ROR], 1.18; 95% confidence intervals [CI], 1.10-1.26; with ICI: ROR 1.87, 95%CI 1.59-2.20); it was even higher in concomitant acetaminophen and ICI users (ROR 1.94, 95%CI 1.65-2.29). However, increased disproportionality of hepatic disorders was not observed in patients taking concomitant loxoprofen and ICI. Multivariable logistic regression showed that the risk of hepatic disorders in acetaminophen users was associated with concomitant use of ICI (ROR, 1.91; 95% CI, 1.49-2.45); (P < 0.01). CONCLUSION: Our findings suggest that the risk of hepatic disorders is greater with concomitant acetaminophen and ICI treatment than with acetaminophen alone.

Study on enteral nutrient components causing decreased gastric phenytoin absorption.

BACKGROUND: Previously, we revealed that coadministration of particular enteral nutrients (ENs) decreases plasma concentrations and gastric absorption of phenytoin (PHT), an antiepileptic drug, in rats; however, the mechanism has not been clarified. METHODS: We measured the permeability rate of PHT using a Caco-2 cell monolayer as a human intestinal absorption model with casein, soy protein, simulated gastrointestinal digested casein protein (G-casein or P-casein) or simulated gastrointestinal digested soy protein (G-soy or P-soy), dextrin, sucrose, degraded guar gum, indigestible dextrin, calcium, and magnesium, which are abundant in the ENs, and measured the solution's properties. RESULTS: We demonstrated that casein (40 mg/ml), G-soy or P-soy (10 mg/ml), and dextrin (100 mg/ml) significantly decreased the permeability rate of PHT compared with the control. By contrast, G-casein or P-casein significantly increased the permeability rate of PHT. We also found that the PHT binding rate to casein 40 mg/ml was 90%. Furthermore, casein 40 mg/ml and dextrin 100 mg/ml have high viscosity. Moreover, G-casein and P-casein significantly decreased the transepithelial electrical resistance of Caco-2 cell monolayers compared with casein and the control. CONCLUSION: Casein, digested soy protein, and dextrin decreased the gastric absorption of PHT. However, digested casein decreased PHT absorption by reducing the strength of tight junctions. The composition of ENs may affect the absorption of PHT differently, and these findings would aid in the selection of ENs for orally administered PHT.

[Comparison of chemotherapy side effects between elderly and young subjects].

UNLABELLED: With the aging of society, the number of elderly patients receiving chemotherapy has increased. Since organ function, particularly the liver and kidney function, is known to decrease with age, there is concern that severe side effects may develop in the elderly because of chemotherapy. It is a considerable challenge to establish safe, effective chemotherapy that enables elderly patients to maintain a favorable QOL. Therefore, we conducted a survey of the current status of chemotherapy side effects. METHODS: The subjects were patients enrolled in physician-led clinical trials between April 2006 and December 2010. A survey of the chemotherapy regimens used, PS, and, side effects(CTC-AE v3.0)was conducted to examine differences in the incidence and Grade of side effects between elderly and younger subjects(aged 65 years or older, and younger than 65 years, respectively). The subjects consisted of9 3 elderly and younger people, with mean ages of 70 and 59. 5 years, respectively. Myelosuppression of Grade 3, or more severe side effects in the elderly and younger subjects, was 22. 5% and 16. 3%, respectively. The incidence of side effects was slightly higher in the elderly than in the younger subjects. In general clinical practice, side effects are controlled by selecting regimens and adjusting doses for the elderly. However, in clinical trials in which the dosage is predetermined regardless of age, the elderly are more prone to develop side effects than young people. We compare and present the current status regarding the side effects, effectiveness, and contents of chemotherapy regimens.

Analysis of the frequency of ceftriaxone-induced encephalopathy using the Japanese Adverse Drug Event Report database.

BACKGROUND: The profile of ceftriaxone-induced encephalopathy is not well understood. AIM: To identify risk factors associated with ceftriaxone-induced encephalopathy. METHOD: In this observational study, anonymised patient data were retrieved from the open-access Japanese Adverse Drug Event Report database for ceftriaxone users aged 20 years or higher. RESULTS: Data of 256,788 individuals and 12,160 cases of encephalopathy were extracted, and 2,939 ceftriaxone users, of whom 193 had encephalopathy, were identified. A disproportionate prevalence of encephalopathy was observed among the ceftriaxone users (reported odds ratio = 1.42; 95% confidence interval [CI] = 1.23-1.65; p < 0.001). Multivariate logistic regression analysis of 2,057 ceftriaxone users showed encephalopathy was associated with female sex (odds ratio [OR] = 1.52; 95% CI, 1.05-2.19; p = 0.027), chronic kidney disease (OR = 2.32; 95% CI, 1.47-3.67; p < 0.001), a ceftriaxone dosage of > 2 g/day (OR = 2.66; 95% CI, 1.66-4.26; p < 0.001), and a treatment duration of > 14 days (OR = 1.94; 95% CI, 1.21-3.11; p = 0.006). CONCLUSION: Patients with chronic kidney disease, receiving ceftriaxone at a dosage of > 2 g/day, being treated for over 14 days, and/or females may be at an increased risk of ceftriaxone-induced encephalopathy.

The Relationship Between Duration of General Anesthesia and Postoperative Fall Risk During Hospital Stay in Orthopedic Patients.

OBJECTIVES: We performed a retrospective observational study to investigate the relationship between general anesthesia duration and postoperative falls of hospitalized patients who underwent orthopedic surgery. METHODS: We used electronic medical record data and incident report data from the Osaka Medical and Pharmaceutical University Hospital. The study included 4,042 patients admitted to the Department of Orthopedic Surgery from 2014 to 2018, and the following exclusion criteria were applied: no surgery, less than 18 years of age, and fall between admission and surgery. This study only considered falls that occurred within 21 days of surgery. The multivariate logistic regression model adjusted for patient background was used to determine the risk of falling according to the duration of general anesthesia. RESULTS: After exclusions, 3,398 patients were included in the analysis. Among them, 45 patients (1.32%) had fallen, of whom 7 (15.6%) were injured and 2 (4.4%) experienced fractures. Multivariate logistic regression analysis to determine the adjusted odds ratio showed that longer general anesthesia duration was an independent risk factor for postoperative falls. In addition, cardiovascular disease had significantly higher associations with postoperative falls. CONCLUSIONS: In the postoperative care of orthopedic patients, the risk of falling should be assessed by considering the duration of general anesthesia in addition to the traditional fall risk factors. Furthermore, falls could be prevented by educating patients and their caregivers about the risk and mobilizing staff to support postoperative patients at a higher risk of falls when they walk in the hospital.

Probability of target attainment of oral antimicrobials for Escherichia coli and Klebsiella pneumoniae based on Monte Carlo simulations.

Although early transition from intravenous to oral antimicrobials can reduce hospitalization duration, susceptibility breakpoints have not been established for many oral antimicrobials against Escherichia coli and Klebsiella pneumoniae bacteremia. Thus, we used population pharmacokinetic models, pharmacokinetic/pharmacodynamic indices, and Monte Carlo simulations to evaluate the probability of target attainment (PTA) for common oral antimicrobial dosages against E. coli and K. pneumoniae. The oral antimicrobial agents evaluated included cephalexin, cefaclor, cefditoren, amoxicillin/clavulanic acid, faropenem, and levofloxacin. For E. coli, the percentage of isolates with minimum inhibitory concentrations for which a PTA >90% was achieved was 53% and less than 20% for levofloxacin and the ß-lactams, respectively. For K. pneumoniae, the percentages of isolates for which a PTA >90% was achieved were comparatively higher (cephalexin, 73%; amoxicillin/clavulanic acid, 83%; levofloxacin, 96%). Our results suggest clinicians should check if pharmacokinetic/pharmacodynamic indices are achieved in individual patients before transitioning to oral antimicrobial therapy.

Risk of Pregabalin-Induced Hypoglycemia: Analysis of the Japanese Adverse Drug Event Report Database.

Pregabalin is a first-line treatment option for neuropathic pain. Recently, some cases of pregabalin-induced hypoglycemia have been reported, which can complicate the treatment of neuropathic pain and worsen patient outcomes. Therefore, a better understanding of the clinical condition of patients with pregabalin-induced hypoglycemia is desirable. In this study, we evaluated the risk of hypoglycemia in patients administered pregabalin, using the Japanese Adverse Drug Event Report database. All patients on pregabalin not taking any antidiabetic agents were screened from April 2004 to July 2020, and data on adverse events related to hypoglycemia, sex, age, weight, and the presence of chronic kidney disease were collected. Gabapentin and duloxetine, which are usually indicated for neuropathic pain, were used for comparison. Among 242 275 patients, 4287 were administered pregabalin, which included 37 patients who reported hypoglycemic incidents. Disproportionality of hypoglycemia was observed in patients administered pregabalin (reporting odds ratio, 2.25; 95%CI, 1.16-3.13; P < .01), whereas this was not the case in patients taking gabapentin and duloxetine. Multivariate logistic regression showed that hypoglycemia in patients on pregabalin was associated with age ≥70 years (odds ratio, 2.76; 95%CI, 1.29-5.91; P < 0.01) and weight <40 kg (odds ratio, 2.97; 95%CI, 1.32-6.71; P < 0.01). These findings suggest that pregabalin may be associated with a higher risk of hypoglycemia, especially in elderly individuals with low body weight. Health care providers may need to be aware of pregabalin-induced hypoglycemia in patients with these risk factors during therapy.

Biologic Disease-Modifying and Other Anti-Rheumatic Drugs Use in Patients with Moderate-to-Severe Juvenile Idiopathic Arthritis Based on a Japanese Nationwide Claims Database.

Purpose: Biologic disease-modifying anti-rheumatic drugs (bDMARDs) are highly effective and safe against juvenile idiopathic arthritis (JIA), which is classified into systemic JIA (sJIA) and the other JIA categories (non-sJIA) according to differences in clinical symptoms and pathophysiology. The purpose of the current study was to investigate trends in patterns of prescribing bDMARDs for moderate-to-severe JIA using a relatively large sample size in Japan. Patients and Methods: A descriptive epidemiological study based on a nationwide claims database in Japan was conducted from 2012 to 2018 using the "JMDC Claims Database" to explain annual changes based on the number of patients prescribed bDMARDs. Study drugs were identified based on the Anatomical Therapeutic Chemical codes, such as methotrexate, glucocorticoids, non-steroidal anti-inflammatory drugs, and bDMARDs. Results: From a database of 6,862,244 patients, the following exclusion criteria were applied: aged ≥16 years, without "M08" in their ICD-10 code as disease, and missing the information of prescription date in the database during the study period, resulting in a final number of 111 JIA patients. We found an increasing trend for adalimumab and tocilizumab and a decreasing trend for methotrexate. Differences in medication use between sJIA and non-sJIA patients were also evident, being consistent with national and international guidelines. Conclusion: Although the introduction of bDMARDs has markedly improved the efficacy of JIA therapy, there are still many short- and long-term safety issues to be examined, including the risk of infection and potential risk of associated malignancy. Future studies are needed to clarify these issues.

Association between history of HBV vaccine response and anti-SARS-CoV-2 spike antibody response to the BioNTech/Pfizer's BNT162b2 mRNA SARS-CoV-2 vaccine among healthcare workers in Japan: A prospective observational study.

INTRODUCTION: Inadequate vaccine response is a common concern among healthcare workers at the frontlines of the COVID-19 pandemic. We aimed to investigate if healthcare workers with history of weak immune response to HBV vaccination are more likely to have weak responses against the BioNTech/Pfizer's BNT162b2 mRNA SARS-CoV-2 vaccine. METHODS: We prospectively tested 954 healthcare workers for the Anti-SARS-CoV-2 spike (S) protein antibody titers prior to the first and second BNT162b2 vaccination doses and after four weeks after the second dose using Roche's Elecsys® assay. We calculated the percentage of patients who seroconverted after the first and second doses. We estimated the relative risk of non-seroconversion after the first BNT162b2 vaccine (defined as anti-SARS-CoV-2-S titer <15 U/mL) among HBV vaccine non-responders (HBs-Ab titer <10 mIU/mL) and weak responders (≥10 and <100 mIU/mL) compared to normal responders (≥100 mIU/mL). RESULTS: Among 954 healthcare workers recruited between March 9 and March 24, 2021 at Osaka Medical and Pharmaceutical University, weak and normal HBV vaccine responders had comparable S-protein titers after the first BNT162b2 dose (51.4 [95% confidence interval 25.2-137.0] versus 59.7 [29.8-138.0] U/mL, respectively). HBV vaccine non-responders were more likely than normal responders to not seroconvert after a single dose (age and sex-adjusted relative risk 1.85 95% confidence interval [1.10-3.13]) although nearly all participants seroconverted after the second dose. After limiting the analysis to 382 patients with baseline comorbidity data, the comorbidity-adjusted relative risk of non-seroconversion among HBV vaccine non-responders to normal responders was 1.32 (95% confidence interval [0.59-2.98]). DISCUSSION: Long term follow-up studies are needed to understand if protective immunity against SARS-CoV-2 wanes faster among those with history of HBV vaccine non-response and when booster doses are warranted for these healthcare workers.