Intestinal secretion of indoxyl sulfate as a possible compensatory excretion pathway in chronic kidney disease.

Indoxyl sulfate (IS) is a protein-bound uremic toxin that progressively accumulates in plasma during chronic kidney disease (CKD), and its accumulation is associated with the progression of CKD. This study examined the intestinal secretion of IS using in situ single-pass intestinal perfusion in a rat model of renal insufficiency, MRP2- and BCRP-overexpressing Sf9 membrane vesicles, and Caco-2 cell monolayers. An in situ single-pass perfusion study in CKD model rats demonstrated that a small amount of IS is secreted into intestinal lumen after iv administration of IS, and the clearance increased AUC-dependently. An excess amount of IS (3 mm) partially inhibited the MRP2- and BCRP-mediated uptake of specific fluorescent substrates, CDCF and Lucifer yellow, respectively, into the membrane vesicles, although IS was not taken up at a physiological concentration, 10 µm. In the Caco-2 cell monolayers, the IS transport was higher in the absorptive direction than in the secretory direction (p < 0.05). p-Aminohippuric acid (PAH) strongly inhibited IS transport in both directions (absorptive, p = 0.142; secretory, p < 0.01). Given that the blood IS levels are much higher than those in the intestinal lumen, it is possible that this unknown PAH-sensitive system contributes to the intestinal IS secretion. Although in situ inhibition study is needed to confirm that this unknown transporter mediates the in vivo intestinal secretion of IS, we speculate that this unknown active efflux system works as a compensatory excretion pathway for excess organic anions such as IS especially in end-stage renal disease.

Temporal trends in antipsychotic prescriptions for pediatric patients using an administrative hospital database in Japan: a retrospective study.

BACKGROUND: Schizophrenia is a psychiatric disorder characterized by hallucinations, delusions, and other symptoms. Although treatment guidelines for schizophrenia have been established in Japan, drugs are not recommended for pediatric schizophrenia. Additionally, the temporal trends in prescribing antipsychotics for pediatric patients with schizophrenia are unclear. Therefore, we aimed to clarify the trends in antipsychotic prescriptions for Japanese pediatric outpatients from 2015 to 2022. METHODS: Administrative data (as of November 2023) of Japanese pediatric outpatients with schizophrenia aged 0-18 years who visited acute-care diagnosis procedure combination hospitals between January 1, 2015, and December 31, 2022, were included in this study. The target drugs for schizophrenia were all indicated for treating schizophrenia and marketed in Japan as of December 2022. Annual prescription trends for antipsychotics during this period were calculated based on their proportions. The Cochran-Armitage trend test was used to evaluate the proportion of prescriptions for each antipsychotic. RESULTS: The main drugs prescribed for these patients were aripiprazole and risperidone. Among male patients, the proportion of prescriptions for aripiprazole increased significantly from 21.2% in 2015 to 35.9% in 2022, whereas that for risperidone decreased significantly from 47.9% in 2015 to 36.7% in 2022 (both P < 0.001). Among female patients, the proportion of prescriptions for aripiprazole increased significantly from 21.6% in 2015 to 35.6% in 2022, whereas that for risperidone decreased significantly from 38.6% in 2015 to 24.8% in 2022 (both P < 0.001). CONCLUSIONS: Aripiprazole and risperidone were primarily prescribed for pediatric schizophrenia in Japan during the study period. Additionally, the proportion of aripiprazole prescriptions increased over time.

Pazopanib-Induced Liver Injury in Patients With Metastatic Renal Cell Carcinoma: A Report of Two Cases.

We report two cases of pazopanib (PAZ)-induced liver injury in patients with metastatic renal cell carcinoma. The first patient was a 70-year-old female who was diagnosed with right renal cell carcinoma and showed tumor embolism in the inferior vena cava. PAZ was started but discontinued after about one month due to a grade four liver injury. The second patient was a 60-year-old male who was diagnosed with left renal cell carcinoma and suspected multiple lung metastases. PAZ was started following a laparoscopic left radical nephrectomy but was stopped after about a month due to a grade three liver injury. We analyzed the plasma PAZ concentrations for treatment evaluation. High plasma PAZ concentrations were observed in both patients after PAZ treatment began. Severe liver injury after PAZ administration may be associated with high plasma PAZ concentrations; hence, we should reduce PAZ dosage early. We also recommend monitoring plasma PAZ concentrations, if possible, so that physicians can either reduce the dosage or discontinue treatment to avoid further liver damage.

Analysis of Risk Factors Associated with Reduced Trough Concentrations of Vancomycin in Relation to Renal Function in a Tertiary Hospital in Japan.

BACKGROUND: Low trough concentrations of vancomycin (VCM) are common in patients receiving the drug, because patients are often administered relatively low doses of VCM due to its high potential for renal toxicity. However, the clinical risk factors associated with low VCM trough concentration in relation to renal function are unclear. METHODS: Patients at our hospital who received VCM intravenously from January 2018 to December 2020 were analyzed. The patients were divided into two groups based on their renal function: normal and lower renal function, such as estimated glomerular filtration rate (eGFR) ≧60 and <60 mL/min/1.73 m2, respectively. In each renal function group, patients' background characteristics, laboratory data and treatments were compared between lower VCM concentration (<10 mg/L) and appropriate VCM concentration (10-20 mg/L) subgroups. RESULTS: Among 101 patients with normal renal function, 47 and 54 patients, respectively, showed lower and appropriate VCM trough concentrations. Elderly age, short stature, and higher C-reactive protein (CRP) level were significantly more common in the lower VCM concentration group compared with appropriate VCM concentration group. Among the 45 patients with renal dysfunction, 20 and 25 patients, respectively, showed lower and appropriate VCM trough concentrations. CRP levels were significantly higher in lower VCM concentration than appropriate VCM concentration subgroups. Multivariate analysis showed that insufficient total VCM doses and higher CRP might have affected the lower VCM trough concentration in patients with normal renal function. CONCLUSION: The results of this study suggest that higher CRP might be one of the risk factors associated with lower VCM concentration in both normal and low renal function patients. Severely ill and emergency patients might receive a lower VCM dose due to underestimation of the acceptable VCM dose.

Severe Pulmonary Mycobacterium abscessus Cases Due to Co-Infection with Other Microorganisms Well Treated by Clarithromycin and Sitafloxacin in Japan.

BACKGROUND: Mycobacterium abscessus frequently causes severe infections, yet its pathophysiological features and treatment regimens have not been established. CASE REPORT: We present five cases of severe pneumonia due to Mycobacterium abscessus infection in Japan. All cases were diabetic patients, with possible acceleration to pneumonia due to co-infection with other microorganisms. However, following a short period of hospitalization and combination therapy with intravenous imipenem/cilastatin and amikacin, all the cases were successfully treated as outpatients with oral clarithromycin and sitafloxacin. CONCLUSION: M. abscessus infections can become severe in the presence of diabetes mellitus and co-infection with other chronic infectious organisms. Sitafloxacin might be a key drug in the treatment of M. abscessus infection in future.

Trends in prescription of anti-seizure medicines for Japanese pediatric outpatients during 2013-2019.

Temporal trends in prescriptions of anti-seizure medicines (ASMs) for children, including newer ASMs, are unclear. We investigated ASM prescription trends for pediatric outpatients in Japan. The MDV analyzer® was used to analyze the MDV database containing de-identified hospital administrative data. Administrative data as of June 2021 including pediatric outpatients (0-17 years) with epilepsy, visiting 123 acute diagnostic procedure combination hospitals during 2013-2019, were used. Annual ASMs prescription trends were calculated, based on proportions. The Cochran-Armitage trend test evaluated the proportion of prescriptions for each ASM. ASMs most often prescribed were valproic acid, carbamazepine, and levetiracetam, regardless of sex. In girls, the proportion of valproic acid and carbamazepine prescriptions decreased from 37.93% to 26.84%, and from 24.80% to 15.78%, respectively (p < 0.0001). Conversely, the proportion of levetiracetam prescriptions increased from 6.40% to 28.18% (p < 0.0001). In boys, the proportion of valproic acid and carbamazepine prescriptions decreased, from 36.58% to 32.20% and from 26.42% to 16.85%, respectively (p < 0.0001). The proportion of levetiracetam prescriptions increased from 5.64% to 23.02% (p < 0.0001). Overall, the proportion of valproic acid and carbamazepine prescriptions declined, whereas levetiracetam prescriptions increased. Trends in ASM prescriptions among pediatric outpatients with epilepsy in Japan have shifted towards more recently available ASMs.

Reduced Prescription of Baloxavir After Suspected Prevalence of a Baloxavir-Resistant Influenza Virus Strain and the Emergence of SARS-CoV-2 in a Tertiary Hospital in Japan.

OBJECTIVE: The use of baloxavir, a new anti-influenza agent, began in Japan from the 2018 to 2019 season and became the focus of attention due to its efficient viral reduction ability; therefore, we should know the prescription changes of anti-influenza agents. METHODS: We analyzed the changes in the prescription of anti-influenza agents between the 2018-19 season and the 2019-20 season in our hospital. RESULTS: The share of baloxavir was 15%, while the shares of oseltamivir and laninamivir were 42% and 31%, respectively in the 2018-2019 season. However, in the 2019-20 season, the share of baloxavir and laninamivir was reduced to 3% and 17%, respectively, in contrast to an increase in the share of oseltamivir (66%). The total prescription of anti-influenza agents for patients decreased in the 2019-20 season (205 patients), compared with the 2018-19 season (509 patients). CONCLUSION: These results suggest significant changes such as a reduction in the prescription of anti-influenza agents, especially baloxavir, likely due to the suspected prevalence of a baloxavir-resistant strain of influenza virus and the emergence of SARS-CoV-2 in Japan.