PURPOSE: We evaluated the efficacy and safety of antiemetic therapy with olanzapine, a neurokinin-1 receptor antagonist (RA), a 5-hydroxytryptamine-3 (5-HT₃) RA, and dexamethasone for preventing chemotherapy-induced nausea and vomiting in patients receiving carboplatin-containing chemotherapy. PATIENTS AND METHODS: Chemotherapy-naïve patients scheduled to receive carboplatin (AUC ≥5) were randomly assigned to receive either olanzapine 5 mg once daily (olanzapine group) or placebo (placebo group) in combination with aprepitant, a 5-HT₃ RA, and dexamethasone. The primary end point was the complete response (CR; no vomiting and no rescue therapy) rate in the overall phase (0-120 hours). Secondary end points included the proportion of patients free of nausea and safety. RESULTS: In total, 355 patients (78.6% male, median age 72 years, 100% thoracic cancer), including 175 and 180 patients in the olanzapine and placebo groups, respectively, were evaluated. The overall CR rate was 86.9% in the olanzapine group versus 80.6% in the placebo group. The intergroup difference in the overall CR rate was 6.3% (95% CI, –1.3 to 13.9). The proportions of patients free of chemotherapy-induced nausea in the overall (88.6% in the olanzapine group v 75.0% in the placebo group) and delayed (89.7% v 75.6%, respectively) phases were significantly higher in the olanzapine group than in the placebo group (both P < .001). Somnolence was observed in 43 (24.6%) and 41 (22.9%) patients in the olanzapine and placebo groups, respectively, and no events were grade ≥3 in severity. CONCLUSION: The addition of olanzapine was not associated with a significant increase in the overall CR rate. Regarding the prevention of nausea, adding olanzapine provided better control in patients receiving carboplatin-containing chemotherapy, which needs further exploration.

The aim of this study was to identify factors affecting the pharmacokinetics of mycophenolic acid (MPA) and its 7-O-glucuronide (MPAG) in systemic lupus erythematosus (SLE) patients. Thirty-one SLE patients in remission maintenance phase treated with mycophenolate mofetil (median 1500 mg/d) and prednisolone and followed-up for up to 56 months (median 13 months) were enrolled. Creatinine clearance and metal medication were significant predictors accounting for interindividual variability in the dose-normalized predose plasma concentration (C0) of MPA (adjusted R2=0.305, p=0.01) in a multivariate analysis. Dose-normalized MPAG C0 was significantly correlated with only creatinine clearance (adjusted R2=0.135, p=0.03). The free fraction of MPA was significantly correlated with only serum albumin (adjusted R2=0.700, p<0.01). The free fraction of MPAG was significantly correlated with serum albumin, metal medication, and age (adjusted R2=0.598, p=0.02). In conclusion, renal function and co-administered metal influenced the pharmacokinetics of MPA and MPAG in SLE patients in remission maintenance phase.

Objective: In the Japanese Pharmacists Act, article 25-2, revised in 2013, it states that pharmacists shall provide the necessary information and guidance to the patient based on pharmaceutical knowledge and experience for ensuring the proper use of the medicine dispensed. The package insert is one of the documents to be referred to when providing the information and guidance. The boxed warnings in package inserts that include the precautions and responses are the most significant parts, however, the suitability of boxed warnings for pharmaceutical practice has not been evaluated. The aim of this study was to investigate the boxed warning descriptions in package inserts of prescription medicines for medical professionals in Japan. Methods: Package inserts of prescription medicines listed in the Japanese National Health Insurance drug price list on March 1st 2015 were collected one by one by hand from the website of the Japanese Pharmaceuticals and Medical Devices Agency (https://www.pmda.go.jp/english/). Package inserts with boxed warnings were classified according to the Standard Commodity Classification Number of Japan based on the pharmacological activity of each medicine. They were also compiled according to their formulations. The boxed warnings were divided into the precautions and responses parts, and their characteristics were compared among medicines. Results: The number of package inserts found on the website of the Pharmaceuticals and Medical Devices Agency was 15,828. Boxed warnings were present in 8.1% of the package inserts. A description of adverse drug reactions accounted for 74% of all precautions. Most of the precautions were observed in the warning boxes of antineoplastic agents. Blood and lymphatic system disorders were the most common precaution. Responses in the boxed warnings directed toward medical doctors, pharmacists, and other healthcare professionals accounted for 100, 77, and 8% of all package inserts with a boxed warning, respectively. Explanations for patients were the second most frequent response. Conclusions: The majority of boxed warnings request therapeutic contribution by pharmacists, and the descriptions of these explanations and guidance by pharmacists to patients were found to be consistent with the Pharmacists Act.

Aberrant systemic IgG responses to the gut microbiota may be implicated in the pathogenesis of ulcerative colitis (UC). In this study, we investigated IgG-targeted bacteria and their predicted functional characteristics in UC. Using fecal samples and autologous sera from 37 patients with UC and 4 healthy controls, we profiled IgG-targeted bacteria under in vitro conditions using 16S rRNA gene sequencing. To correct for background bacterial abundance, we calculated the IgG+ Probability Score (IPS), which integrates the sample-specific IgG-binding rate to isolate candidate IgG-targeted taxa. Systemic IgG responses were selectively targeted at specific bacterial taxa rather than uniformly directed toward the entire gut microbiota. Active UC and elevated systemic inflammatory markers were associated with increased IPS in oral-associated commensals, including Granulicatella, as well as mucin-degrading taxa. Predictive functional profiling indicated the predicted enrichment of pathways hypothesized to be related to host-derived mucin degradation, capsular polysaccharide biosynthesis, and amino acid biosynthesis. Furthermore, exploratory Random Forest models using IPS features highlighted candidate taxa that differed among clinical parameters (UC exacerbation, Clinical Activity Index, and C-reactive protein), although their classification performance was not independently validated. In conclusion, our in vitro profiling indicates that systemic IgG in UC has the capacity to selectively target specific bacterial taxa associated with disease activity and systemic inflammation. Analyzing the IgG-targeted microbiota via IPS profiling deepens our understanding of host–microbiota interactions in UC and provides a valuable framework for evaluating candidate immune-targeted bacteria associated with disease activity.

This study aimed to evaluate the relationships between the pharmacokinetics of tolvaptan and its metabolites (DM-4103 and DM-4107) and liver injury in heart failure patients, using relevant laboratory test values and markers of hepatocyte injury and biliary cholestasis. The plasma concentrations of tolvaptan, DM-4103, and DM-4107 were determined using LC-MS/MS in 51 Japanese heart failure patients. The relationships between the concentrations and the N-terminal fragment of pro-B-type natriuretic peptide (NT-proBNP), AST, and ALT were assessed. K18 and glutamate dehydrogenase as a marker of liver injury and CP-I and CP-III as indicators of OATP activity were also determined. The median concentrations of tolvaptan, DM-4103, and DM-4107 were 16.2, 287, and 38.0 ng/mL, respectively. AST, ALT, and T-Bil were significantly decreased after tolvaptan administration. They were negatively correlated with tolvaptan concentration. AST was also negatively correlated with DM-4107 concentration. CP-III was positively correlated with DM-4103 concentration; however, CP-I was negatively correlated with DM-4103 concentration. K18 and glutamate dehydrogenase were not correlated with tolvaptan concentration. Low-dose tolvaptan did not cause liver injury. Pharmacokinetics of tolvaptan may be associated with potential amelioration of liver function in heart failure patients.