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Medical personnel actively provide patients taking capecitabine with information on the items to prevent and treat hand-foot syndrome (HFS). However, they are typically unable to ascertain the extent of patient compliance with the recommended items. Thus, the aim of the present study was to ascertain the association between patient compliance with preventative measures for HFS and the development of HFS. Subjects included 90 patients who were treated with a drug regimen that included capecitabine. Patients were treated at one of four facilities between July 2015 and January 2017. The main parameters studied were the extent to which items to prevent and treat HFS were (or were not) followed, and the associaiton between this extent and the development of HFS symptoms. A manual prepared by a pharmaceutical company that manufactures capecitabine describes 15 routine items to follow in order to prevent and treat HFS. The two activities patients most often performed were 'applying a moisturizer' (74.1%) and 'keeping one's skin clean (e.g., washing one's hands and feet)' (64.7%). The two activities patients least often performed were 'using sunscreen on exposed areas' (14.1%) and 'using soft insoles' (11.8%). Patients who performed more items to prevent and treat HFS were significantly less likely to develop symptoms of HFS (P=0.022). Based on these findings, it is recommended that medical personnel provide instructions to the patients regarding the specific items necessary to prevent and treat HFS, and to follow-up with the patients regarding their compliance, with an emphasis on the items they are less likely to take and on the instructions to avoid external irritants. Following these guidelines should lead to qualitative improvement in HFS management.

The purpose of this study was to examine whether tetrahydrobiopterin (BH4), a cofactor of nitric oxide (NO) synthase, attenuates gastric ischemia-reperfusion injury induced by clamping of the celiac artery. Gastric injury was assessed by a formation of gastric mucosal erosions. The gastric injury was observed at 30 and 60 min after reperfusion following 30-min ischemia and was reduced by superoxide dismutase (SOD), catalase, or NO synthase inhibitors. Therefore, reactive oxygen species (ROS) and NO seem to be implicated in the ischemia-reperfusion injury. Treatment with BH4 reduced the ischemia-reperfusion injury. Pretreatment with sepiapterin, a precursor of BH4, also reduced the ischemia-reperfusion injury with an increase in BH4 content in serum and stomach. Both the increase in BH4 content and the protective effect of sepiapterin were prevented of pretreatment with N-acetylserotonin, an inhibitor of BH4 synthesis. These results suggest that the increase in BH4 content may protect against gastric ischemia-reperfusion injury via reduction of ROS and/or NO toxicity. BH4 might be useful as a therapeutic agent for gastric ischemia-reperfusion injury.

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BackgroundWe formulated mianserin suppositories for the treatment of delirium and evaluated their pharmacokinetics by measuring plasma drug concentrations in dogs and healthy human volunteers.MethodsMianserin suppositories were prepared by a melting technique using Tetramide® tablets and Witepsol H-15 as the suppository base. Pharmacokinetics of this 30-mg mianserin preparation were evaluated in three beagle dogs and three healthy adult males, in line with ethics committee approval. Plasma mianserin levels were determined using gas chromatography–mass spectrometry.ResultsIn dogs, the maximum plasma mianserin concentration (Cmax) was 1.3 ± 0.4 ng/mL, the time to Cmax (tmax) was 5.5 ± 4.3 h, and the area under the plasma concentration-time curve from 0 to 24 h (AUC0-24) was 18.9 ± 1.9 h・ng/mL. In humans, the Cmax was 14.6 ± 6.3 ng/mL, the tmax was 8 h, and the AUC0-24 was 266 ± 103 h・ng/mL.ConclusionsThe current study characterized the pharmacokinetics of mianserin suppositories in dogs and humans. As compared to oral administration, the suppositories produced a lower Cmax and a delayed tmax, although AUC0-24 values were comparable. It will be necessary to identify an appropriate dose that produces an adequate plasma mianserin concentration for effective and safe clinical use.Trial registrationUMIN000013853.

Background: Despite a range of treatment options, about 25% of patients with painful bone metastases suffer from uncontrolled pain. This Phase 3, randomized, double-blind, placebo-controlled trial (24-week treatment/24-week follow-up) examined the efficacy and safety of tanezumab, a monoclonal antibody against nerve growth factor, in subjects with moderate to severe cancer pain due to bone metastasis or multiple myeloma receiving background opioid therapy.Methods: Subjects from 15 countries (Europe, South America, Asia-Pacific regions) were randomized and received double-blind subcutaneous placebo or tanezumab 20 mg at baseline, week 8, and week 16 while continuing optimized opioid therapy. The primary endpoint was change in daily average pain intensity (0 ¼ no pain to 10 ¼ worst possible pain) at the index bone metastasis cancer pain site from baseline to week 8, evaluated via analysis of covariance. Adverse events (AEs) and pre-specified joint safety events (rapidly progressive osteoarthritis [RPOA] type 1 or 2, primary osteonecrosis, subchondral insufficiency fracture, or pathologic fracture; adjudicated by an external expert committee) were also assessed.Results: Tanezumab 20 mg (N ¼72) met the primary endpoint by demonstrating significantly (p ¼ 0.038 with a ¼ 0.048) greater improvement in daily average pain intensity at the index bone metastasis cancer pain site at week 8 compared with placebo (N ¼ 73). LS mean (95% CI) change in pain was -1.25 (-1.94, -0.55) for placebo and -2.03 (-2.73, -1.33) for tanezumab 20 mg. Differences past week 8 were not statistically significant. During the treatment period, the AE profile of tanezumab 20 mg was generally consistent with AEs expected in subjects with cancer pain due to bone metastasis and the known safety profile of tanezumab. The proportion of subjects adjudicated with a pre-specified joint safety event during the study was 0% for placebo and 2.8% for tanezumab 20 mg (pathological fracture near the site of bone metastasis, n ¼ 2). No events of RPOA were reported.Conclusions: Tanezumab 20 mg improved metastatic cancer-related bone pain compared with placebo and the AE profile was generally consistent with previous studies of tanezumab.Clinical trial identification: NCT02609828.

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1047 Background: Taxane-based regimens have been widely used to treat breast cancer. Accordingly, it has become important to identify subgroups in which anthracyclines are indispensable. Thus, we initiated a randomized phase II neoadjuvant chemotherapy (NAC) study to compare taxane with and without anthracycline in hormone-negative subtypes. Methods: Eligibility criteria were hormone-negative, an age younger than 80 years and ECOG PS0-1. According to HER2 status, patients were randomly assigned to TC (75/600 mg/m2) q3wks ×6 or FEC (500/100/500 mg/m2) q3wks ×3 followed by D (100 mg/m2) q3wks ×3. The primary endpoint was the rate of pathological complete response (pCR; Grade 3 and Quasi-pCR; Grade 3+2b). Secondary endpoints were safety, breast-conserving surgery ratio, disease-free survival, overall survival, and predictive factors (HER2, Ki-67, P-53, CK5/6, EGFR, and TOP2A by IHC and TOP2A by FISH) for each regimen. Results: 97 out of 103 patients were successfully analyzed (47 for TC6 and 50 for FEC-D). Severe adverse events (Grade ≥2) were frequently observed in FEC-D-treated patients with statistical significance (poor appetite, nausea/vomiting: p<0.001; febrile neutropenia: p=0.016). The pCR rate tended to be higher in FEC-D-treated patients compared with that of TC6-treated patients (pCR: 36.0 vs. 25.5%, n.s.; Quasi-pCR: 46.0 vs. 40.4%, n.s.). There was no significant difference of pCR rates in the HER2 and triple negative (TN) subtypes between each regimen. Among predictors, only positive markers CK5/6 and EGFR predicted the superiority of the FEC-D treatment (p=0.05). Conclusions: TC6 was safe and relatively active even in HER2 subtype patients. Therefore, the concurrent use of trastuzumab with TC could be a reasonable option for NAC in HER2 subtype patients. However, anthracyclines are required to treat basal-type TN cancer. Clinical trial information: UMIN000002215.