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Background Pegfilgrastim-induced aortitis is a rare but serious adverse event in patients undergoing anticancer therapy with granulocyte colony-stimulating factor analogs. Despite previous case series and systemic reviews, the exact incidence, clinical presentation, and CT manifestations of pegfilgrastim-induced aortitis remain unclear. Purpose To clarify the incidence and clinicoradiologic characteristics of pegfilgrastim-induced aortitis. Materials and Methods Pegfilgrastim administration records from January 2015 to March 2021 were retrospectively collected from the drug prescription database of a single center and were matched with the relevant findings in the CT database. Corresponding CT images within 6 months were available for a total of 1462 doses of pegfilgrastim in 674 patients. Four radiologists reviewed the CT images for the presence of aortitis in two steps. Clinical information and the distribution of aortitis on CT images were examined for patients with a diagnosis of pegfilgrastim-induced aortitis. Results Pegfilgrastim-induced aortitis was observed in 18 of 674 patients (mean age, 62 years ± 13 [SD]; 424 men), resulting in incidence rates of 2.7% per patient (95% CI: 1.6, 4.2) and 1.2% per dose (95% CI: 0.7, 1.9). The most common original primary malignancies were esophageal cancer (

Effects of GSK3beta inhibition on the formation of invadopodium-like microstructures and matrix degradation by U251 cells.

Source and working dilutions of the primary antibodies used for Western blotting, immunofluorescence and immunohistochemical staining and pull-down assay.

Background Vancomycin has a narrow therapeutic window, and an increase in its serum concentration-to-dose ratio during treatment can cause renal toxicity. Therefore, this study was aimed at finding a marker to identify patients at risk of increasing serum vancomycin during treatment. Methods This was a retrospective cohort study of patients treated with vancomycin at Kanazawa University Hospital, Japan, from April 2012 to May 2015. Spearman correlation coefficients were calculated to determine the correlations between changes in vancomycin concentration-to-dose ratio and initial values or changes in laboratory data and other parameters. In addition, a multiple regression analysis was conducted. Results One hundred ninety-nine patients for whom 2 or more points of data on therapeutic drug monitoring (TDM) of intravenous vancomycin treatment were available and did not undergo dialysis were included in the study. Changes in vancomycin concentration-to-dose ratio were associated with C-reactive protein (CRP) and sodium (Na) levels on the initial day of TDM and with changes in white blood cell count, Na, and estimated glomerular filtration rates (eGFRs). Multiple regression analysis helped identify CRP and Na levels on the initial day of TDM and change in eGFR as independent influencing variables. Conclusions A high serum CRP level on the initial day of TDM is an independent predictor of increasing vancomycin concentration-to-dose ratio in patients receiving intravenous vancomycin treatment, even if eGFR remains unchanged.

Erlotinib shows pH-dependent solubility and its absorption is decreased in patients receiving gastric acid suppression therapy. Here, we examined whether administration of erlotinib in acidic solutions would improve its solubility and absorption characteristics. In vitro, the solubility of erlotinib in HCl solution increased with decreasing pH, and was far higher than that in tap water. The solubility in apple juice (pH 3.7) was higher than that in HCl solution of the same pH. In vivo, the absorption of erlotinib administered in tap water was decreased in omeprazole-treated (OP) rats, used as a model of gastric acid suppression, compared to control rats. In the OP rats, the plasma concentrations in the groups given erlotinib in apple juice and in HCl (pH 3.7) were significantly higher than in the tap water group in the initial phase of absorption. AUC in OP rats given erlotinib in apple juice was 1.69-fold larger than that of control rats given erlotinib in tap water, and 2.49-fold larger than that of OP rats given erlotinib in tap water. Thus, administration of erlotinib in an acidic beverage to patients receiving gastric acid suppression therapy might be effective to increase solubility and absorption.

Many stroke patients cannot urinate independently due to motor and cognitive dysfunctions. This study examined whether a continuous continence self-management program during acute and convalescent phases is associated with independence in voiding behavior.A retrospective cohort study was conducted among stroke patients registered in the Council of Kaga Local Stroke Network, Japan, from 2015 to 2019. In the intervention group (n = 941), a multidisciplinary continence care team and ward nurses provided continence care in the acute phase and shared the information with the staff in the convalescent ward. The control group (n = 579) received traditional voiding care from ward nurses. The primary and secondary outcomes were independence in voiding behavior at discharge from the convalescent ward and length of hospital stay, respectively.At discharge from the convalescent wards, the proportion of patients who voided at the toilet or bedside commode was higher in the intervention group than in the control group (76.3% vs. 62.4%, p 0.001). The continuous continence self-management program was associated with independence in voiding behavior (adjusted odds ratio: 1.801, 95% confidence interval [CI]: [1.102, 2.942]; p = 0.019) and length of hospital stay (β: -0.178, 95% CI: [-14.320, -7.607]; p 0.001) after adjusting for other variables.The program was associated with increasing independent voiding behavior and shortened the length of hospital stay, suggesting the importance of promoting treatments for lower urinary tract symptoms and rehabilitation by a multidisciplinary continence care team for stroke patients.

Many stroke patients experience motor and cognitive dysfunctions that make living at home challenging. We aimed to identify the factors associated with hospital discharge to home in older stroke patients in convalescent rehabilitation wards where intensive and comprehensive inpatient rehabilitation are performed following acute-phase treatment.: A retrospective cohort study was conducted among 1227 older stroke patients registered in the database of the Council of Kaga Local Stroke Network, Japan, between 2015 and 2019. Patients' basic characteristics, discharge destination, type and severity of stroke, cognitive status, and activities of daily living (ADL) including continence were evaluated.: The proportion of subjects discharged to home was 62.3%. The mean hospital stay in the home discharge group was shorter than that in the non-home discharge group (111 days vs. 144.6 days, P0.001). The following factors were associated with discharge to home: age (adjusted odds ratio [AOR]: 2.801, 95% confidence interval [CI] [1.473, 2.940]; P0.001), sex (AOR: 1.513, 95% CI [1.112, 2.059]), stroke type (AOR: 1.426, 95% CI [1.013, 2.007]), low cognitive status (AOR: 3.750, 95% CI [2.615, 5.379]), low level of bladder control (AOR: 2.056, 95% CI [1.223, 3.454]), and low level of bowel control (AOR: 2.823, 95% CI [1.688, 4.722]).: Age, sex, stroke type, cognitive function, and ADL scores for bladder and bowel control were associated with discharge to home. Improving continence management regarding both voiding and defecation may be a promising care strategy to promote hospital discharge to home in older stroke patients.

Purpose Multidrug resistance protein 1 (MDR1) is located at the interface between two syncytiotrophoblast layers in rodent placenta, and may influence fetal drug distribution. Here, we quantitatively compare the functional impact per single MDR1 molecule of MDR1 at the placental barrier and blood-brain barrier in mice. Methods MDR1A and MDR1B proteins were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Paclitaxel or digoxin was continuously administered to pregnant Mdr1a−/−/Mdr1b−/− or wild-type mice, and the drug concentrations in the maternal and fetal plasma and maternal brain were quantified by LC-MS/MS. Results MDR1A and MDR1B proteins are expressed in the membrane of mouse placental labyrinth, and total MDR1 at the placental barrier amounts to about 30% of that at the blood-brain barrier. The fetal-to-maternal plasma concentration ratio of digoxin was only marginally affected in Mdr1a−/−/Mdr1b−/− mice, while that of paclitaxel showed a several-fold increase. No such difference between the two drugs was found in the maternal brain distribution. The impact per single MDR1 molecule on the fetal distribution of digoxin was calculated to be much lower than that on the brain distribution, but this was not the case for paclitaxel. Our pharmacokinetic model indicates that the impact of placental MDR1 is inversely correlated to the ratio of permeability through gap junctions connecting the two syncytiotrophoblast layers to passive diffusion permeability. Conclusion Our findings indicate that murine placental MDR1 has a minimal influence on the fetal concentration of certain substrates, such as digoxin, due to bypass transfer, probably via connexin26 gap junctions.

Background/aim High-dose methotrexate (HD-MTX) is pivotal chemotherapy in the treatment of patients with osteosarcoma. Blood concentrations of MTX are associated with several side effects, but there are large individual differences in the elimination of MTX. The aim of this study was to explore risk factors for delayed elimination of MTX in children, adolescents and young adults with osteosarcoma. Patients and methods We conducted a retrospective study on Japanese patients with osteosarcoma who were treated with HD-MTX at Kanazawa University Hospital from April 2006 to March 2015. Risk factors for delayed elimination of methotrexate were identified by multiple logistic regression analysis. Results A total of 92 cycles of HD-MTX therapy were analyzed. Female and lower creatinine clearance (CCr) were identified as independent risk factors for delayed elimination of MTX. Conclusion Knowing the factors associated with delayed elimination of MTX could lead to safer and optimized chemotherapy for patients with osteosarcoma.

Background Corticosteroid-induced psychiatric disorders (CIPDs) represent an adverse effect that can cause severe emotional and behavioral problems. The aim of the present study was to assess the incidence and risk factors of CIPDs. Methods A retrospective analysis of 92 pediatric and young adult patients with hematologic malignancies was conducted. Results The incidence of CIPDs in patients receiving a treatment regimen with prednisolone or dexamethasone was 64.9% and 77.5%, respectively, both of which were significantly higher than that in patients not receiving corticosteroids. Independent risk factors and adjusted odds ratios (95% confidence intervals) related to severe CIPD were 2.15 (1.11–4.18) for dexamethasone (using prednisolone as the reference) and 0.81 (0.75–0.87) for age, suggesting that the odds increase with decreasing age. Frequently observed symptoms, respectively in terms of behavioral and emotional problems were defiance, crying, psychomotor excitement, dysphoria, irritability, and depression. To our knowledge, this is the first report to mention the risk factors and characteristics for clinical symptoms of CIPDs during the developmental process. Conclusions Healthcare professionals should predict and prepare for psychiatric adverse events prior to chemotherapy in the clinical settings, especially in patients in younger age and receiving a treatment regimen with dexamethasone.

Background: High-dose methotrexate (HD-MTX) therapy is widely implemented for leukemia, osteosarcoma, and lymphoma. Although various measures have been taken to avoid toxicity from high serum MTX concentrations, there are many cases of delayed elimination of MTX. Objective: We suspected that delayed elimination of serum MTX was caused by unknown interactions between MTX and concomitant drugs. Methods: Concerning concomitant drugs in the case of delayed elimination of MTX, we performed screening tests in 35 patients who had undergone HD-MTX therapy. We then investigated the risk factors for delayed MTX elimination in 94 patients with leukemia, lymphoma, or osteosarcoma retrospectively. Results: The percentages of concomitant use of Stronger Neo-Minophagen C (SNMC), a glycyrrhizin preparation, and vincristine were higher in the delayed group. The percentage of delayed MTX elimination in patients receiving HD-MTX therapy was 41%. Multiple logistic regression analysis revealed that the concomitant use of SNMC solely was a significant risk factor for delayed MTX (odds ratio = 12.20; 95% CI = 1.06-139.84). Conclusion and Relevance: Concomitant use of SNMC was shown to be related to delayed elimination of serum MTX, and our results suggested a previously unknown drug-drug interaction between MTX and SNMC.

Oxytocin-enhanced prosocial behaviour depends on individual characteristics. This study investigated the relationship between oxytocin and competitiveness, which is another important social trait and predicts economic and social outcomes. In this double-blind, randomized, and placebo-controlled study of 192 male participants, we examined whether oxytocin moderates competitiveness and whether the effect of oxytocin on competitiveness is amplified in individuals with autistic traits. While our results show no relationship between oxytocin and competitiveness, we observed suggestive patterns: albeit not significantly, oxytocin reduced and enhanced competitiveness among participants without autistic traits and among their counterparts with autistic traits, respectively.

BACKGROUND/AIM The control of chemotherapy-induced nausea and vomiting during bleomycin, etoposide, and cisplatin (BEP) treatment is important for maintaining treatment intensity. The effects of palonosetron and granisetron were compared in BEP chemotherapy. PATIENTS AND METHODS The administration of palonosetron on days 1 and 5 (Pal method) and granisetron daily (days 1-5, Gra method) were compared in terms of their efficacy and cost-effectiveness. RESULTS Additional rescue antiemetic agents were used in 15 of 32 and 30 of 30 cycles in the Pal and Gra method groups, respectively (p

We previously showed that adhesive aggregates were formed when levofloxacin hydrate tablets and lansoprazole orally disintegrating (OD) tablets were suspended in water in the clinical context. In this study, we have clarified the factors causing aggregate formation, focusing on the role of pharmaceutical additives and electrostatic interaction. Co-suspension of enteric-coated proton pump inhibitor (PPI) esomeprazole magnesium hydrate with levofloxacin resulted in aggregate formation, whereas the non-enteric-coated PPI vonoprazan fumarate did not. A comparison of pharmaceutical additive in the two PPIs highlighted polysorbate 80 and methacrylic acid copolymer LD as candidates causing aggregation. When these pharmaceutical additives were added to levofloxacin, only methacrylic acid copolymer LD induced aggregate formation. Since levofloxacin is zwitterionic, we examined another zwitterionic ingredient, ampicillin sodium, and found that it also formed aggregates with methacrylic acid copolymer LD, while benzylpenicillin sodium, which is not zwitterionic, did not form aggregates. When we next examined a series of zwitterionic quinolone antimicrobial drugs, we found that ofloxacin, which is highly soluble, formed aggregates with lansoprazole OD tablets, whereas poorly soluble quinolone antimicrobial drugs did not form aggregates. Further, although cefepime hydrochloride and cephalexin did not form aggregates with methacrylic acid copolymer LD in tap water, aggregates were formed when a suspension of cefepime hydrochloride or cephalexin with methacrylic acid copolymer LD was adjusted to pH 7.0. Our results indicate that electrostatic interaction between zwitterionic ingredients and methacrylic acid copolymer LD can result in aggregate formation under conditions where the drug and methacrylic acid copolymer LD are both sufficiently soluble.

Hepatic arterial infusion (HAI) chemotherapy is expected to be a more effective and safer method to treat the hepatic metastasis of pancreatic cancer than intravenous (iv) administration because of higher tumor exposure and lower systemic exposure. To clarify the uptake mechanism of nucleoside anticancer drugs, including gemcitabine (GEM), in pancreatic cancer, we investigated the uptakes of radiolabeled uridine (a general substrate of nucleoside transporters) and GEM in pancreatic cancer cell lines MIA-PaCa2 and As-PC1. Uridine uptake was inhibited by non-labeled GEM and also by S-(4-nitrobenzyl)-6-thioinosine (NBMPR; an inhibitor of equilibrative nucleoside transporters, ENTs) in a concentration-dependent manner, suggesting that ENTs contribute to uridine uptake in pancreatic cancer cells. As for GEM, saturable uptake was mediated by high- and low-affinity components with Km values of micromolar and millimolar orders, respectively. Uptake was inhibited in a concentration-dependent manner by NBMPR and was sodium ion-independent. Moreover, the concentration dependence of uptake in the presence of 0.1 μM NBMPR showed a single low-affinity site. These results indicated that the high- and low-affinity sites correspond to hENT1 and hENT2, respectively. The results indicated that at clinically relevant hepatic concentrations of GEM in GEM-HAI therapy, the metastatic tumor exposure of GEM is predominantly determined by hENT2 under unsaturated conditions, suggesting that hENT2 expression in metastatic tumor would be a candidate biomarker for indicating anticancer therapy with GEM-HAI.

ECa 233 is a standardized extract of Centella asiatica, characterized as a white powder containing triterpenoid glycosides not less than 80% with a ratio of madecassoside to asiaticoside of 1.5±0.5:1. Although pharmacological and toxicological profiles of ECa 233 have been successively reported, the pharmacokinetic data needed for further therapeutic development are not fully elucidated. This study aimed to investigate the pharmacokinetics of multiple oral dosing of ECa 233 at 100 mg/kg/day for 7 days in rats. Plasma, tissues, urine, and feces were collected from 0 to 24 h after dosing on days 1 and 7. The concentrations of asiaticoside, madecassoside, asiatic acid, and madecassic acid were simultaneously analyzed by liquid chromatography-tandem mass spectrometry. No significant change was observed in physical and blood biochemical parameters of the animals treated with ECa 233 for 7 days. The maximum plasma concentration and area under the curve at day 7 of madecassoside and asiaticoside decreased by 70–80% from day 1. However, both triterpenoid glycosides were extensively distributed and accumulated, resulting in significantly higher concentrations at pharmacologically relevant organs. Madecasssic acid and asiatic acid are major metabolites mainly found in and excreted via feces. Moreover, multiple dosing of ECa 233 increased mRNA expression of Abcb1a and Abcc2 in the small intestine by approximately 2- to 3-fold. This is the first study to identify an inductive effect of a standardized extract of C. asiatica after multiple oral dosing in rats. Potential drug-herb interactions when ECa 233 is coadministered with Abcb1a and Abcc2 substrates calls for further investigations.

Background Ritodrine hydrochloride (RD), a β2-adrenergic agonist, is widely used as a tocolytic medication to suppress premature labor, but can cause neonatal hypoglycemia, a potentially severe side effect. We examined the incidence and risk factors of neonatal hypoglycemia following maternal intravenous administration of RD. Methods This was a retrospective study of neonates, who had birth weight of ≥2000 g and were delivered at 36 weeks gestation or later in Kanazawa University Hospital from August 2013 to July 2016. We defined neonatal hypoglycemia as blood glucose level

Background/Aim: The control of chemotherapy-induced nausea and vomiting during bleomycin, etoposide, and cisplatin (BEP) treatment is important for maintaining treatment intensity. The effects of palonosetron and granisetron were compared in BEP chemotherapy. Patients and Methods: The administration of palonosetron on days 1 and 5 (Pal method) and granisetron daily (days 1-5, Gra method) were compared in terms of their efficacy and cost-effectiveness. Results: Additional rescue antiemetic agents were used in 15 of 32 and 30 of 30 cycles in the Pal and Gra method groups, respectively (p

Background Combination therapy of linezolid (LZD) and rifampicin (RFP) may be more effective than monotherapy for treating gram-positive bacterial infections, but several studies have suggested that RFP decreases LZD exposures, thereby increasing the risk of therapeutic failure and emergence of LZD-resistant strains. However, the mechanism of the drug-drug interaction between LZD and RFP is unknown. Methods We conducted a prospective, open-label, uncontrolled clinical study in Japanese patients receiving LZD and RFP to evaluate the effect of coadministered RFP on the concentration of LZD. In animal study in rats, the influence of coadministered RFP on the pharmacokinetics of LZD administered intravenously or orally was examined. Intestinal permeability was investigated with an Ussing chamber to assess whether coadministered RFP alters the absorption process of LZD in the intestine. Results Our clinical study indicated that multiple doses of RFP reduced the dose-normalized trough concentration of LZD at the first assessment day by an average of 65%. In an animal study, we found that multiple doses of RFP significantly decreased the area under the concentration-time curve, the maximum concentration and the bioavailability of orally administered LZD by 48%, 54% and 48%, respectively. In contrast, the pharmacokinetics of intravenously administered LZD was unaffected by the RFP pretreatment. However, investigation of the intestinal permeability of LZD revealed no difference in absorptive or secretory transport of LZD in the upper, middle and lower intestinal tissues between RFP-pretreated and control rats, even though RFP induced gene expression of multidrug resistance protein 1a and multidrug resistance-associated protein 2. Conclusions Therapeutic drug monitoring may be important for avoiding subtherapeutic levels of LZD in the combination therapy. The drug-drug interaction between LZD and RFP may occur only after oral administration of LZD, but is not due to any change of intestinal permeability of LZD. Trial registration UMIN, UMIN000004322. Registered 4 October 2010.

The failure of current treatment options for glioblastoma stems from their inability to control tumor cell proliferation and invasion. Biologically targeted therapies offer great hope and one promising target is glycogen synthase kinase-3β (GSK3β), implicated in various diseases, including cancer. We previously reported that inhibition of GSK3β compromises the survival and proliferation of glioblastoma cells, induces their apoptosis, and sensitizes them to temozolomide and radiation. Here, we explore whether GSK3β also contributes to the highly invasive nature of glioblastoma. The effects of GSK3β inhibition on migration and invasion of glioblastoma cells were examined by wound-healing and Transwell assays, as well as in a mouse model of glioblastoma. We also investigated changes in cellular microarchitectures, cytoskeletal components, and proteins responsible for cell motility and invasion. Inhibition of GSK3β attenuated the migration and invasion of glioblastoma cells in vitro and that of tumor cells in a mouse model of glioblastoma. These effects were associated with suppression of the molecular axis involving focal adhesion kinase, guanine nucleotide exchange factors/Rac1 and c-Jun N-terminal kinase. Changes in cellular phenotypes responsible for cell motility and invasion were also observed, including decreased formation of lamellipodia and invadopodium-like microstructures and alterations in the subcellular localization, and activity of Rac1 and F-actin. These changes coincided with decreased expression of matrix metalloproteinases. Our results confirm the potential of GSK3β as an attractive therapeutic target against glioblastoma invasion, thus highlighting a second role in this tumor type in addition to its involvement in chemo- and radioresistance. Mol Cancer Ther; 14(2); 564–74. ©2014 AACR.

Hepatic arterial infusion (HAI) chemotherapy is expected to be a more effective and safer method to treat the hepatic metastasis of pancreatic cancer than intravenous (iv) administration because of higher tumor exposure and lower systemic exposure. To clarify the uptake mechanism of nucleoside anticancer drugs, including gemcitabine (GEM), in pancreatic cancer, we investigated the uptakes of radiolabeled uridine (a general substrate of nucleoside transporters) and GEM in pancreatic cancer cell lines MIA-PaCa2 and As-PC1. Uridine uptake was inhibited by non-labeled GEM and also by S-(4-nitrobenzyl)-6-thioinosine (NBMPR; an inhibitor of equilibrative nucleoside transporters, ENTs) in a concentration-dependent manner, suggesting that ENTs contribute to uridine uptake in pancreatic cancer cells. As for GEM, saturable uptake was mediated by high- and low-affinity components with K

Methotrexate (MTX) and salazosulfapyridine (SASP) are disease-modifying drugs that are commonly used in the treatment of rheumatoid arthritis (RA), and combination therapy with MTX and SASP is recommended for RA patients who show an inadequate response to monotherapy with either drug. This study was designed to examine the interaction between the two drugs from the viewpoint of serum MTX concentration in Japanese RA patients, who were receiving combination therapy with relatively low doses of MTX and SASP. This is a 24-week open-label intervention study of stable RA patients (n = 10) with low disease activity. In these patients, who had received SASP/MTX combination therapy for at least 12 weeks, SASP was discontinued, and the patients received MTX monotherapy for the next 24 weeks. The primary outcome was change of serum MTX concentration at 12 weeks after discontinuation of SASP. Two disease activity markers, simplified disease activity index (SDAI) and disease activity score-C reactive protein (DAS28-CRP), were assessed as secondary outcomes at 24 weeks after discontinuation of SASP. We also monitored levels of matrix metalloproteinase-3 (MMP-3) and inflammatory cytokines. Patients were asked to complete a questionnaire after the study. Serum MTX concentration in RA patients who discontinued SASP increased more than 2-fold within 4 weeks, and the higher level was maintained thereafter. No significant differences were detected in SDAI, DAS28-CRP, MMP-3 or inflammatory cytokines. Most participants reported no change in physical condition after withdrawal of SASP, and most preferred MTX monotherapy for future treatment. Withdrawal of SASP from patients receiving SASP/MTX caused a rapid, marked increase of serum MTX concentration, without any apparent change in disease parameters or side effects. Our results suggest that SASP can be discontinued without adverse effects in stable RA patients receiving combination therapy, at least among Japanese patients receiving relatively low doses of the two drugs. UMIN000024507 . October 21, 2016 retrospectively registered.

Background Bladder cancer patients receiving methotrexate, vinblastine, adriamycin and cisplatin (MVAC) chemotherapy are co-administered with dexamethasone as an anti-emetic. We examined whether or not dexamethasone affects the severity and onset day of MVAC-induced severe neutropenia. Methods This was a retrospective study of bladder cancer patients treated with MVAC chemotherapy with or without dexamethasone as an antiemetic at Kanazawa University Hospital during January 2005 - December 2009. Patients were categorized into three groups; no dexamethasone use (Dex (−)), dexamethasone on day 2 (Dex 1 day), and dexamethasone on days 2, 3 and 4 (Dex multiday). We evaluated the incidence of grade 3/4 neutropenia and the day of onset of first severe neutropenic episode during the first course of MVAC chemotherapy. Logistic regression was used to investigate whether co-administration of dexamethasone was a risk factor for severe neutropenia. Results Episodes of grade 3/4 neutropenia occurred in 3 out of 6 (50.0%), 11 out of 12 (91.7%) and 6 out of 6 (100%) patients in the Dex (−), Dex 1 day, and Dex multiday groups, respectively. The appearance day of first severe neutropenia in the Dex multiday group (13.2 ± 1.0) was significantly accelerated compared to the Dex (−) group (17.7 ± 2.1). Univariate logistic regression analysis revealed that dexamethasone is a risk factor for severe neutropenia (OR 17.0; 95%CI: 1.3–223.1). Conclusions Co-administration of dexamethasone for anti-emesis brings forward the first appearance of neutropenia, and increases the severity of neutropenia, in bladder cancer patients receiving MVAC chemotherapy.

Background Continuous hemodiafiltration (CHDF) is used as renal replacement therapy for critically ill patients with renal failure, and to treat hypercytokinemia. Since CHDF also clears therapeutic agents, drug pharmacokinetics (PK) should be dependent upon CHDF conditions. Although the antibiotic biapenem (BIPM) is used in patients undergoing CHDF, the optimal therapeutic regimen in such patients has not been fully clarified. In this study, we investigated the PK of BIPM in patients with various levels of renal function undergoing CHDF with polysulfone (PS) membrane, and used PK models to identify the optimal administration regimen. Methods BIPM (300 mg) was administered by infusion in patients undergoing CHDF (n = 7). Blood and filtrate-dialysate were collected for compartment and non-compartment analysis. Results The sieving coefficient of PS membrane was 1.00 ± 0.06 (mean ± S.D., n = 7), and CHDF clearance of BIPM was found to be the sum of the dialysate flow rate (QD) and filtrate flow rate (QF). Non-CHDF clearance showed inter-individual variability (4.82 ± 2.48 L/h), depending on residual renal function and non-renal clearance. Based on the average PK parameters obtained with a compartmental model, maximal kill end point (over 40 % T > MIC4 μg/mL) was achieved with regimens of 300 mg every 6 h, 300 mg every 8 h, and 600 mg every 12 h. Monte Carlo simulation indicated that 300 mg infusion for 1 h every 6 h was optimal, and the probability of target attainment at MIC2 μg/mL was 90.2 %. Conclusions Our results establish the optimal regimen of BIPM in patients with various levels of renal function undergoing CHDF with a PS membrane.

The purpose of this manuscript is to report the pharmacokinetics of docetaxel during hyperthermic intraperitoneal chemotherapy (HIPEC) after peritonectomy.Eleven patients with peritoneal metastasis (PM) underwent peritonectomies combined with 40 min of HIPEC with 40 mg/body of docetaxel. The pharmacokinetics of docetaxel were studied by using high-performance liquid chromatography.The docetaxel concentration at the start of HIPEC (0 min) was 9.084 ± 0.972 mg/L. The concentration gradually decreased to 5.599 ± 0.458 mg/L 40 min after HIPEC. In contrast, serum docetaxel levels increased during HIPEC, reaching a maximum level of 0.1334 ± 0.0726 mg/L at 40 min. The clearance (CLp) was 3.164 ± 1.383 L/hr, and the area under the curve (AUC) ratio was 95.12 ± 87.32. The AUC ratio of less-extensive peritonectomies was significantly higher than that of extended peritonectomies. The docetaxel concentration in the tumor tissue increased at 40 min (4.45 mg/gr). The apparent permeability (Papp, 40 min) was 1.47 ± 0.67 mm/40 min. No severe adverse effects were observed after HIPEC.From these results, 40 mg is a safe dose for docetaxel combined with HIPEC, and the locoregional intensity of docetaxel is enough to control PM less than 1.47 mm in diameter.

Approximately half of autism spectrum disorder (ASD) individual suffer from comorbid intellectual disabilities (ID). Oxytocin (OXT) receptors are highly expressed in temporal lobe structures and are likely to play a modulatory role in excitatory/inhibitory balance, at least based on animal model findings. Thus, it is feasible that in the highly representative group of Kanner type ASD subjects OXT could have a beneficial effect on social communication and social interaction. The aim of this pilot study was to investigate the feasibility and adverse events, such as epilepsy, of the long-term administration of intranasal OXT for adolescent and adult ASD subjects with ID because such patients frequently have seizures. We also addressed the question on how to scale the OXT effects to the core symptoms of social deficits because of the relative difficulty in obtaining objective measurements. Twenty-nine males (aged 15-40 years old) participated in a randomized, double-blind, placebo-controlled crossover study (each for 8 weeks) with OXT (16 international units per day). Except for seizures experienced by one participant, other serious adverse events did not occur. The primary and secondary outcomes measured using the Childhood Autism Rating Scale and several standard scales, respectively, revealed no difference between the OXT and placebo groups. Instead, in an exploratory analysis, the social interactions observed in the play sessions or in daily-life were significantly more frequent in the initial half period in the OXT-first arm of the crossover trial. There were also significant correlations between the plasma OXT concentration and subscale scores for irritability on the Aberrant Behavior Checklist. In conclusion, this pilot study demonstrates that long-term administration of intranasal OXT is tolerable in a representative cohort of ASD individuals with ID and suggests that future multicenter trials of OXT are warranted and should include measurements of reciprocal social interactions based on daily life under closer surveillance for epilepsy. Trial registration: UMIN000007250.