Effects of piperacillin/tazobactam or cefepime on folinate dose in patients receiving high-dose methotrexate: A retrospective cohort study using Japanese administrative claims data.

INTRODUCTION: Delayed methotrexate (MTX) clearance with the co-administration of piperacillin/tazobactam (PIPC/TAZ) has been reported. Penicillins have been associated with reduced MTX clearance but the evidence is limited. There are no cases described with cefepime but penicillins are listed as interacting with MTX. We aimed to reveal whether the co-administration of PIPC/TAZ or CFPM affects MTX clearance using data from an administrative database. METHODS: We used data from the JMDC database, a large insurance claims database constructed in Japan. We included patients who were prescribed PIPC/TAZ or CFPM between days 1 and 3 in high-dose MTX (HD-MTX). We compared one co-administration episode (with PIPC/TAZ or CFPM) to one control episode (without), as a match-control study of two different episodes in the same patient. The primary outcomes were the duration and cumulative dose of leucovorin (LV) as a surrogate indicator of delayed MTX clearance. RESULTS: Three patients who were co-administered PIPC/TAZ and 16 patients who were co-administered CFPM with HD-MTX were included. In the PIPC/TAZ group, the duration and the cumulative doses of LV were similar in co-administration and control episode (median 3.0 vs. 3.0 days and 288.0 vs. 219.0 mg). In the CFPM group, the duration and the cumulative doses of LV were not significantly different in co-administration and control episode (3.0 vs. 4.0 days and 169.5 vs. 258.0 mg). CONCLUSIONS: Our findings revealed that PIPC/TAZ did not necessarily cause a delay in MTX clearance during HD-MTX therapy. Moreover, the co-administration of CFPM with HD-MTX did not affect MTX clearance.

Clinical usefulness of saphenous vein graft in major arterial reconstruction during extended pancreatectomy.

PURPOSE: Extended pancreatectomy for locally advanced pancreatobiliary malignancy often involves combined major arterial resection (AR) and reconstruction (ARc). By limiting candidate inflow for ARc after combined resection of the celiac arterial system over a long distance, we evaluated whether great saphenous vein graft (GSVG) is an alternative conduit for obtaining non-anatomical arterial inflow. METHODS: ARc with GSVG conduit was undertaken prior to resection. GSVG was harvested and anastomosed end-to-side with the reconstructing artery and then mostly passed via the retroperitoneal para-inferior vena cava route. Side-to-end anastomosis of GSVG inflow was established with the right common iliac artery or abdominal aorta. RESULTS: Among 468 consecutive pancreatobiliary surgeries, ARc with GSVG was undertaken in seven cases. Primary cancers were in the pancreas in six patients and distal bile duct in one. Radical surgery was performed with pancreaticoduodenectomy in six patients and total pancreatectomy in one. Hepatic artery (HA) was concomitantly resected and reconstructed by GSVG in six patients or by the jejunal artery in one patient. Median operative time and intraoperative blood loss were 763 min and 350 ml, respectively. Serum level of AST, ALT, and LDH in patients with HA reconstruction by GSVG peaked by the second postoperative day and promptly normalized. Postoperative morbidity (CD ≥ III) was encountered in one patient. No surgical mortality was observed. Postoperative serum liver enzymes promptly decreased in ARc patients with GSVG to HA. CONCLUSION: Arterial reconstruction with GSVG prior to resection was performed securely and might help to reduce postoperative liver dysfunction.

Conversion pancreaticoduodenectomy with dual arterial reconstructions for locally advanced pancreatic cancer: Case report and literature review.

INTRODUCTION: Extended pancreatectomy for initially unresectable locally advanced (URLA) pancreatic carcinoma (PC) often requires combined arterial resection/reconstruction. By limiting candidate arterial inflow after combined resection of the celiac arterial system over a long distance, great saphenous vein graft (GSVG) is an alternative conduit for obtaining non-anatomical arbitrary arterial inflow. PRESENTATION OF CASE: A 66-year-old woman was diagnosed with URLA pancreatic head carcinoma involving the region from the celiac axis (CA) to the common hepatic and proximal splenic artery (SA). She received 10 courses of modified FOLFIRINOX followed by concurrent chemoradiotherapy including S1 with favorable response. The duration of disease control and normalization of serum carbohydrate antigen 19-9 (CA19-9) exceeded 10 months, and conversion surgery was planned. Extended pancreaticoduodenectomy (PD) required concomitant resection of the CA to the proper hepatic and SA. The dual arterial reconstructions involved a GSVG interposition from the abdominal aorta to the distal SA to preserve the entire stomach, and from the mesenteric second jejunal artery to the right hepatic artery. The patient achieved pathological R0 resection with a histological response of Evans grade IIB. DISCUSSION: Reconstruction of the distal SA with GSVG in extended PD enabled preservation of the subtotal stomach and distal pancreas, even when the root of the CA was transected. CONCLUSION: Multiple arterial reconstructions using GSVG might be useful in extended pancreatectomy to preserve visceral organs, offer better quality of life in terms of oral intake and nutritional status, and control blood glucose than after total pancreatectomy concomitant with subtotal gastrectomy.

Site-selective cross-coupling of dichlorinated benzo-fused nitrogen-heterocycles with Grignard reagents.

Site-selective cross-coupling of dihaloarenes constitutes a useful method for synthesis of multi-substituted arenes. In this paper, we report the site-selective cross-coupling of dichlorinated benzo-fused nitrogen-heterocycles having two chloro groups on the benzene ring. These dichlorinated heterocycles reacted with Grignard reagents in the presence of PdCl(2)(PCy(3))(2) at the positions ortho to the nitrogen-based substituents with high selectivities. A mechanism in which interaction between Lewis acidic Mg and Cl of the ortho position facilitates C-Cl bond cleavage is proposed.

A Risk Prediction Flowchart of Vancomycin-Induced Acute Kidney Injury to Use When Starting Vancomycin Administration: A Multicenter Retrospective Study.

We previously constructed a risk prediction model of vancomycin (VCM)-associated nephrotoxicity for use when performing initial therapeutic drug monitoring (TDM), using decision tree analysis. However, we could not build a model to be used at the time of initial administration due to insufficient sample size. Therefore, we performed a multicenter study at four hospitals in Japan. We investigated patients who received VCM intravenously at a standard dose from the first day until the initial TDM from November 2011 to March 2019. Acute kidney injury (AKI) was defined according to the criteria established by the "Kidney disease: Improving global outcomes" group. We extracted potential risk factors that could be evaluated on the day of initial administration and constructed a flowchart using a chi-squared automatic interaction detection algorithm. Among 843 patients, 115 (13.6%) developed AKI. The flowchart comprised three splitting variables (concomitant drugs (vasopressor drugs and tazobactam/piperacillin) and body mass index ≥ 30) and four subgroups. The incidence rates of AKI ranged from 9.34 to 36.8%, and they were classified as low-, intermediate-, and high-risk groups. The accuracy of flowchart was judged appropriate (86.4%). We successfully constructed a simple flowchart predicting VCM-induced AKI to be used when starting VCM administration.

Higher incidence of acute kidney injury in patients treated with piperacillin/tazobactam than in patients treated with cefepime: a single-center retrospective cohort study.

BACKGROUND: Piperacillin/tazobactam (PIPC/TAZ) and cefepime (CFPM) are commonly used for the treatment of nosocomial and healthcare-associated infections. Recent reports have suggested that the incidence of acute kidney injury (AKI) in patients treated with a combination of vancomycin (VCM) and PIPC/TAZ is higher than that in patients treated with CFPM. However, there have been few reports on a comparison of the incidences of AKI in patients treated with PIPC/TAZ monotherapy and patients treated with CFPM. In this study, we investigated whether the incidence of AKI in patients treated with PIPC/TAZ is higher than that in patients treated with CFPM. METHODS: This study was a single-center retrospective observational study. Patients who died during the therapeutic period, patients younger than 18 years of age, and patients undergoing hemodialysis were excluded. Primary outcomes were the incidence of AKI and the AKIN stages defined by the Acute Kidney Injury Network. Secondary outcomes were discontinuation and/or change of antibiotics and initiation of dialysis due to AKI. We also investigated the time to onset and the risk factors of AKI in this population. RESULTS: There were 163 patients in the PIPC/TAZ group and 103 patients in the CFPM group. The incidence of AKI in patients treated with PIPC/TAZ (8.6%) was significantly higher than that in patients treated with CFPM (0.9%) (odds ratio (OR), 9.53; 95% confidence interval (CI), 1.41-408; p= 0.011). AKI severity was mostly stage 1 in both groups. There was no discontinuation and/or changes of antibiotics and there was no initiation of dialysis in either group. The onset of AKI in the PIPC/TAZ group (median period of 4 days) was earlier than that in the CFPM group. PIPC/TAZ was determined to be an independent risk factor of AKI in multivariate analysis (adjusted OR, 9.56; 95% CI, 1.21-75.3; p = 0.032). CONCLUSIONS: This study showed that the incidence of AKI in patients who received PIPC/TAZ was higher than that in patients who received CFPM. Furthermore, the onset of AKI was earlier in patients who received PIPC/TAZ than in patients who received CFPM. PIPC/TAZ was an independent risk factor of AKI in this study population.

Measurement of plasma concentration of gemcitabine and its metabolite dFdU in hemodialysis patients with advanced urothelial cancer.

OBJECTIVE: We investigated the pharmacokinetics of gemcitabine and its metabolite in two male patients (52 and 56-year-old) with advanced urothelial cancer receiving hemodialysis three times a week. METHODS: Gemcitabine, 1000 mg/m(2) in 100 ml of saline, was intravenously administered for 30 min. The concentration of gemcitabine and its metabolite 2',2'-difluorodeoxyuridine (dFdU) was measured at several given time points using a high-pressure liquid chromatography assay. Pharmacokinetic parameters were determined using the two-compartment modeling program. RESULTS: Gemcitabine was rapidly eliminated from plasma even in patients with renal dysfunction. No obvious differences in pharmacokinetic parameters such as the t(1/2), AUC and C(max) of gemcitabine were observed between the patients on hemodialysis and those with normal renal function in previous reports. On the other hand, dFdU showed a sustained level until hemodialysis was initiated. Hemodialysis could reduce the plasma dFdU level by approximately 50%. CONCLUSIONS: According to the previous information, no dose modification of gemcitabine may be required for patients with renal impairment or hemodialysis. However, gemcitabine should be given with caution because only limited information is available, and the clinical effect of sustained and/or accumulated dFdU is unknown.

Characterization of secretory intestinal transport of the lactone form of CPT-11.

PURPOSE: It has been reported that a significant portion of the lactone form of 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptothecin (CPT-11) is excreted into the gastrointestinal lumen via the intestinal membrane and that carboxylesterase activity, which converts CPT-11 to SN-38, was detected in the intestine. It is possible that a reduction in the excretion of CPT-11 lactone into the gastrointestinal lumen induces the gastrointestinal toxicity. The purpose of this study was to investigate the characteristics of transporter(s) that contribute to the jejunal efflux of the lactone form of CPT-11. METHODS: The serosal-to-mucosal permeation rate of CPT-11 lactone was investigated in everted sac studies. RESULTS: The secretory transport required metabolic energy and was diminished by sulfobromophthalein (BSP) and 1-naphthol, inhibitors of the ME3277 transport system. However, inhibitors of breast cancer resistance protein (Bcrp), multidrug resistance-associated protein 2 (Mrp2) and P-glycoprotein (P-gp) did not affect the secretion of CPT-11 lactone. CONCLUSIONS: The results suggest that a specific transport system, which is identical to the ME3277 transport system, plays a major role in the secretion of CPT-11 lactone.

[Pharmacokinetic study of cancer chemotherapy].

We reported that the rate of conversion of lactone to carboxylate forms of irinotecan (CPT-11) and its metabolites plays a major role in the biliary excretion of these compounds. Sulfobromophthalein partially inhibited the secretion of SN-38-glucronide into the gastrointestinal lumen, whereas little change was seen in that of active metabolite SN-38. Co-administration of sulphobromophthalein with CPT-11 might lower the late-onset gastrointestinal toxicity observed during treatment with CPT-11 without lowering anticancer activity. In the ileum, the level of transport in the direction form the serosal layer to mucosal layer was significantly greater than that in the direction form the mucosal layer to serosal layer, whereas a significant difference was not observed in the jejunum. This secretory transport required metabolic energy was diminished by sulfobromophthalein. A specific transport system plays a major role in the secretion of SN-38 and that this secretory transport system predominantly exists in the ileum. Uptake of SN-38 was significantly reduced at 4 degrees C. Baicalin inhibited the uptake of SN-38. A specific transport system mediates the uptake of SN-38 across the apical membrane in Caco-2 cells. Inhibition of this transporter would be a useful means for reducing late-onset diarrhea.

Uptake of irinotecan metabolite SN-38 by the human intestinal cell line Caco-2.

PURPOSE: The aim of this study was to investigate the transport mechanisms of transporters that contribute to the intestinal uptake of 7-ethyl-10-hydroxycamptothecin (SN-38). METHODS: Human intestinal epithelial Caco-2 cells were used to investigate the mechanistic basis of transepithelial uptake of SN-38. We investigated the characteristics of SN-38 uptake into Caco-2 cells. The effects of baicalin and sulfobromophthalein (BSP) on the uptake of SN-38 by Caco-2 cells were examined. RESULTS: Uptake of SN-38 was significantly reduced at 4 degrees C. Baicalin inhibited the uptake of SN-38 in a concentration-dependent manner. BSP significantly reduced the uptake of SN-38. However, probenecid, pravastatin and grepafloxacin did not affect the uptake of SN-38. CONCLUSIONS: The results suggest that a specific transport system mediates the uptake of SN-38 across the apical membrane in Caco-2 cells.

Secretory transport of irinotecan metabolite SN-38 across isolated intestinal tissue.

PURPOSE: The purpose of this study was to investigate the transport mechanisms of transporters that contribute to the intestinal efflux of 7-ethyl-10-hydroxycamptothecin (SN-38). METHODS: The intestinal transport of SN-38 was studied in rat intestinal tissue mounted in Ussing chambers. RESULTS: In the ileum, the level of transport from the serosal layer to the mucosal layer was significantly greater than that from the mucosal layer to the serosal layer, whereas a significant difference was not observed in the jejunum. This secretory transport required metabolic energy and was diminished by sulfobromophthalein. However, mitoxantrone, an inhibitor of breast cancer resistance protein (BCRP), did not affect the ileal secretion of SN-38. CONCLUSIONS: The results suggest that a specific transport system, which is distinct from BCRP, plays a major role in the secretion of SN-38 and that this secretory transport system predominantly exists in the ileum.

Biliary excretion of irinotecan and its metabolites.

PURPOSE: The aim of this study was to investigate the excretion of irinotecan hydrochloride (CPT-11) and its metabolites into the gastrointestinal lumen via the biliary route after intravenous administration of lactone and carboxylate forms of CPT-11. METHODS: Biliary excretions of CPT-11 and its metabolites, SN-38 and SN-38-glucuronide, were investigated by an in vivo administration study using rats. The biliary excretion profiles for both the lactone and carboxylate forms of CPT-11 and its metabolites were determined. RESULTS: After the i.v. injection of the lactone form of CPT-11, the cumulative biliary excretion of SN-38-glucuronide was much greater than that of CPT-11 and SN-38, and biliary excretion of SN-38 was less than that of CPT-11. Further, CPT-11 and SN-38 were mainly excreted into bile as carboxylate forms. After the administration of the CPT-11 carboxylate form, biliary excretion of SN-38-glucuronide was significantly smaller than that after the administration of CPT-11 lactone form. On the other hand, biliary excretion of CPT-11 and SN-38 was greater after dosing with the CPT-11 carboxylate form than that after the CPT-11 lactone form. CONCLUSIONS: The results suggest that the rate of conversion of lactone to carboxylate forms of CPT-11 and its metabolites plays a major role in the biliary excretion of these compounds.

Pharmacokinetic modulation of irinotecan metabolites by sulphobromophthalein in rats.

The purpose of this study was to modulate the pharmacokinetics of irinotecan metabolites, SN-38 and SN-38-glucuronide, by possibly reducing biliary excretion, which in turn could lower irinotecan toxicity. SN-38-glucuronide is associated with severe diarrhoea that occurs after irinotecan therapy as a result of enteric injury caused by SN-38. Sulphobromophthalein is used clinically as a drug for testing liver function and is considered to be a safe drug. We investigated the effect of sulphobromophthalein on the disposition of irinotecan metabolites after CPT-11 (7-ethyl-10-[10-4-(1-piperidino)-1-piperidino]-carbonyloxy-camptothecin) administration. Wistar rats were administered CPT11 (500 microg/body) in saline as a bolus injection into the femoral vein through a catheter. The volume of drug solution injected into each animal was 1 mL. Rats were either administered CPT-11 alone or simultaneously with sulphobromophthalein (20 mg/body). After administration, blood and bile samples were taken at appropriate intervals and analysed by HPLC. Co-administration of sulphobromophthalein partially inhibited the biliary excretion of SN-38-glucuronide with a concomitant increase in its area under the plasma concentration-time curve (AUC) but did not significantly alter the biliary excretion and AUC of the active metabolite SN-38. These results suggested that cotreatment of CPT-11 with sulphobromophthalein might decrease intraluminal SN-38 concentrations without altering the pharmacokinetics of SN-38.

Cross-priming of CD8(+) T cells in vivo by dendritic cells pulsed with autologous apoptotic leukemic cells in immunotherapy for elderly patients with acute myeloid leukemia.

OBJECTIVE: The prognosis for elderly patients with acute myeloid leukemia (AML) remains dismal. To explore the potential of immunotherapy for improving clinical outcomes for these patients, we performed a phase I clinical trial of dendritic cell (DC)-based immunotherapy for elderly patients with AML. MATERIALS AND METHODS: Autologus monocytes were obtained after reducing tumor burden by chemotherapy. Immature DCs induced with granulocyte-macrophage colony-stimulating factor and interleukin-4 were pulsed with autologous apoptotic leukemic cells as antigens. DCs were administered intradermally to four patients five times at 2-week intervals. To facilitate DC migration to lymph nodes, injection sites were pretreated with killed Streptococcus pyogenes OK-432 one day before. DCs were coinjected with OK-432 to induce maturation and interleukin-12 production in vivo. RESULTS: Antileukemic responses were observed by an interferon-γ enzyme-linked immunospot assay or a tetramer assay in two of four patients. In a human leukocyte antigen-A∗2402-positive patient, induction of CD8(+) T-cell responses to WT1- and human telomerase reverse transcriptase - derived peptides were observed, indicating cross-priming in vivo. The two patients with antileukemic immunity showed longer periods of disease stabilization than the other two patients. CONCLUSIONS: This study demonstrates the immunogenicity of autologous DCs that cross-present leukemia-associated antigens from autologous apoptotic leukemic cells in vivo in elderly patients with AML.

Different patterns of vascular response between patients with or without diabetes mellitus after drug-eluting stent implantation: optical coherence tomographic analysis.

OBJECTIVES: We performed this study to investigate with optical coherence tomography (OCT) the vascular response after sirolimus-eluting stent (SES) implantation between patients with and those without diabetes mellitus (DM). BACKGROUND: The difference in vascular response after SES implantation between patients with and those without DM has not been fully evaluated with OCT. METHODS: Optical coherence tomography was performed to examine 74 nonrestenotic SES implanted in 63 patients (32 with DM and 31 without DM) at 9 months after SES implantation. For struts showing neointimal coverage, the neointimal thickness on the luminal side of each strut section was measured, and neointimal characteristics were classified into high, low, and layered signal pattern. RESULTS: Baseline patient characteristics and lesion and procedural characteristics data were similar between the 2 groups. In total, 11,422 struts were analyzed. High signal neointima was observed in 90.2 ± 13.9%, low signal neointima in 7.3 ± 10.0%, and layered neointima in 2.7 ± 5.8%/stents. There was higher incidence of low signal neointima (10.5 ± 10.3% vs. 4.5 ± 5.6%, p = 0.003), neointimal thickness was larger (median: 106.8 µm, interquartile range: 79.3 to 130.4 µm vs. median: 83.5 µm, interquartile range: 62.3 to 89.3 µm; p < 0.0001), and neointimal coverage of stent struts was higher (92.1 ± 6.2% vs. 87.2 ± 11.9%; p = 0.03) in DM patients. CONCLUSIONS: High signal neointimal pattern was predominantly observed, and low or layered signal pattern was observed in some cases. In DM patients, low signal neointima was observed with high frequency. Neointimal coverage and neointimal thickness was also higher in DM patients as compared with non-DM patients.

The volatile anesthetics halothane and isoflurane differentially modulate proinflammatory cytokine-induced p38 mitogen-activated protein kinase activation.

PURPOSE: Volatile anesthetics affect the cardiovascular and immune systems. Toward a better understanding of the molecular mechanisms behind the modulation exerted by these agents, we focused on the effects of halothane and isoflurane on the activation of p38 mitogen-activated protein kinase (MAPK), which plays a critical role in the cellular responses to extracellular stimuli such as lipopolysaccharide (LPS) and proinflammatory cytokines, including tumor necrosis factor (TNF) and interleukin 1 (IL-1). METHODS: Human umbilical vein endothelial cells and HeLa cells, an established cell line, were examined by molecular biological methods. Cells were treated with proinflammatory compounds with or without the volatile anesthetics. p38 MAPK activation was investigated by Western blotting analysis with phosphospecific anti-p38 MAPK antibodies. RESULTS: Isoflurane activated p38 MAPK by itself, but halothane did not. Halothane or isoflurane augmented the LPS- and TNF-induced activation of p38 MAPK. In contrast, neither halothane nor isoflurane enhanced the p38 MAPK activation induced by IL-1. Neither of the anesthetics affected H(2)O(2) or MAPK kinase 3 (MKK3)-induced p38 MAPK activation. CONCLUSION: Our in vitro results indicate that the volatile anesthetics used in the clinical field and in animal experiments modify the p38 MAPK signaling cascade and suggest that the target molecules of the anesthetics are not unique and the anesthetics regulate them differentially at clinically relevant doses.