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Summary Objective: To develop a simple analytical method for monitoring serum and urine concentrations of mycophenolic acid (MPA), an active metabolic constituent of the immunosuppressive pro-drug mycophenolate mofetil, and its glucuronide. Methods: Serum samples were prepared by solid-phase extraction (SPE), while urine samples were simply diluted with water. Serum was added to an SPE cartridge, then washed twice with 5% methanol solution. The analytes were eluted with methanol containing benzoic acid as internal standard for mycophenolic acid glucuronide (MPAG). The resultant eluate was directly injected into a high-performance liquid chromatograph (HPLC) to determine MPAG. For the assay of MPA, the remaining eluate was dried under nitrogen and resolved in a mixture of acetonitrile and 20 mm phosphate buffer (pH 3&bdot;0). Results: The present methods were reproducible and accurate based on the intra- and inter-assay, and had detection limits of 0&bdot;225 μg/mL for MPA and 9&bdot;0 μg/mL for MPAG. The present methods enabled us to monitor the time course of changes in the concentrations of MPA and MPAG in serum and urine in a patient with a renal transplant during 12 h after ingestion of mycophenolate mofetil. Conclusion: The HPLC method described should be useful for the routine monitoring of serum and urine concentrations of MPA and MPAG during immunosuppressive medication for renal transplantation. [ABSTRACT FROM AUTHOR]

Uncooled 25 Gbit/s direct modulation of 1.3 µm DFB lasers is demonstrated. The 150 µm-long semi-insulating buried-heterostructure AlGaInAs quantum-well DFB lasers show clear eye-openings with dynamic extinction ratio of 5 dB up to 70°C. 13 km singlemode-fibre transmission experiments using the devices show low power penalty within 1.3 dB between 25 and 70°C. These characteristics are the first achievement by 1.3 µm directly modulated lasers. [ABSTRACT FROM AUTHOR]

Background Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by worsening dyspnea and progressive loss of lung function. Acute exacerbation of IPF is associated with high morbidity and mortality. Several studies have provided evidence of an association between lung cancer and IPF, with a prevalence of lung cancer in IPF patients ranging from 9.8% to 38%. Although the efficacy of nintedanib for IPF has been demonstrated, it has remained unknown whether this agent also reduces the risk of chemotherapy-induced acute exacerbation of IPF. Patients with interstitial pneumonia have been excluded from most prospective clinical trials for NSCLC because of the risk of acute exacerbation, with a few prospective single-arm phase II studies having been reported. In addition, it has been difficult to perform a randomized prospective clinical trial for patients with advanced NSCLC and IPF because of their rarity. Therefore, the optimal chemotherapy regimen for advanced NSCLC with IPF has thus remained unclear. Trial design Chemotherapy-naïve patients with advanced NSCLC associated with IPF (enrolment target of n = 240) are randomized at a 1:1 ratio to receive four cycles of carboplatin (AUC 6 on day 1) plus nab-paclitaxel (100 mg/m2 on days 1, 8, and 15) administered every 3 weeks either without (arm A) or with (arm B) nintedanib (150 mg b.i.d. daily), to be followed in arm B by single-agent administration of nintedanib (150 mg b.i.d. daily). The primary end point of the study is time to acute exacerbation of IPF. Study enrolment began in May 2017 and is to continue for 3 years. Legal entity responsible for the study Isamu Okamoto. Funding Nippon Boehringer Ingelheim and Japan Agency for Medical Research and Development. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to identify a target range for inosin-5'-monophosphate dehydrogenase (IMPDH) activity in maintenance therapy with tacrolimus (TCL), and to apply the measurement of IMPDH activity to the therapeutic drug monitoring for mycophenolate mofetil (MMF). Methods: Eleven patients with renal transplants and 10 healthy volunteers were investigated. All patients were treated with a combination of TCL, steroid and MMF for 2 months after transplantation, and were in stable and good condition. IMPDH activity was determined indirectly by measuring xanthosine 5'-monophophate in cell lysates supplemented with IMP and [beta]-nicotine adenine dinucleotide using an high-performance liquid chromatography (HPLC) method. Results: The within-run reproducibility of the assay was excellent, with relative standard deviation (RSD) values of 0·41-4·08%. The mean differences between the spiked concentrations of xanthosine 5'-monophophate and their real values (mean relative errors; MREs) were within a range of 2·66-8·89%, showing good accuracy. The interday RSD values were 1·51-6·12% and MREs ranged from 2·10% to 8·89%. Cell lysates showed a 5-6 nmol/L IC50 mycophenolic acid (MPA) concentration. TCL, cyclosporine and prednisolone did not affect IMPDH activity. The peak MPA concentration was achieved at 1 h after dosing. IMPDH activity decreased to 75% and 67% at 1 and 2 h after dosing respectively. Therefore, the inhibition rates of MPA against IMPDH activity may be adequate at 25-40% in TCL maintenance therapy. Conclusion: Inosin-5'-monophosphate dehydrogenase activity in cell lysates could be reliably determined by HPLC. A 25-40% inhibition of IMPDH activity may be an appropriate range for preventing rejection with MPF but this requires further validation using larger studies with harder outcomes such as rejection episodes. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to identify a target range for inosin-5′-monophosphate dehydrogenase (IMPDH) activity in maintenance therapy with tacrolimus (TCL), and to apply the measurement of IMPDH activity to the therapeutic drug monitoring for mycophenolate mofetil (MMF). Methods: Eleven patients with renal transplants and 10 healthy volunteers were investigated. All patients were treated with a combination of TCL, steroid and MMF for 2 months after transplantation, and were in stable and good condition. IMPDH activity was determined indirectly by measuring xanthosine 5′-monophophate in cell lysates supplemented with IMP and β-nicotine adenine dinucleotide using an high-performance liquid chromatography (HPLC) method. Results: The within-run reproducibility of the assay was excellent, with relative standard deviation (RSD) values of 0·41–4·08%. The mean differences between the spiked concentrations of xanthosine 5′-monophophate and their real values (mean relative errors; MREs) were within a range of 2·66–8·89%, showing good accuracy. The interday RSD values were 1·51–6·12% and MREs ranged from 2·10% to 8·89%. Cell lysates showed a 5–6 nmol/L IC50 mycophenolic acid (MPA) concentration. TCL, cyclosporine and prednisolone did not affect IMPDH activity. The peak MPA concentration was achieved at 1 h after dosing. IMPDH activity decreased to 75% and 67% at 1 and 2 h after dosing respectively. Therefore, the inhibition rates of MPA against IMPDH activity may be adequate at 25–40% in TCL maintenance therapy. Conclusion: Inosin-5′-monophosphate dehydrogenase activity in cell lysates could be reliably determined by HPLC. A 25–40% inhibition of IMPDH activity may be an appropriate range for preventing rejection with MPF but this requires further validation using larger studies with harder outcomes such as rejection episodes. [ABSTRACT FROM AUTHOR]

In order to control the material circulation in the Closed Ecology Experiment Facilities (CEEF), it is necessary to clarify material flow in the Closed Plant Experiment Facility (CPEF) of CEEF. We tried to grow rice plants and measure the nitrogen contents in rice plant and nutrient solution in plant cultivation bed to trace the material balance in CPEF. The measurements were carried out under the condition of 750 ppm (v/v) CO2 at SHAPE="SOL" ALIGN="C" STYLE="S">2619°C in the plant cultivation room. The measurements showed the absorbed nitrogen amount in plant was less than the outflow nitrogen amount from nutrient solution. This difference between absorbed and outflow quantity reached to 17%. [Copyright &y& Elsevier]

A column-switching high-performance liquid chromatographic analysis was established to monitor the serum concentration of mycophenolic acid, the active metabolite from mycophenolate mofetil administered for the prophylaxis of acute organ rejection in renal transplantation. The system consisted of two pumps for solvent delivery, a column-switching valve, a precolumn, and a reversed-phase analytical column. The present method enabled us to determine MPA by injecting serum samples directly into HPLC without any pretreatment. The mobile phases with different amounts of organic solvent were delivered to the precolumn and analytical column by separate lines, and samples were applied to the precolumn. The column switching valves were switched automatically following the processes for the elimination of protein and the drug analysis. The peak heights of MPA were linearly related to the concentrations (r=0.999) in the range of 0.1–20 μg/ml, and the limit of quantification was 0.1 μg/ml (S/N ratio=3). This method was accurate and reproducible on the basis of the results of recovery (94.0–98.0%) and small coefficient of variations of intra and inter-assay (less than 8.3%). [ABSTRACT FROM AUTHOR]

Low-driving-current temperature-stable 10 Gbit/s direct modulation was achieved for optimised 200 µm-long short cavity 1.3 µm p-doped quantum dot lasers. Driving conditions were 25.2 mAp-p for the modulation current and 23.4 mA for the bias current through the whole temperature range from 20 to 90°C. [ABSTRACT FROM AUTHOR]

We studied the injection current dependence of room-temperature lasing spectra of a 1.3-μm self-assembled InAs/GaAs quantum-dot laser both experimentally and theoretically. Starting from the ground-state lasing with a few longitudinal modes, the spectra showed splitting, broadening, excited-state lasing, and quenching of the ground-state lasing as the current increased. We could explain this unique current dependence by numerical simulation based on our quantum-dot laser theory, taking into account the inhomogeneous and homogeneous broadening of the optical gain as well as the carrier relaxation processes in the spatially isolated quantum dots. Through the simulation, we found that the homogeneous broadening of the ground state is kept between 5 and 10 meV under the ground-state lasing, while it increases up to 20 meV under the excited-state lasing. [ABSTRACT FROM AUTHOR]

Introduction: To explore severe toxicities induced by irinotecan-based chemotherapy and UGT1A1*6/*28 and SLCO1B1*15/*15 genotypes. Case Report: A 66-year-old Japanese male diagnosed with left pharyngeal carcinoma (T2N2bM0, stage IVA) was treated with irinotecan (70 mg/m(2)) on days 1, 8 and 15 in combination with docetaxel (60 mg/m(2)) on day 1 of a 28-day cycle. After the first cycle, he suffered marked toxicities, including grade 4 diarrhea and febrile grade 4 neutropenia. Plasma concentrations of irinotecan, SN-38 and SN-38G were measured, and extensive accumulation of SN-38 was observed. Genotyping of UGT1A1 and OATP1B1 proteins showed UGT1A1*6/*28 and SLCO1B1*15/*15, respectively, which are known to lead to extremely low glucuronidation and transport activities of substrate drugs. Conclusion: The severe toxicities in this patient are attributable to the extensive accumulation of SN-38, which may result from a synergistic or additive effect of low metabolic (UGT1A1*6/*28) and transport (SLCO1B1*15/*15) capabilities. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to develop a limited sampling strategy (LSS) for monitoring the use of mycophenolic acid (MPA) in maintenance therapy with tacrolimus (TCL) in renal transplant patients. Methods: Eighteen adult patients receiving a first transplant were investigated. All patients were treated with a combination of TCL, steroid and mycophenolate mofetil (MMF). Besides the predose trough concentration ( C0), whole blood samples were taken for measurement of the MPA concentration at 0·5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 h for a 14-point 12-h pharmacokinetic (PK) profile. Using stepwise linear regression analysis, an abbreviated area under the concentration time curve (AUC) was calculated using all 14, and any combination of sampling points to give an estimating equation with up to three predictors. Results: The equation derived from C2, C7 and C12, for AUC estimation: AUC = (2·05 × C2) + (8·51 × C7) + (2·29 × C12) + 4·24. was found to be optimal. Using this formula, there was an excellent correlation between the estimated 3-point AUC and AUC0–12 h. To assess the agreement between the abbreviated methods and the full PK profile, we plotted the average AUC of the abbreviated estimates and the full PK profile. This Bland-Altman analysis indicated good agreement to within ±2 SD and a prediction variability of 7·56 μg × h/mL. Conclusion: Our proposed three-sampling-point estimate of AUCs is clinically acceptable. However, the sampling times are inconvenient for outpatients, and is recommended only for monitoring MMF treatment of inpatients with suspected toxicity or at high risk of organ rejection. [ABSTRACT FROM AUTHOR]

Chronic hemodialysis (HD) patients increase erythrocyte susceptibility to hemolysis and impair cell survival. We explored whether electrolyte-reduced water (ERW) could palliate HD-evoked erythrocyte impairment and anemia. Forty-three patients undergoing chronic HD were enrolled and received ERW administration for 6 month. We evaluated oxidative stress in blood and plasma, erythrocyte methemoglobin (metHb)/ferricyanide reductase activity, plasma metHb, and proinflammatory cytokines in the chronic HD patients without treatment (n=15) or with vitamin C (VC)- (n=15), vitamin E (VE)-coated dialyzer (n=15), or ERW treatment (n=15) during an HD course. The patients showed marked increases (15-fold) in blood reactive oxygen species, mostly H2O2, after HD without any treatment. HD resulted in decreased plasma VC, total antioxidant status, and erythrocyte metHb/ferricyanide reductase activity and increased erythrocyte levels of phosphatidylcholine hydroperoxide (PCOOH) and plasma metHb. Antioxidants treatment significantly palliated single HD course-induced oxidative stress, plasma and RBC PCOOH, and plasma metHb levels, and preserved erythrocyte metHb /ferricyanide reductase activity in an order VC>ERW>VE-coated dialyzer. However, ERW had no side effects of oxalate accumulation easily induced by VC. Six-month ERW treatment increased hematocrit and attenuated proinflammatory cytokines profile in the HD patients. In conclusion, ERW treatment administration is effective in palliating HD-evoked oxidative stress, as indicated by lipid peroxidation, hemolysis, and overexpression of proinflammatory cytokines in HD patients.Kidney International (2006) 70, 391–398. doi:10.1038/sj.ki.5001576; published online 7 June 2006 [ABSTRACT FROM AUTHOR]

Summary:Hepatic veno-occlusive disease (VOD) is a severe complication of hematopoietic stem cell transplantation (SCT). When monitored with hand-held color Doppler ultrasonography during day −7 to +35 around SCT, reversed blood flow in the segmental branches of the portal vein was detected in nine of 56 patients who had undergone SCT. Three of nine patients had clinical evidence of VOD, but six patients did not fulfill the criteria for diagnosis of VOD initially. Two patients progressed to clinical VOD at a later date and the reversed portal flow disappeared with or without treatment for VOD in the other four patients. Monitoring for reversed portal flow with color Doppler ultrasonography may be a useful tool for the early diagnosis of VOD, and may improve prognosis by allowing early initiation of treatment.Bone Marrow Transplantation (2005) 36, 1071–1075. doi:10.1038/sj.bmt.1705170; published online 10 October 2005 [ABSTRACT FROM AUTHOR]