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Study question Does sperm DNA integrity affect clinical outcomes of ICSI? Summary answer Use of high DNA integrity sperm selected by microfluidics sperm sorting results in lower miscarriage rates in the patients of 39-years old and more. What is known already High sperm DNA damage is associated with decreased normal fertilization, embryo development and pregnancy rates, and an increased miscarriage rate. On the other hand, oocytes from older women have decreased pregnancy rate, and increased miscarriage rate because of possibility of low ability to repair sperm with DNA fragmentation, and dramatical increases of aneuploidy as women age. A microfluidic sperm selection chamber (MSS, ZyMōt™; DxNow) is a device designed to collect sperm with higher chromatin integrity than density gradient centrifugation (DGC). Study design, size, duration Sperm analysis was performed by sperm chromatin dispersion (SCD) test and comet assay in the same sample of 15 cases between October 2020 and February 2021. ICSI outcomes by DGC and MSS were compared with blastocyst development, and pregnancy rates in vitrified-thawed single blastocyst transfers cycle for 518 cases between August 2018 and May 2021. Participants/materials, setting, methods SCD test was optimized as a rapid procedure, with sperm showing a halo deemed normal, and those without a halo abnormal. Comet assay results were analyzed using CometScore 2.0, with comparison of %Tail DNA. ICSI outcomes were analyzed using multiple logistics regressions of male and female ages. Main results and the role of chance We found a positive correlation between male age and sperm DNA fragmentation rates in raw semen using SCD test (r = 0.70) and Comet assay (r = 0.42). Higher DNA integrity sperm could select using MSS than DGC. In this study with ICSI outcomes, 170 of 318 (53.5%) blastocyst transfers resulted in pregnancy, and 49 (28.8%) subsequently miscarried. The data were classified according to less than or more than 39 years old of male age detected by multiple logistics regressions. In patients with ≥39 years of male age, the female age was significantly higher and blastocyst and pregnancy rates were significantly lower, and the miscarriage rate was significantly higher than Limitations, reasons for caution The sample size for each study was small. Analysis of sperm DNA fragmentation and samples in ICSI outcomes were not the same. The retrospective nature of ICSI outcomes in this study does not allow controlling of unknown confounders. Wider implications of the findings Sperm DNA fragmentation depended on male age affected fertility outcomes. However, when male age is higher, masking the effect of male age by female age. In this study, we found out the improvement of ICSI outcome by using high DNA integrity sperm selected by MSS in both ≥39 years. Trial registration number Not applicable

Recently 11 Malassezia species were isolated. Attention has focused on the relationship between Malassezia species and Malassezia-related disease. The causal fungus of Pityriasis versicolor is M. globosa. The conditions of mycelial form induction are not clear for M. globosa.

Quartz glasses of KU-1 and KS-4V are candidate window materials for the ITER optical diagnostics in UV and visible range. The temperature dependence of the radiation-induced transmission losses in UV range has been investigated under γ-ray irradiation for the KU-1 and KS-4V quartz glasses up to 10 MGy. The KU-1 and KS-4V quartz glass samples were irradiated at room temperature, 100, 200 and 300 °C. Dose rate was 0.46–1.1 MGy, and 2.6 Gy/s from 1.1 to 10.4 MGy. It was confirmed that there is no significant loss in wavelength range longer than 350 nm for both window materials. Transmission loss in KU-1 is larger than that in KS-4V under temperature below 200 °C. KU-1 has large temperature dependence. On the other hand, temperature dependence is not clear in KS-4V above 100 °C. Prominent recover of the transmission loss was not observed after irradiation for each sample. From the transmission loss point of view, KS-4V is better window material than KU-1 at temperature below 200 °C. KU-1 is available at 300 °C.

Radiation effects on proton-conducting polymer, perfluorosulfonic acid (PFSA) membranes were studied as the absorbed dose dependence of the electrical characteristics. V-I characteristic was measured under irradiation of y-rays and of 14 MeV neutrons. Under the neutron irradiation, the electrical conductivity of membranes decreased with an exponential form. In the case of the γ-ray irradiation, the electrical conductivity increased with increase of the dose and the membranes showed higher conductivity than before the irradiation, as much as 150 times after irradiation to a dose of more than 100 kGy. The effects on the electrical conductivity under irradiation is explained by structural changes in membranes caused by radiation effects as well as by changes at the interface between electrodes and membranes.

Phosphorus ion implantations of 6H-SiC in the mean phosphorus concentration of the implanted layer of ∼1 × 10 18 cm −3 were performed both at multi-fold energy between 9 and 21 MeV and at 340 keV. In the high-energy implantations at room temperature, 400, 800 and 1200 °C and in the 340 keV implantations at 800 °C, electron spin resonance spectra arising from isolated shallow phosphorus donors have been observed after post-implantation annealing at 1650 °C, but were not observed in as-implanted state.

Radical polymerization of vinyl monomers as initiated by the diphenylphosphinoyl (DPO) radical which is formed by the photo-cleavage of 2,4,6-trimethylbenzoyl diphenylphosphine oxide (TMDPO) was investigated by continuous-wave electron spin resonance (cw ESR) and Fourier-transform (FT) ESR. Well-resolved hyperfine structures (hfs’s) of the starting radicals were observed by the time-resolved cw ESR for vinyl acetate, ethyl vinyl ether, styrene, methyl methacrylate (MMA), and isoprene. The rates of formation and the spin-lattice relaxation were determined by time-resolved FT ESR for these starting radicals. In the polymerization of MMA and isoprene the primary propagating radicals were found for the first time by the observation of their well-resolved hfs’s with timeresolved cw ESR. On the basis of the kinetic analysis including the spin-lattice relaxation, the rates of formation and the spin-lattice relaxation were determined by simulation of the time profile of FT ESR for the primary propagating radicals of MMA and isoprene. The rate of the primary propagating step was found to be by two orders greater than an average value of whole propagating steps as obtained by a steady-state measurement.

Annealing behaviours of defects in electron-irradiated diamond were studied using the positron annihilation technique. For a type IIa specimen after 3 MeV electron irradiation with a dose of 1 × 1018 cm-2, the major species of vacancy-type defects was determined to be neutral monovacancies, V0. The trapping rate of positrons by V0 decreased above 600 °C annealing, but the annihilation mode of positrons trapped by vacancy-type defects was observed even after 900 °C annealing. For a type Ib specimen after the irradiation, the major species of vacancy-type defects was determined to be negative monovacancies, and the formation of nitrogen-monovacancy pairs, N-V, was observed after 650 °C annealing. The annihilation probability between positrons and electrons with a broad momentum distribution was found to be increased by the trapping of positrons by N-V.

Defects in synthesized and natural diamond were studied using the positron annihilation technique. For a synthesized type IIa specimen, the lifetime of positrons annihilating from the free state was determined to be 98.7 ps. For a synthesized type Ib specimen, the effects of the annihilation of positrons trapped by open spaces introduced by substitutional nitrogen atoms on the positron parameters were discussed. After electron irradiation, the species of the major vacancy-type defects was identified to be a neutral and/or negatively charged monovacancy. For natural type IIa and IIb specimens, the annihilation mode of positrons trapped by vacancy clusters was observed. For the natural type IIb specimen, the temperature dependence of the trapping rate of the vacancy clusters was explained assuming that these clusters act as compensators for acceptor impurities (boron).

2512 (1996)]. The trapping coefficient of single-negative silicon vacancies was also derived.

Pegylated interferon (Peg-IFN) plus ribavirin combination therapy is effective in patients with hepatitis C virus (HCV) infection and normal alanine aminotransferase levels (NALT). However, it remains unclear whether the risk of hepatocellular carcinoma (HCC) incidence is actually reduced in virological responders. In this study, HCC incidence was examined for 809 patients with NALT (ALT ≤ 40 IU/mL) treated with Peg-IFN alpha-2b and ribavirin for a mean observation period of 36.2 ± 16.5 months. The risk factors for HCC incidence were analysed by Kaplan-Meier method and Cox proportional hazards model. On multivariate analysis among NALT patients, the risk of HCC incidence was significantly reduced in patients with sustained virological response (SVR) or relapse compared with those showing nonresponse (NR) (SVR vs NR, hazard ratio (HR): 0.16, P = 0.009, relapse vs NR, HR: 0.11, P = 0.037). Other risk factors were older age (≥65 years vs60 years, HR: 6.0, P = 0.032, 60-64 vs60 years, HR: 3.2, P = 0.212) and male gender (HR: 3.9, P = 0.031). Among 176 patients with PNALT (ALT ≤ 30 IU/mL), only one patient developed HCC and no significant risk factors associated with HCC development were found. In conclusion, antiviral therapy for NALT patients with HCV infection can lower the HCC incidence in responders, particularly for aged and male patients. The indication of antiviral therapy for PNALT (ALT ≤ 30 IU/mL) patients should be carefully determined.

The association between the extent of left ventricular (LV) hypertrophy and severity of ventricular or atrial arrhythmias are examined. Two-dimensional echocardiography and 24-h Holter electrocardiography monitoring were performed in 60 patients with hypertrophic cardiomyopathy (HCM). According to the distribution of the LV hypertrophy, the patients were divided into three groups: 1. Apical hypertrophy (APH), 2. Septal hypertrophy, and 3. Extensive hypertrophy. Ventricular arrhythmias were found in 82% of the patients and supraventricular arrhythmias were detected in 70% of the patients. Lown grade III and IV arrhythmias occurred significantly more frequently in patients with extensive than with septal hypertrophy. Lown grade III to IV arrhythmias did not occur in patients with APH. Present results show a significant association between the extent of LV hypertrophy and the severity of ventricular arrhythmias in HCM.

A laminated material composed of glass cloth/polyimide film/epoxy resin will be used as an insulating material for superconducting coil of International Thermonuclear Experimental Reactor (ITER). In order to keep safe and stable operation of the superconducting coil system, it is indispensable to evaluate radiation resistance of the material, because the material is exposed to severe environments such as high radiation field and low temperature of 4 K. Especially, it is important to estimate the amount of gases evolved from the insulating material by irradiation, because the gases affect on the purifying system of liquid helium in the superconducting coil system. In this work, the gas evolution from the laminated material by gamma ray irradiation at liquid nitrogen temperature (77 K) was investigated, and the difference of gas evolution behavior due to difference of composition in the epoxy resin was discussed. It was found that the main gases evolved from the laminated material by the irradiation were hydrogen, carbon monoxide and carbon dioxide, and that the amount of gases evolved from the epoxy resin containing cyanate ester was about 60% less than that from the epoxy resin containing tetraglycidyl‐diaminophenylmethane (TGDDM).

A small transducer for distinguishing color with high spectral selectivity is proposed. It consists of an Si p-n junction photodiode and a filter consisting of an electrically controlled birefringence (ECB) mode liquid-crystal cell mounted on the photodiode. Since the spectral transmittance of the filter can be electronically tuned by regulating the applied voltage across the liquid-crystal cell, a filter having continuously different spectral response with time can be realized. The filter can accurately distinguish colors by observing the photodiode output at increasing or decreasing voltage across the liquid-crystal cell. Eight kinds of colored paper are discerned by the transducer. >

A rectilinearly wide plasma has been formed by electron cyclotron resonance (ECR). The ECR magnetic field is generated in the long range using a pair of 300-mm length magnets with oppositely facing poles. Microwave of 2.45-GHz frequency is supplied through a quartz window from a slotted waveguide placed between the magnets. A preliminary experiment is conducted to acquire basic data for sputtering targets to fabricate wide, uniform thin films. It is established by simulation that sputtering directivity obeys the square-root cosine law. Two planar titanium targets are lined up in parallel with the slotted waveguide. They are so tapered as to point their edges at each other and soaked in the uniform plasma. Uniform films are formed within an area of 180×180 mm2 in a 200-mm width plasma by sputtering the tapered targets and varying the direction of substrate surface to the targets.

Polyimide films and glass fiber reinforced plastics (GFRPs) are used as insulating and structural materials for superconducting magnets in a neutrino beam line of the Japan Proton Accelerator Research Complex (J‐PARC). It is indispensable to evaluate radiation resistance of these materials, because they are required to keep their electrical and mechanical properties in a high radiation field of 30 kGy/year at low temperature of 4 K. In this work, the gas evolution resulting from chemical reactions induced in the polyimide films and GFRPs by γ‐ray irradiation at 77 K was investigated. It was found that the main component of the evolved gas was hydrogen. The amount of hydrogen evolved from the superconducting magnet system used in the neutrino beam line was estimated to be 0.37 mol/year corresponding to 0.01 L/year as the volume of liquid hydrogen. It indicates that the hydrogen evolved from the organic materials will not influence the operation of the helium purifying system.

Radiation resistance of organic materials used in superconducting magnets for a 50 GeV–750 kW proton beam line for the J‐PARC neutrino experiment was studied with respect to mechanical properties. Specimens cooled at a liquid nitrogen temperature of 77 K were irradiated by gamma rays from 60Co with the maximum dose beyond 10 MGy. The flexural strength of glass‐fiber reinforced plastics (GFRPs), the tear strength of polyimide films and the tensile lap‐shear strength of adhesive films were evaluated. It was verified that the organic materials used in the superconducting magnets have the sufficient radiation resistance, and the degradation of their mechanical properties after the 10 years operation was estimated to be negligible.

Response characteristics of the alanine-polystyrene dosimeter were studied at an absorbed dose of 5 kGy over the low irradiation temperature range −196 ∼ 30°C, and the ESR analysis temperature range 0 ∼ 50°C in the dose range 0.1 ∼ 10 kGy. The irradiation temperature coefficient previously estimated for the temperature range from 0 ∼ 70°C (+0.24%/°C) was verified down to −15°C, although about 8% lower values were obtained at −78 and −196°C based on the correction using the above coefficient. ESR intensity decreases with temperature during ESR analysis following the function of the reciprocal of absolute temperature based on Boltzmann's constant. The average temperature coefficient for three different dose levels during ESR analysis of the alanine-polystyrene dosimeter is −0.25%/K in the temperature range 0 ∼ 50°C.

Uniform, large-area TiO/sub 2/ thin films are formed by reactive sputtering deposition in an electron cyclotron resonance (ECR) sheet plasma. The plasma source consists of a pair of long permanent magnets and a slot antenna. The antenna is set up between magnets whose N poles face each other. The generated plasma are uniform in one direction. To make the thin-films uniform in large area, two triangular targets are adopted and substrates are turned at two different angles with respect to the targets. The target form and substrate angle are determined by simulation and experiment. The thin-films are characterized with a profilometer and an X-ray diffractometer. The films of TiO/sub 2/, especially rutile having high refractive index, are useful for optical coating. The generated films are of anatase that has refractive index of 2.5. Crystallization is improved by controlling the electric potential of the substrates and by annealing as well.

Background The prognosis of gastric cancer with peritoneal metastasis is extremely poor. Neither systemic chemotherapy nor surgery alone prolongs survival of patients significantly. Methods Patients diagnosed with advanced gastric cancer underwent staging laparoscopy and received chemotherapy when peritoneal dissemination and/or cancer cells on peritoneal cytology were confirmed. The chemotherapy regimen consisted of S-1, weekly intravenous and intraperitoneal paclitaxel, which was verified in our phase II trial (Ann Oncol 2009). S-1 was administered at 80 mg/m2/day for 14 consecutive days, followed by 7 days rest. Paclitaxel was administered intravenously at 50 mg/m2 and intraperitoneally at 20 mg/m2 on days 1 and 8. Clinical response of chemotherapy was assessed by computed tomography, gastroendoscopy, peritoneal cytology and second-look laparoscopy. Radical gastrectomy was carried out when macroscopic curative resection was made achievable by chemotherapy. Chemotherapy was restarted after operation as soon as possible. Overall survival, relapse free survival, morbidity and mortality of gastrectomy were evaluated. Results Out of 100 patients with peritoneal metastasis who received chemotherapy, 60 patients underwent gastrectomy after response to chemotherapy, including 54 with macroscopic metastasis and 6 with positive peritoneal cytology only. A median of three courses were administered preoperatively (range 1–16). Total or distal gastrectomy with lymphnode dissection was carried out in 54 or 6 patients, respectively. The median survival time was 34.5 months. The median relapse-free survival was 16.7 months. The first site of relapse was the peritoneum in 24 patients and the other organ site in 17 patients. Postoperative complications included anastomotic leakage and pancreatic fistula in two patients each, which were healed conservatively. There were no treatment-related deaths. Conclusions Gastrectomy combined with S-1, intravenous and intraperitoneal paclitaxel is safe and active for gastric cancer patients with peritoneal metastasis.

SRPX2 (Sushi repeat-containing protein, X-linked 2) has recently emerged as a multifunctional protein that is involved in seizure disorders, angiogenesis and cellular adhesion. Here, we analyzed this protein biochemically. SRPX2 protein was secreted with a highly post-translational modification. Chondroitinase ABC treatment completely decreased the molecular mass of purified SRPX2 protein to its predicted size, whereas heparitinase, keratanase and hyaluroinidase did not. Secreted SRPX2 protein was also detected using an anti-chondroitin sulfate antibody. These results indicate that SRPX2 is a novel chondroitin sulfate proteoglycan (CSPG). Furthermore, a binding assay revealed that hepatocyte growth factor dose-dependently binds to SRPX2 protein, and a ligand–glycosaminoglycans interaction was speculated to be likely in proteoglycans. Regarding its molecular architecture, SRPX2 has sushi repeat modules similar to four other CSPGs/lecticans; however, the molecular architecture of SRPX2 seems to be quite different from that of the lecticans. Taken together, we found that SRPX2 is a novel CSPG that is overexpressed in gastrointestinal cancer cells. Our findings provide key glycobiological insight into SRPX2 in cancer cells and demonstrate that SRPX2 is a new member of the cancer-related proteoglycan family.

Background The cell surface receptor tyrosine kinase c-Met and its ligand, the hepatocyte growth factor (HGF), are implicated in tumor cell migration, invasion, survival and proliferation. EMD 1214063 is a novel potent and highly selective reversible, ATP-competitive small molecule c-Met inhibitor. Methods This is a phase I, first in human (FIH) clinical trial with escalating doses of EMD 121406(NCT 01014936). The primary objective is to determine the MTD. Secondary objectives include evaluation of safety, pharmacokinetics, anti-tumor effect and pharmacodynamics (Pd). Eligible patients had advanced solid tumors not amenable to standard therapies. Following a classical 3 + 3 dose escalation scheme, successive cohorts of patients were treated with once daily oral EMD 1214063 according to two 21-day-cycle schedules, either days 1-14 followed by a 7-day rest(regimen 1, R1), or continuous three times weekly administration (regimen 2, R2). Pd markers were evaluated in paired tumor biopsies. Results As of 30 March 2011, a total of 41 patients had been enrolled, 21 in R1 and 20 in R2. The dose was escalated from 30 mg/day to 115 mg/day in R2 and to 230 mg/day in R1. One DLT was reported in R1 at 115 mg/day, an asymptomatic, grade 4 lipase and G3 amylase elevation. No other DLTs or treatment-related SAEs were observed. The remaining treatment-related AEs of grade 2 or higher included nausea (n = 1), vomiting (n = 1), anorexia (n = 1), diarrhea (n = 1), and fatigue (n = 1) in R1, and neutropenia (n = 1) in R2. 37 patients (90%) had no drug-related toxicity greater than grade 1. At the dose levels investigated, median Cmax and AUC values increased with dose. Immunohistochemical analysis of a patient with pre- and on-treatment biopsies showed a decrease in phospho-c-Met staining intensity under treatment. Preliminary anti-tumor activity has been observed, including an unconfirmed PR in one patient and stable disease lasting for at least 4 months in 5 patients. One patient with sarcomatoid bladder carcinoma and multiple MET copies due to polysomy of chromosome 7 achieved SD for 16+ months. Conclusions The MTD has not yet been reached and dose escalation of EMD 1214063 continues. Updated results of this FIH study will be presented.

The clinical significance of the serum crosslinked N-telopeptide of type I collagen (NTx) as a prognostic marker for non-small-cell lung cancer (NSCLC) was evaluated. We have revealed that a high serum NTx level (>22 nmol bone collagen equivalents (BCE)/L) appears to be a risk factor for a reduction in overall survival in patients with NSCLC. Introduction: Lung cancer is the leading cause of cancer-related death. Many patients with lung cancer are in its advanced stages at the time of diagnosis. The 5-year survival rate for lung cancer is 10% to 20%, and the prognosis for patients with lung cancer is still poor. The crosslinked N-terminal telopeptide of type I collagen (NTx) is a metabolite of type I collagen, the main constituent of bone matrix. Patients and Methods: We measured serum NTx levels in patients who underwent staging during hospitalization for the initial treatment of lung cancer in our department. We examined whether serum NTx levels would be relevant to the prognosis of non-small-cell lung cancer (NSCLC). Results: This study included 176 patients with lung cancer (125 men and 51 women), including 109 with adenocarcinoma, 53 with squamous cell carcinoma, 6 with large-cell carcinoma, and 8 with other cancer types. Univariate and multivariate analysis using the Cox proportional hazards model revealed a particularly close associ- ation between sex, performance status, disease stage, and serum NTx levels and overall survival (OS). A median OS of 368 days was observed for patients with a serum NTx level 22 nmol BCE/L, which was significantly longer than the 197 days for patients with a serum NTx level 22 nmol BCE/L (hazard ratio (HR), 2.02; 95% confidence interval (CI), 1.36-2.99; log-rank P.00037). Conclusions: We have revealed that a high serum NTx level ( 22 nmol BCE/L) appears to be a risk factor for a reduction in OS in patients with NSCLC.

E3810 is a new H+,K(+)-ATPase inhibitor with a substituted benzimidazole, which is under clinical investigation for peptic ulcer treatment in Japan and the USA. Three separate studies were conducted to evaluate the safety and to establish the pharmacokinetic profile of E3810 after oral administration to healthy male subjects. E3810 was administered as: single oral doses (1, 3, 10, 20, 40 and 80 mg) in fasting conditions, a single oral dose (20 mg) after a meal and repeated oral doses (20 and 40 mg) once daily for 7 days. The concentrations of E3810 and its metabolites in plasma and urine were determined by HPLC methods with UV detection. E3810 was generally well tolerated by all subjects. In the single-dose study, Cmax and AUC increased with increasing doses in the dose range examined. The mean plasma half-life was about 1.0 hour and was dose-independent. The apparent oral clearance of E3810 ranged from 4.37 to 8.40 ml/min/kg. No significant deviation from linear pharmacokinetics was observed. Approximately, 30% of a dose was excreted into the urine as thioether carboxylic acid-E3810 and its glucuronide. The mean serum protein binding was 96.3%. No effect of food intake on the Cmax and AUC was observed while tmax after a meal was 1.7 hours longer than that in the fasting conditions. No appreciable change in drug pharmacokinetics was observed during repeated oral dosing of E3810.

The use of gonadotrophin-releasing hormone agonist (GnRHa) in combination with human menopausal gonadotrophin (HMG) for ovulation induction has been advocated for the treatment, particularly by in-vitro fertilization (IVF) of various types of infertility. The present study was designed to compare the clinical efficacy of HMG alone with a short protocol of GnRHa/HMG for treatment of unexplained infertility. A total of 91 couples with unexplained infertility were randomly assigned to one of two treatments; either HMG with intra-uterine insemination (IUI) (45 patients, 62 cycles) or GnRHa/HMG with IUI (46 patients, 69 cycles) treatments. Progesterone concentrations on the day of human chorionic gonadotrophin (HCG) administration were significantly higher in HMG (1.5 +/- 0.9 ng/ml) versus GnRHa/HMG (0.8 +/- 0.6 ng/ml; P < 0.05) cycles. Furthermore, GnRHa suppressed the occurrences of premature luteinization (GnRHa/HMG 5.8% and HMG 24.2% respectively). However, there were no significant differences in HMG dose requirements, plasma oestradiol concentrations or follicular development on the day of HCG administration between the two groups. Nor were any significant differences found in the pregnancy rates between the two treatment protocols (GnRHa/HMG 13.0% and HMG 11.3% respectively). Our results suggest no beneficial effect of GnRHa/HMG compared to HMG alone for the treatment of unexplained infertility, based on pregnancy rates.

Many types of rewritable optical disks have been proposed and studied. Some of them are currently used for computer data storage and audio/video signal recording. Of these types, a phase-change rewritable (PCR) type shows great promise as a future optical recording media. It can be easily overwritten, and the carrier-to-noise ratio (CNR) is high over wide range of wavelengths, from 400nm to 900nm.1) A phase-change media shows high performance characteristics, but it has not been shown that a high performance phase-change media can be mass-produced, as MO media is.

E2020 is a new cholinesterase inhibitor with a novel chemical structure, which is under clinical investigation for use in Alzheimer's disease in Japan and the USA. Three separate studies were conducted to evaluate the safety and to establish the pharmacokinetic profile of E2020 after oral administration to healthy male subjects. E2020 was administered as: (1) single oral doses (0.3 mg, 1 mg, 2 mg, 5 mg, 8 mg and 10 mg) in a fasting condition, (2) a single oral dose (2 mg) after a meal and (3) repeated oral doses (2 mg once daily for 21 days). The concentrations of E2020 and its metabolites in plasma, serum, urine and feces were determined by HPLC methods with UV detection. E2020 was generally well tolerated by all subjects. In the single-dose study, there was a linear relationship between dose and mean AUC. The mean plasma half-life was about 50 hours and was dose-independent. The total clearance and renal clearance of E2020 were also dose-independent and the mean values after 10 mg dosing were 9.7 l/hour and 0.86 l/hour, respectively. The cumulative total urinary and fecal excretion of the sum of unchanged E2020 and its metabolites at 264 hours after the administration of the single 10-mg-dose was 36.1% and 8.6% of the dose, respectively. The mean serum protein binding was 92.6%. No effect of food intake on the pharmacokinetics was observed. Evaluation of the mean trough levels and AUC0-24 of E2020 indicated that a steady-state was achieved after approximately 2 weeks of daily dosing.

The development of a new alloy for the cylinders of injection moulding machines processing advanced reinforced polymers is described. Corrosion and wear tests produced a new composition that has comparable corrosion resistance to Hastelloy C together with wear resistance superior to currently used nickel based alloys containing a hard boride phase. The new alloy can be bonded to the interior of cylinders using a reaction sintering hipping route and has performed satisfactorily in service trials.

The safety and pharmacokinetics of E1040, a new injectable cephem antibiotic, were evaluated in healthy volunteers. In single-dose studies, 125, 250, 500, 1000 and 2000 mg of E1040 were administered by I.V. infusion over 1 hour. Results of 5 minutes I.V. infusions of 500, 1000 and 2000 mg of the drug were also studied. Plasma concentration-time profiles were well suited to a two-compartment open model. The half-life of elimination from plasma was 1.85 +/- 0.16 hours, and the Cmax and AUC paralleled the doses given. The mean urinary recovery within the first 24 hours was 85.7 +/- 6.43% of the dose. In a multiple-dose study, 2000 mg of E1040 (I.V. over 1 hour) was administered every 12 hours (total 9 times) and no abnormal accumulation of the drug in plasma was observed. There were no significant differences in plasma levels or in urinary recoveries between single- and multiple-dose regimens. There were no subjective or objective abnormal findings definitely attributable to the drug except that one subject given 250 mg over 1 hour reported diarrhea, and another complained of nausea during the infusion of 2000 mg over 5 minutes. From these results E1040 was concluded to be safe and well tolerated.

1 The effects of two assay methods, HPLC and EIA, on theophylline plasma levels (n = 254) and pharmacokinetics (n = 6) were examined on blood samples obtained from asthmatic patients and normal adult male volunteers. 2 The standard curves obtained and the plasma level values during plasma level monitoring of theophylline measured with two methods are well correlated each other within concentration range of 2.5 to 20.0 microgram/ml (P less than 0.001). EIA, however in general, appears to give a lower value than HPLC. 3 The values of plasma theophylline half-life and clearance analyzed using a two-compartment open system model were found different between the two assay methods and dissimilar to those previously reported by using ultraviolet method. 4 The sampling end-point and/or assay sensitivity particularly to measure a lower level of theophylline (less than 2.5 microgram/ml) can influence the pharmacokinetics for a potent bronchodilator with a narrow therapeutic margin, theophylline.

Patients received pivmecillinam (PMPC) after prophylactic use of various antimicrobial chemotherapeutic agents following prostatectomy, and their clinical responses were assessed for effectiveness in the treatment and prevention of postoperative infection. The data were also analyzed to explore the relationship between bacterial isolates obtained during the postoperative course and the antimicrobial agents administered prophylactically against postoperative infection. Therapeutic effect of PMPC: Treatment of postoperative infections with PMPC was effective in 36 (53.7%) out of 67 patients who had undergone prostatectomy. Prophylactic effect of PMPC: The use of PMPC provided effective prevention of infection in 22 (64.7%) out of 34 patients from whom no bacterial pathogen had been isolated before postoperative antimicrobial chemotherapy. Therapeutic responses to PMPC, compared between different types of operative procedure: There was little or no difference in therapeutic effectiveness of PMPC against postoperative infection when compared between two types of operative procedure, transurethral prostatectomy and subcapsular removal of the prostate. Incidence and types of bacterial isolates following prophylactic chemotherapy with various agents after prostatectomy: Possibly because cephapirin (CEPR) and ticarcillin (TIPC) were mainly administered, alone or in combination, for prophylaxis against postoperative infection, Serratia and Pseudomonas were most frequently isolated. The findings offer suggestions as to the appropriate combination of antimicrobial agents to be used for prophylactic purposes. Effectiveness of PMPC in the presence or absence of a preoperative indwelling urethral catheter: The use of PMPC was more effective both in the treatment and prevention of postoperative infection in cases without preoperative indwelling urethral catheterization than in those with it.

Effects of cinnarizine on immune response in mice were investigated. Mice were orally administered with cinnarizine and were immunized with sheep red blood cells (SRBC) intravenously. Numbers of plaque forming cells (PFC) to SRBC in spleen of these mice were assayed and delayed-type hypersensitivity (DTH) response to SRBC was measured. 1) PFC response in immunization with 5 X 10(6) cells/mouse of SRBC was enhanced by administration of 25 mg/kg of cinnarizine, while the response in immunization with 5 X 10(8) cells/mouse was suppressed by 25 to 200 mg/kg of cinnarizine. 2) From study on timing of administration, suppression of PFC response by 6.25 to 200 mg/kg of cinnarizine was observed at 24 hr. after the immunization. 3) 12.5 to 200 mg/kg of cinnarizine suppressed polyclonal B cell activation induced by lipopolysaccharide (LPS). 4) Colchicine induced suppressor T cell inactivation was prevented by administration of 50 mg/kg of cinnarizine and it was suggested that cinnarizine may induce suppressor T cells from the study of adoptive cell transfer system. 5) 50 mg/kg of cinnarizine showed the suppression of DTH response in expression phase, but not in induction phase. It was concluded that immune responses in mice were modified by cinnarizine.

The pharmacokinetics of coenzyme Q10 (CoQ10) in man was studied by utilizing deuterium-labelled coenzyme Q10 (d5-CoQ10). The absence of an isotope effect in the disposition of d5-CoQ10 in man was confirmed from the plasma concentration time curves after simultaneous oral dosing of d5-CoQ10 and unlabelled CoQ10. After oral administration of 100 mg of d5-CoQ10 to 16 healthy male subjects, the mean plasma CoQ10 level attained a peak of 1.004 +/- 0.370 micrograms/ml at 6.5 +/- 1.5 h after administration, and the terminal elimination half-life was 33.19 +/- 5.32 h. In most of the subjects, plasma d5-CoQ10 showed a second peak at 24 h after dosing. This unusual plasma level curve was well described by a newly proposed compartment model based upon the assumption that absorbed CoQ10 is taken up by the liver and then transferred mainly to VLDL and redistributed from the liver to the systemic blood.