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Vedolizumab is a humanized monoclonal antibody against the α4β7 integrin and is approved for treatment of inflammatory bowel diseases. In this study, we evaluated the immunogenicity of vedolizumab using a simple drug-tolerant assay developed in our laboratory. Serum vedolizumab trough levels and anti-vedolizumab antibody (AVA) levels were measured using new immunoassays in 37 patients with ulcerative colitis (UC) under vedolizumab maintenance therapy. The median vedolizumab trough level at week 30 was 16.0 μg/ml (interquartile range, 7.3-24.4). The vedolizumab trough level of the patients with clinical remission (partial Mayo score ≤1) was significantly higher than that of clinically active patients (16.7 μg/ml vs 6.8). The cut-off value of vedolizumab level predicting clinical remission at week 30 was 7.34 μg/ml. The median AVA level of patients under vedolizumab maintenance therapy was similar to that of healthy controls (n = 20) (0.032 μg/ml-c vs 0.022). One of 37 patients (2.7%) was judged to be AVA positive. There was no significant difference in serum AVA and vedolizumab trough levels between biologics-naïve (n = 19) and biologics-switched (prior anti-TNFα-exposed) patients (n = 18). In conclusion, the simple drug-tolerant assay developed in our laboratory demonstrated low immuno-genicity of vedolizumab. Prior use of anti-TNFα drugs did not affect the immunogenicity of vedolizumab.

Background Endoscopic retrograde cholangiopancreatography (ERCP) often requires deep sedation. Dexmedetomidine, a highly selective α2-adrenoceptor agonist with sedative activity and minimal effects on respiration, has recently been widely used among patients in the intensive care unit. However, its use in endoscopic procedures in very elderly patients is unclear. In this study, we retrospectively investigated the safety and efficacy of dexmedetomidine sedation during ERCP. Methods The study included 62 very elderly patients (aged over 80 years) who underwent ERCP from January 2014, with sedation involving dexmedetomidine (i.v. infusion at 3.0 μg/kg/h over 10 min followed by continuous infusion at 0.4 μg/kg/h) along with midazolam. For comparison, the study included 78 patients who underwent ERCP before January 2014, with midazolam alone. We considered additional administration of midazolam as needed to maintain a sedation level of 3–4, according to the Ramsay sedation scale. The outcome measures were amount of midazolam, adverse events associated with sedation, and hemodynamics. Results The incidence of decreased SpO2 and median dose of additional midazolam were significantly lower in the dexmedetomidine group than in the conventional group. The minimum systolic blood pressure and minimum heart rate during and after examination was significantly lower in the dexmedetomidine group than in the conventional group. However, serious acute heart failure or arrhythmia was not noted. Conclusions Dexmedetomidine can decrease the incidence of respiratory complications and the total dose of other sedative agents. It can be used as an alternative to conventional methods with midazolam for adequate sedation during ERCP in very elderly patients.

Conventional synthetic disease-modifying anti-rheumatic drugs, including methotrexate, may not be tolerated by all patients with rheumatoid arthritis (RA), and limited international data for etanercept (ETN) monotherapy are available. The aim of this review was to summarize the clinical program for ETN monotherapy in Japanese patients with RA, which has included a pharmacokinetic study, clinical trials for registration, long-term studies, and once-weekly dosing studies. Pharmacokinetic results showed that serum concentrations of ETN were linear with dose levels and were similar to other international studies. Across interventional studies, 652 Japanese patients with active RA were treated with ETN. In the registration studies, ETN treatment led to consistent improvement in American College of Rheumatology 20/50/70 scores, European League Against Rheumatism Good Response, Disease Activity Score 28 erythrocyte sedimentation rate remission, and Health Assessment Questionnaire disability index. In the long-term studies, efficacy was maintained for up to 180 weeks. Similar results were seen in the once-weekly studies. Across the studies, more than 870 patient-years of exposure to ETN were recorded. Discontinuations owing to lack of efficacy or adverse events were modest and no new safety signals were recorded. These studies demonstrated that ETN monotherapy is efficacious and well-tolerated in Japanese patients with RA.

Safety, tolerability, and pharmacokinetics of tigecycline in 76 healthy Japanese subjects were determined in three randomized, double-blind, placebo-controlled studies. Subjects in an ascending single-dose study (n = 40) received 25-150 mg intravenously, whereas subjects in two multiple-dose studies received every 12-hour (q12h) dosing with 25 mg (n = 10) or 25, 50, or 100 then 50 mg (n = 30). Serial blood samples and urine were collected, drug concentrations determined, and pharmacokinetic parameters calculated. Fecal samples were also collected in the second multiple-dose study. After 10 days of tigecycline 50 mg q12h, mean ± standard deviation pharmacokinetics in 8/10 subjects were: maximum concentration 1,118 ± 127 ng/mL, area under the concentration-time curve 0-12 hours 3,261 ± 937 ng h/mL, clearance 0.25 ± 0.05 L/h/kg, half-life 60.7 ± 23.4 hours, and volume of distribution 11.9 ± 2.3 L/kg. The most common adverse events were nausea and vomiting. Changes in total bilirubin were also observed. Enterococci in the intestinal microflora were reduced, whereas the number of Enterobacteriaceae and Bacteroides remained relatively constant. Several strains of Bacteroides spp. resistant to tigecycline treatment were found in fecal samples on days 30 and 31. The pharmacokinetic profile of tigecycline was similar to non-Japanese subjects; tolerability and change in intestinal microflora were also similar.

Thirty Japanese (J) and 32 American (A) healthy subjects received single doses of etanercept by subcutaneous injection, in 3 separate trials. Serum samples were collected for 480 hours after dosing. Concentrations were determined using enzyme-linked immunosorbent assay methods. Pharmacokinetic parameters were calculated using both non-compartmental and compartmental methods. Etanercept was slowly absorbed, with mean+/-SD time to maximum serum concentration of 47+/-15 hours (J), and 51+/-20 hours (A). The maximum serum concentration and area under the concentration time curve increased for doses 10 mg, 25 mg, and 50 mg, in a linear relationship. Etanercept was slowly eliminated, with observed mean+/-SD half-life of 80+/-25 hours (J) and 75+/-15 hours (A) and mean+/-SD apparent clearance of 144+/-65 mL/h (J) and 132+/-74 mL/h (A). Very low concentrations of etanercept were observed in the urine samples collected in the Japanese subjects. All adverse reactions observed resolved without issue, and none required discontinuation from the study.

Safety, tolerability, and pharmacokinetics of tigecycline in 76 healthy Japanese subjects were determined in three randomized, double-blind, placebo-controlled studies. Subjects in an ascending single-dose study (n = 40) received 25-150 mg intravenously, whereas subjects in two multiple-dose studies received every 12-hour (q12h) dosing with 25 mg (n = 10) or 25, 50, or 100 then 50 mg (n = 30). Serial blood samples and urine were collected, drug concentrations determined, and pharmacokinetic parameters calculated. Fecal samples were also collected in the second multiple-dose study. After 10 days of tigecycline 50 mg q12h, mean ± standard deviation pharmacokinetics in 8/10 subjects were: maximum concentration 1,118 ± 127 ng/mL, area under the concentration-time curve 0-12 hours 3,261 ± 937 ng h/mL, clearance 0.25 ± 0.05 L/h/kg, half-life 60.7 ± 23.4 hours, and volume of distribution 11.9 ± 2.3 L/kg. The most common adverse events were nausea and vomiting. Changes in total bilirubin were also observed. Enterococci in the intestinal microflora were reduced, whereas the number of Enterobacteriaceae and Bacteroides remained relatively constant. Several strains of Bacteroides spp. resistant to tigecycline treatment were found in fecal samples on days 30 and 31. The pharmacokinetic profile of tigecycline was similar to non-Japanese subjects; tolerability and change in intestinal microflora were also similar.

We performed preoperative combined therapy using nedaplatin (CDGP) and radiation in 12 patients with squamous cell carcinoma originating from the oral cavity and maxillary sinus, and examined for any adverse events that may have occurred during this therapeutic regimen. Regarding the irradiation, external irradiation utilizing a 6 MV linac (linear accelerator) at a dose of 2.0 Gy/day was performed 5 times a week, with the target total radiation dose set at 40 Gy. In addition, CDGP was intravenously administered 30 minutes before irradiation at a dose of 5 mg/m2/day. Mucositis was observed in all 12 subjects, however, the severity was observed to be grade 1-2 with no major differences in comparison to the patients given standard radiation monotherapy. Two subjects developed grade 3 leucopenia and were thus given granulocyte colony stimulating factor (G-CSF). In addition, grade 2 and grade 3 thrombocytopenia were both observed in one subject each. The subject with grade 3 thrombocytopenia required a platelet transfusion during surgery. No marked changes in serum creatinine levels were noted. These findings are therefore considered to provide evidence supporting the safety of this combination therapy.

A repeated oral dose toxicity study of methotrexate (MTX) was conducted in order to examine whether the enhancement of MTX toxicity would occur in unilaterally nephrectomized (UNX) rats. UNX rats or sham-treated (SHAM) rats received dosages of 0, 0.06, 0.2 or 0.6 mg/kg/day (control animals received physiological saline). Toxic effects of MTX observed in this study were not different from studies already conducted, i.e., myelo- and lympho-toxicity, gastrointestinal toxicity, hepatotoxicity, pulmonary toxicity and renal toxicity were evident in the animals given MTX. Toxic effects of MTX in the UNX rats were more severe than those in the SHAM rats; a higher number of dead and moribund animals was observed among the UNX rats, and abnormal clinical signs appeared a few days earlier in the UNX rats. In the hematological examination, a decreased number of the blood cells in the UNX rats was observed at the lower dose level as compared to SHAM rats. The nontoxic dose of MTX in SHAM rats and UNX rats was 0.06 mg/kg/day and below 0.06 mg/kg/day, respectively. According to the results of a toxicokinetic examination conducted in the animals receiving 0.2 mg/kg/day, AUC and T 1/2terminal of MTX in the UNX rats were higher than those of SHAM rats. It was considered that the enhancement of the MTX toxicity in UNX rats was caused by the longer exposure of MTX in UNX rats. Serum UN and Cr of the UNX rats receiving physiological saline were higher than those of the corresponding SHAM rats, which suggested a slightly decreased GFR had been induced in UNX rats in this study. However, decreased PSP excretion was not observed in the UNX rats and urine volume of the UNX rats was equivalent to that of SHAM rats. Thus, it was considered that vicarious hypertrophy occurred in the residual kidney and decreased renal function was not evident in the UNX rats. This study demonstrated that the enhancement of toxicity of MTX had occurred even though a decreased renal function was not evident.

To clarify whether levofolinate calcium (1-LV) enhances 5-fluorouracil (5-FU) toxicity, a 4-week toxicity study of 5-FU (10 mg/kg/day) in combination with 1-LV (6, 20 or 60 mg/kg/day) was conducted in rats. In the 5-FU alone group, a decrease in body weight gain, food consumption, RBC parameter and WBC counts were detected. Histopathologically, lymphoid depletion of lymphatic organs, hematopoiesis enhancement of the spleen and myelosuppression were observed. In the group for which 5-FU was combined with 1-LV, the RBC counts decreased, extramedullary hematopoiesis increased and the suppression of lymphatic organs was enhanced. Changes in the lymphatic organs were observed at 20 mg/kg/day of 1-LV and above. In monitoring of blood drug concentrations of 1-LV, 5-methyl tetrahydrofolic acid, a metabolite of 1-LV, and 5-FU after the 1st and 14th dosings, there was no apparent difference between 5-FU alone and 5-FU combined with 1-LV in Cmax and AUC0-infinity. The potentiation induced by 1-LV in the toxicity of 5-FU appeared to be mainly immuno-suppression and myelosuppression, which were related to the anti-tumor activity of 5-FU. Plasma concentrations of 5-FU and 1-LV in this study overwhelmed the concentrations that enhancement of thymidylate synthetase (TS) inhibition due to 5-FU was observed by addition of 1-LV in vitro. Therefore toxic potentiation of 5-FU due to simultaneous 1-LV dosing is presumed to be concerned with an increased ternary complex (FdUMP-TS-5,10-methylenetetrahydrofolate) formation and a greater extent of TS inhibition.

The C3 convertase of the classical pathway of the complement system is a liable complex, C4b,2a, and is activated by limited proteolysis of two components, C4 and C2, by C1s. By utilizing iodine-treated C2 and size exclusion high-performance liquid chromatography (HPLC), we have succeeded in isolating for the first time the classical pathway C3 convertase. Size exclusion HPLC demonstrated that the apparent molecular mass of the C3 convertase was 280K daltons. The C3 convertase decay-dissociates spontaneously into C4b and C2a. The decay-dissociation is a temperature-dependent reaction and the half-lives of the C3 convertase at 24, 30, and 37 degrees C were estimated to be 400, 180, and 60 min, respectively. The decay-dissociation was also dependent on pH and was accelerated by increasing pH. In addition, the decay-dissociation of the C3 convertase was accelerated by C2b. This result suggests that C2b acts as a feedback inhibitor on the activation of the classical pathway of complement system.