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Yasuhisa Ono,1 Yusuke Taneda,1 Tomomi Takeshima,2 Kosuke Iwasaki,2 Atsutaka Yasui1 1Medical Department, Nippon Boehringer Ingelheim, Tokyo, Japan; 2Milliman Inc., Tokyo, JapanCorrespondence: Yasuhisa OnoNippon Boehringer Ingelheim, 2-1-1 Osaki, Shinagawa-ku, Tokyo 141-6017, JapanTel +81-3-6417-2612Fax +81-3-5435-2918Email yasuhisa.ono@boehringer-ingelheim.comBackground: Observational studies using large claims databases for diabetes patients have been increasingly conducted. While validation of outcomes is important in such studies, validation studies from Japan are still scarce and small in scale with questions remaining on the representativeness of their findings. We examined the positive predictive value (PPV) of outcomes that often develop in type 2 diabetes patients: cardiovascular outcomes including congestive heart failure (CHF), myocardial infarction (MI), stroke-related diseases, and renal outcomes including end stage renal disease (ESRD), and death using a large Japanese database containing administrative claims and electronic medical record (EMR) data.Patients and Methods: We used patient-level administrative claims data from 2003 and EMR data from 1985 to the most recent data up to December 2018 provided by Real World Data Co., Ltd. The database consisted of data from over 200 hospitals including ≥ 12 million uniquely identifiable patients. Among patients who had ≥ 1 type 2 diabetes diagnosis in the EMR, those who had administrative claims for each outcome were identified, and then the PPV was calculated for each outcome using the EMR as the gold standard.Results: The numbers of patients identified for each outcome were 1,700 for MI, 2,027 for hemorrhagic stroke, 3,722 for ESRD, 4,723 for ischemic stroke, 5,404 for CHF, 6,678 for any type of stroke, and 10,815 for death. PPVs ranged from 67.4% for ESRD, 78.7% for MI, 80.3% for death, 85.7% for ischemic stroke, 88.9% for any type of stroke, 89.9% for hemorrhagic stroke, and 95.7% for CHF. A post hoc analysis showed PPV for ESRD as 83.8%.Conclusion: This large-scale validation study on diagnosis in administrative claims showed reasonable PPVs for the outcomes. We believe that the definitions of outcomes can be considered to be appropriate for future studies using Japanese administrative claims data.Keywords: ESRD, stroke, myocardial infarction, CHF, PPV, outcomes definition

Introduction: This study aimed to evaluate the impacts of dapagliflozin on 24-hour glucose variability and diabetes-related biochemical variables in Japanese patients with type 2 diabetes who had received basal insulin supported oral therapy (BOT)., Research Design and Methods: Changes in mean daily blood glucose level before and after 48-72 hours of add-on or no add-on of dapagliflozin (primary end point) and diabetes-related biochemical variables and major safety variables during the 12 weeks (secondary end point) were evaluated in the multicenter, randomized, two-arm, open-label, parallel-group comparison study., Results: Among 36 participants, 18 were included in the no add-on group and 18 were included in the dapagliflozin add-on group. Age, gender, and body mass index were comparable between the groups. There were no changes in continuous glucose monitoring metrics in the no add-on group. In the dapagliflozin add-on group, mean glucose (183-156 mg/dL, p=0.001), maximum glucose (300-253, p<0.01), and SD glucose (57-45, p<0.05) decreased. Time in range increased (p<0.05), while time above the range decreased in the dapagliflozin add-on group but not in the no add-on group. After 12-week treatment with dapagliflozin add-on, 8-hydroxy-2'-deoxyguanosine (8OHdG), as well as hemoglobin A1c (HbA1c), decreased., Conclusions: This study showed that the mean daily blood glucose and other daily glucose profiles were amended after 48-72 hours of dapagliflozin add-on in Japanese patients with type 2 diabetes who received BOT. The diabetes-related biochemical variables such as HbA1c and urinary 8OHdG were also obtained during the 12 weeks of dapagliflozin add-on without major adverse events. A preferable 24-hour glucose profile in 'time in ranges' and an improvement in reactive oxygen species by dapagliflozin warrant us to evaluate these benefits in larger clinical studies., Trial Registration Number: UMIN000019457., Competing Interests: Competing interests: YT and KO have received lecture fees from Ono Pharmaceutical. SY have received lecture fees from AstraZeneca. KK, MSa, and MSh have received lecture fees from Ono Pharmaceutical and AstraZeneca., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The cardiovascular and kidney safety of glucose-lowering drugs is a key concern in type 2 diabetes (T2D). We evaluated cardiorenal outcomes with glucose-lowering drugs in Asian patients, who comprise over half of T2D cases globally., Research Design and Methods: A rapid evidence assessment was conducted for phase III or IV, double-blind, randomized clinical trials of glucose-lowering drugs reporting cardiovascular or kidney outcomes for Asian T2D patients (Embase, Medline, Cochrane Library databases: 1 January 2008-14 June 2020)., Results: Fifty-four publications reported exploratory data for Asians from 18 trials of dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose co-transporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and insulin analogs. SGLT2 inhibitors and several GLP-1 receptor agonists were associated with reduced cardiovascular risk in Asian T2D patients, while DPP-4 inhibitors exhibited cardiovascular safety. SGLT2 inhibitors also appeared to reduce renal risk; however, kidney outcomes were lacking for DPP-4 inhibitors other than linagliptin and GLP-1 receptor agonists in Asian patients. Insulin data were inconclusive as the only trial conducted used different types of insulin as both treatment and comparator., Conclusions: Cardiorenal outcomes with glucose-lowering drugs in Asian T2D patients were similar to outcomes in the overall multinational cohorts of these trials. DPP-4 inhibitors appear to demonstrate cardiovascular safety in Asians, while SGLT2 inhibitors and some GLP-1 receptor agonists may reduce cardiorenal and cardiovascular risk, respectively.

Background: Previous studies have suggested that high mean glucose levels and glycemic abnormalities such as glucose fluctuation and hypoglycemia accelerate the progression of atherosclerosis in patients with type 2 diabetes. Although continuous glucose monitoring (CGM) that could evaluate such glycemic abnormalities has been rapidly adopted, the associations between CGM-derived metrics and arterial stiffness are not entirely clear., Methods: This exploratory cross-sectional study used baseline data from an ongoing prospective, multicenter, observational study with 5 years of follow-up. Study participants included 445 outpatients with type 2 diabetes and no history of apparent cardiovascular disease who underwent CGM and brachial-ankle pulse wave velocity (baPWV) measurement at baseline. Associations between CGM-derived metrics and baPWV were analyzed using multivariate regression models., Results: In a linear regression model, all CGM-derived metrics were significantly associated with baPWV, but HbA1c was not. Some CGM-derived metrics related to intra-day glucose variability, hyperglycemia, and hypoglycemia remained significantly associated with baPWV after adjusting for possible atherosclerotic risk factors, including HbA1c. Based on baPWV ≥ 1800 cm/s as indicative of high arterial stiffness, multivariate logistic regression found that some CGM-derived metrics related to intra-day glucose variability and hyperglycemia are significantly associated with high arterial stiffness even after adjusting for possible atherosclerotic risk factors, including HbA1c., Conclusions: Multiple CGM-derived metrics are significantly associated with baPWV and high arterial stiffness in patients with type 2 diabetes who have no history of apparent cardiovascular disease. These metrics might be useful for identifying patients at high risk of developing cardiovascular disease.

Aims: This phase 2, double-blind, randomized, placebo-controlled trial (ClinicalTrials.gov NCT02702011) with 4 sites in Japan investigated the pharmacodynamics (PD), pharmacokinetics (PK) and safety profile of empagliflozin in Japanese participants with type 1 diabetes mellitus (T1DM) as adjunctive therapy to insulin., Materials and Methods: Participants using multiple daily injections of insulin for ≥12 months, with HbA1c of 7.5%-10.0%, entered a 2-week, open-label, placebo run-in period, followed by a 4-week, double-blind period during which participants were randomized 1:1:1:1 to receive empagliflozin 2.5 mg (n = 13), empagliflozin 10 mg (n = 12), empagliflozin 25 mg (n = 12) or placebo (n = 11). The primary objective was to assess the effect of empagliflozin vs placebo on urinary glucose excretion (UGE) after 7 days of treatment., Results: PD: Empagliflozin resulted in a dose-dependent significant increase in 24-hour UGE compared with placebo (UGE placebo-corrected mean [95% confidence interval] change from baseline: 2.5 mg, 65.10 [43.29, 86.90] g/24 h; 10 mg, 81.19 [58.80, 103.58] g/24 h; 25 mg, 98.11 [75.91, 120.31] g/24 h). After 4 weeks of treatment, UGE increase was associated with improved glycaemic control, reduced body weight and decreased insulin needs. Empagliflozin treatment also resulted in dose-dependent increases in serum ketone bodies and free fatty acids. PK: Plasma empagliflozin levels increased in a dose-dependent manner and peaked at 1.5 hours. In this short study, empagliflozin was well tolerated, with no increase in rate of hypoglycaemia and no diabetic ketoacidosis events reported., Conclusions: Based on this short-duration phase 2 study, the PK/PD profile of empagliflozin in Japanese participants with T1DM is comparable to that of non-Japanese participants., (© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Activation of Wnt/β-catenin signaling is essential for colorectal carcinogenesis. Tankyrase, a member of the poly(ADP-ribose) polymerase (PARP) family, is a positive regulator of the Wnt/β-catenin signaling. Accordingly, tankyrase inhibitors are under preclinical development for colorectal cancer (CRC) therapy. However, Wnt-driven colorectal cancer cells are not equally sensitive to tankyrase inhibitors, and cellular factors that affect tankyrase inhibitor sensitivity remain elusive. Here, we established a tankyrase inhibitor-resistant cell line, 320-IWR, from Wnt/β-catenin-dependent CRC COLO-320DM cells. 320-IWR cells exhibited resistance to tankyrase inhibitors, IWR-1 and G007-LK, but remained sensitive to a PARP-1/2 inhibitor, olaparib, and several anti-CRC agents. In 320-IWR cells, nuclear localization of active β-catenin was decreased and expression of β-catenin target genes was constitutively repressed, suggesting that these cells repressed the Wnt/β-catenin signaling and were dependent on alternative proliferation pathways. 320-IWR cells exhibited upregulated mTOR signaling and were more sensitive to mTOR inhibition than the parental cells. Importantly, mTOR inhibition reversed resistance to tankyrase inhibitors and potentiated their anti-proliferative effects in 320-IWR cells as well as in CRC cell lines in which the mTOR pathway was intrinsically activated. These results indicate that mTOR signaling confers resistance to tankyrase inhibitors in CRC cells and suggest that the combination of tankyrase and mTOR inhibitors would be a useful therapeutic approach for a subset of CRCs.

Objectives: To evaluate the effectiveness of a vein visualization display system using near-infrared light ("Vein Display") for the safe and proper selection of venipuncture sites for indwelling needle placement in the forearm., Methods: Ten second year nursing students were recruited to apply an indwelling needle line with and without Vein Display. Another ten participants were recruited from various faculty to serve as patients. The quality of the venipuncture procedure at various selected sites was evaluated according to a scale developed by the authors. Time, scores and patterns of puncture-site selection were compared with respect to three different methods: [1] attempt 1 (tourniquet only), [2] attempt 2 (Vein Display only) and [3] attempt 3 (both). To validate the effectiveness of Vein Display, 52 trials were conducted in total., Results: We found that venipuncture site selection time was significantly improved with the Vein Display, particularly in the case of difficult to administer venipuncture sites. Overall, we found no significant difference with respect to venipuncture quality, as determined by our scale., Conclusion: These results suggest that equipment such as the Vein Display can contribute immensely to the improvement of practical skills, such as venipuncture, especially in the context of elderly patients., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The aim of this study was to investigate the clinical efficacy and safety of sitagliptin in Japanese patients with type 2 diabetes., Methods: A total of 3,247 subjects treated with sitagliptin were retrospectively recruited. Glucose parameters were collected at baseline, and 1, 3 and 6 months after initiation of sitagliptin. In addition, we explored factors that can be used to predict sitagliptin-induced reduction in HbA1c using linear mixed effect model. Factors associated with hypoglycemic events were examined by logistic analyses., Results: We analyzed the available data of 3,201 subjects (1,287 females). Treatment of sitagliptin significantly reduced HbA1c level from 7.44±1.20% at baseline to 6.73±0.99% at 6 months (P < 0.0001). Linear mixed effect model analyses demonstrated that reduction of HbA1c was associated with higher baseline HbA1c level, younger age, lower BMI and sitagliptin monotherapy. During this study, 82 cases of hypoglycemia were recorded. Logistic analyses indicated that hypoglycemic events were more frequent in female patients, and patients with low BMI, long history of type 2 diabetes, high HbA1c and on combination therapy experienced. Other adverse events were rare and mild., Conclusions: Sitagliptin is effective for diabetic management and generally well tolerated in Japanese patients with type 2 diabetes. This trial was registered with UMIN (no. 000004121).

Introduction: One consequence of population aging is an increase in the number of elderly patients with diabetes mellitus. These elderly patients often experience atherosclerotic complications, and diabetes prevention and management are strongly desired to promote health and reduce the financial burden on the healthcare system. In this study, we conducted an age-specific evaluation of the effectiveness and safety of comprehensive management with newly initiated insulin therapy over a 1-year period in elderly (≥65 years) compared with non-elderly (≤64 years) Japanese patients with uncontrolled diabetes [glycated hemoglobin (HbA1c) ≥ 8% for ≥ 3 months]., Methods: This retrospective single-center cohort study was conducted in Japan. We screened all outpatients with diabetes mellitus who visited the clinic for diabetes treatment between December 2006 and March 2011. Of these patients, 132 with type 2 diabetes who were newly initiated on insulin therapy for continued poor glycemic control and undergoing comprehensive management through self-monitoring of blood glucose (SMBG) were registered to the study., Results: Thirty-two of 132 registered patients were excluded from the analysis. Among the 100 patients (67 non-elderly, 33 elderly) included in the analysis, median age and proportion of male patients was 69 years and 66.7%, respectively, among the elderly, and 52 years and 68.7%, respectively, among the non-elderly patients. After initiation of insulin therapy, median HbA1c levels improved from 9.6% to 7.2% in elderly patients, and from 10.8% to 7.3% in non-elderly patients at baseline and 12 months. Severe hypoglycemic events were not observed in either patient group; however, uncontrolled diabetes was ongoing in 31.8% of non-elderly and 15.4% of elderly patients, and obesity was associated with poor glycemic control., Conclusion: Our results indicate that the effectiveness and safety of newly initiated insulin therapy are similar between elderly and non-elderly Japanese patients with uncontrolled diabetes, and highlight the importance of comprehensive management using SMBG to avoid hypoglycemia. Better glycemic control supported by adequate intensive management is required to improve mortality and morbidity.

The organization of the stomach in the compound styelid ascidian, Polyandrocarpa misakiensis, is described, and the morphology and cell types of the stomach is discussed from the phylogenetic viewpoint. The stomach is a sac-like organ whose wall is formed into longitudinal folds. The stomach consists of external and internal epithelium. The internal epithelium is simple columnar, except for the bottom of the folds. There are five cell types: absorptive cells, zymogenic cells, endocrine cells, ciliated mucous cells, and undifferentiated cells. The absorptive cells have numerous microvilli. The apical region of these cells is occupied by coated vesicles. The zymogenic cells have a conical outline and a few microvilli on their apical surfaces. There are secretory granules in the apical region of zymogenic cells. The endocrine cells have low cell height and electron-dense granules around the nucleus. Endocrine cells have one or two cilia and a few microvilli on the apical surfaces. The basolateral part of these cells often bulges into the adjoining cells. Immunoelectron microscopy revealed that some endocrine cells have serotonin-like immunoreactivity. The ciliated mucous cells are restricted to a single ventral groove. They have numerous microvilli and a few cilia on their apical surfaces. Moderately electron-dense granules are accumulated in the apical part of the ciliated mucous cells. Undifferentiated cells, filled with free ribosomes, form a pseudostratified epithelium in the base of each fold. The nucleus of undifferentiated cells has a prominent nucleolus. The pseudostratified epithelium of the pyloric caecum consists of electron-dense and electron-light cells.

A diastereoselective Henry reaction of chiral aldehydes with nitroalkanes was developed using a chiral sulfonyldiamine (L1)-CuCl complex. The reaction of (R)-2-phenylpropanal and nitromethane was smoothly catalyzed by the (S,S,S)-L1-CuCl complex to give the adduct with 99/1 syn/anti selectivity in 99% ee. In the reaction of (S)-2-phenylpropanal and nitroethane, the (R,R,R)-L1-CuCl catalyst yielded the expected three contiguous stereogenic centers in a highly syn-selective Henry reaction.

The size and morphology of organs are largely determined by a genetic program. However in some cases, an epigenetic mechanism influences the process of organ development. Particularly, epigenetic factors such as hemodynamic stress and blood pressure affect the morphogenesis of cardiac chambers and valves. Here, we report that the epigenetic influences affect the cardiomyocyte production. Taking advantage of longer developmental period of medaka fish, we could examine the later emerging tissue responses to the defect of ventricular beating, which occurred in the hozuki (hoz) mutant that harbors the mutated ventricular myosin heavy chain (vmhc) gene. The mutant showed a remarkable ventricular enlargement, and we showed that this enlargement was due to an excess production of ventricular cardiomyocytes in addition to the lack of concentric chamber growth. By experimental blockade of blood flow, we demonstrated that an elevated cardiac pressure was responsible for the aberrant cardiomyocyte production. From these data, we propose that the epigenetic tissue response to a stressed situation controls the production of cardiomyocytes to attain a fine tuning of heart formation., (Copyright 2010 Elsevier Inc. All rights reserved.)

The colonial ascidian Aplidium yamazii exhibited an allorejection reaction when two allogeneic colonies were brought into contact at their growing edges or at artificial cut surfaces. This species has no vascular network in the tunic, unlike the botryllid ascidians, which have a vascular network throughout the colony's common tunic. In the allorejection reaction induced by contact at the growing edges, some small, hard-packed tunic masses were formed at the contact points. Histological and electron microscopic investigation of these tunic masses revealed that they contained aggregates of tunic cells, with tunic phagocytes being the major cell type present. Some of the tunic phagocytes in these tunic masses appeared to be disintegrating. When allogeneic colonies were placed in contact at their artificial cut surfaces, the colonies partially fused, then separated. In this allorejection reaction, some loosely packed tunic masses remained in the gap between the two withdrawn colonies. These results strongly suggest that the tunic phagocytes are likely to be the major effector cells in the allorejection reaction. We also propose that the tunic phagocytes are not only the effector cells in the allorejection reaction but also bear the sites of allorecognition.

The patient was a 70-year-old man who was diagnosed inoperable because of liver metastases of advanced gastric cancer and his respiratory dysfunction. He received docetaxel at the starting dose of 40 mg/m(2) by iv infusion over 1 hour on day 1 and TS-1 at the full dose of 80 mg/m(2) daily for two weeks every three weeks. After 6 cycles of this combination therapy, gastric cancer with liver metastases entirely disappeared. No re-growth of gastric cancer has been seen for three years with chemotherapy of TS-1. This chemotherapy shows a high degree of safety and efficacy in this patient.

We report a new type of mass spectrometry based on a time-of-flight mass spectrometer combined with an ion attachment ionization technique (IA-TOF). In contrast to electron ionization mass spectra, IA-TOF mass spectra are not complicated by peaks due to fragmentation of the molecular ion; the adduct ion formed in IA does not fragment. We developed a tabletop IA-TOF system and evaluated its performance by analyzing specimens originally in the gas, liquid, and solid phases. We obtained fragment-free spectra covering a mass range up to m/z 3400 with a mass resolution of about 4700. Our IA-TOF system realizes accurate and versatile real-time mass spectrometry., (Copyright (c) 2007 John Wiley & Sons, Ltd.)

A 49-year-old man with asymptomatic osteochondroma was found to have a pseudoaneurysm of the left popliteal artery. An angiography showed a popliteal artery pseudoaneurysm adjacent to a femoral osteochondroma. The osteochondroma was excised and the popliteal artery containing the tear was also excised by end-to-end anastomosis. Vascular complication of osteochondroma is extremely rare. Paul reported the first case of a popliteal artery pseudoaneurysm due to osteochondroma in 1953. A computerized literature search revealed 40 additional cases reported in English, providing sufficient detail to allow comparison. The average age of the patients was 22.6 years (range 9-51) and most cases identified involved males (30 of 41, 73%). Most pseudoaneurysm were located in the popliteal artery. This report discusses the authors' experience with this disorder and a review of the literature in English.

Purpose: To describe our experience with arthroscopy of the proximal interphalangeal (PIP) and metacarpophalangeal (MP) joints and to assess the value of this technique., Type of Study: Case series., Methods: Arthroscopy was performed on 27 PIP joints and 16 MP joints of 21 patients with rheumatoid arthritis (mean age, 47.2 years; range, 26 to 62 years). After arthroscopic examination, 24 joints were treated with joint irrigation only and 19 were treated with arthroscopic synovectomy. All procedures were performed on an outpatient basis. The diameter of the arthroscope was 1.5 mm, and mini-forceps and a mini-shaver system with a 2.5-mm cutter were used for biopsy and synovectomy. We developed new portals for the PIP joints on the dorsal-lateral aspect, more lateral than previously reported portals., Results: The articular cartilage and synovial membrane of the PIP and MP joints were well visualized, and arthroscopy revealed cartilage changes and synovial proliferation. Because the PIP joint space was not wide enough to insert the arthroscope into the palmar cavity, the palmar part of the articular surfaces and the volar synovium could not be inspected. Synovial biopsy of the dorsal joint capsule was easily performed under arthroscopic visualization. Synovectomy of the dorsal joint capsule and both the radial and ulnar recesses was also possible using the 2-portal technique with a mini-shaver system. No intraoperative or postoperative complications were encountered., Conclusions: Arthroscopy of the PIP and MP joints is useful in assessing articular cartilage and synovium and for synovial biopsy. Arthroscopic synovectomy can be performed safely with the 2-portal technique.

As a continuing study of chemical characterization of crude drug processing, we have been analyzing the chemical constituents in licorice roots before and after processing. At first, we analyzed chemical constituents in licorice roots of various origins. Next, we have developed the HPLC analytical method, by which saponins and flavonoids, major constituents in various licorice roots, were determined simultaneously in a quantitative manner. In this paper, by means of the HPLC analytical method, chemical constituents in licorice roots, processed and unprocessed, were determined. It was found that nonglycosidic flavonoid constituents were mostly lost while root bark removing, whereas, in roasted licorice roots, sugar chains in the saponin and glycosidic flavonoid constituents were hydrolyzed stepwise during roasting through hydrothermolysis.

Pharmacokinetic, bacteriological and clinical studies on biapenem (L-627), a newly developed carbapenem antibiotic, were performed in the field of pediatrics. 1. Antibacterial activities of biapenem against 54 strains of Streptococcus pneumoniae isolated in 1993 were compared with those of 13 other antibiotics, consisting primarily of beta-lactam compounds. Minimal inhibitory concentrations (MICs) of biapenem were < or = 0.78 micrograms/ml against all strains, and excellent values were obtained even against benzylpenicillin (PCG)-resistant strains. Based on MIC80 values, biapenem, imipenem, and cefuzonam showed highest antibacterial activities, followed by cefotaxime. 2. Blood concentrations and urinary excretion were studied after intravenous drip infusion of 6.0 mg/kg and 6.1 mg/kg of biapenem, given over 30 min., to two children (ages: 4 years and 11 years). Blood drug concentrations were 14.7 and 37.6 micrograms/ml, respectively (mean: 26.2 micrograms/ml), at 30 min. after starting infusion (at completion of infusion). Blood concentrations then declined gradually with half-lives of 0.66 and 1.16 hrs., respectively (mean: 0.91 hrs.). After 5.5 hrs., blood concentrations were no longer measurable in the former and 0.46 micrograms/ml in the latter. Urinary recovery rates of drug in the first 6 hrs. after starting administration were 65.8% and 60.9%, respectively (mean 63.4%). 3. Penetration of the drug to the cerebrospinal fluid (CSF) was studied in 2 patients with purulent meningitis. Biapenem, 31.6 mg/kg, was administered four times daily by 30-min. intravenous drip infusion. CSF concentration 1 hr. after administration was 8.54 micrograms/ml on the day of the start of treatment (day 0), and 3.00, 2.04, 16.1, 4.16, 3.24, and 1.60 micrograms/ml on days 1-7 of treatment, respectively. In a patient similarly administered with the drug at 33.7 mg/kg four times daily, the CSF concentration at 1.5 hrs. after administration was 2.62 micrograms/ml on the next day of the start of treatment. On days 2-7 of treatment, CSF concentrations at 0.5-1 hr. after administration were 4.60, 12.9, 20.6, and 1.32 micrograms/ml, respectively. 4. Clinical efficacy was evaluated in 27 patients with pediatric infections. The dose administered per dosage was 5.2-33.7 mg/kg. Three or four dosages were given daily. The duration of therapy ranged from 3 1/3 to 11 days. Total administered doses were between 0.675 and 20.475 g. Clinical efficacy was evaluated in a total of 24 patients (purulent meningitis 1, acute otitis media 1, acute bronchitis 2, acute pneumonia 19, acute urinary tract infection 1). Responses to treatment were excellent in 14 patients and good in 10 patients.(ABSTRACT TRUNCATED AT 400 WORDS)

We conducted a pharmacokinetic and clinical studies on cefozopran (CZOP), a new cephem antibiotic for injection. 1. Changes in serum levels of the agent after intravenous bolus injection at a dose of 20 mg/kg to 4 pediatric patients (age: 5-10 years) were observed. The levels at 30 minutes after injection were 32.9-73.4 micrograms/ml average: 55.4 +/- 18.1 micrograms/ml), then the levels gradually decreased with half-lives of 1.67-2.24 hours (average: 1.85 +/- 0.27 hours) to 0.8-1.8 micrograms/ml (average: 1.2 +/- 0.4 micrograms/ml) at 8 hours after injections. Urinary levels reached at the maximum as, 1,773-3,450 micrograms/ml (average: 2,693 +/- 698 micrograms/ml) within 0-2 hours or 2-4 hours after injection, and recovery rates from urine in the first 8 hours after injection were 55.4-91.1% (average: 71.6 +/- 16.8%). 2. Transition to cerebrospinal fluid was examined in cases with purulent meningitis and aseptic meningoencephalitis. In the meningitis case, the level in cerebrospinal fluid 1 hour after administration was 8.8 micrograms/ml in the second day after the start of 4 times a day intravenous bolus injections with 42.5 mg/kg at each dose; The ratio of the drug level in cerebrospinal fluid to that in serum was 24.0%. In the meningoencephalitis, the levels in cerebrospinal fluid 1 hour after administrations were 1.1 micrograms/ml and 1.5 micrograms/ml in the second and the sixth days respectively, after the start of 4 times a day intravenous bolus injections with 50 mg/kg at each dose; the ratio of the levels in cerebrospinal fluid to those in sera were 0.93% and 2.41% respectively, at the second and the sixth day. 3. CZOP was clinically evaluated in 29 cases (ages: 2 months to 15 years) of pediatric infectious diseases. The agent was administered 3-4 times daily with 17-50 mg/kg at each dose, continued for 5-13 days. Total doses were 1.95-24.05 g. Clinical efficacy was evaluated in a total of 28 cases (1 case of purulent meningitis, 2 cases of acute purulent tonsillitis, 20 cases of acute pneumonia, 3 cases of urinary tract infections, 1 case of purulent lymphadenitis in cervical part and 1 case of cellulitis in face); The efficacies were "excellent" in 22 cases and "good" in 6 cases.(ABSTRACT TRUNCATED AT 400 WORDS)

Four neutral trisaccharides were isolated from goat colostrum by dialysis, and ion-exchange, activated charcoal column, preparative paper, and Bio-Gel P-4 column chromatography. The following structures were elucidated by GC analysis of hydrolysis products and by 400-MHz 1H NMR spectroscopy: alpha-L-Fuc p-(1-->2)-beta-D-Gal p-(1-->4)-D-Glc, alpha-D-Gal p- (1-->3)-beta-D-Gal p-(1-->4)-D-Glc, beta-D-Gal p-(1-->3)-beta-D-Gal p-(1-->4)-D-Glc, and beta-D-Gal p-(1-->6)-beta-D-Gal p-(1-->4)-D-Glc. beta-D-Glc pNAc-(1-->6)-beta-D-Gal p-(1-->4)-D-Glc, previously reported to be present in goat milk, was not detected in this study. beta-D-Glc pNAc-(1-->6)-beta-D-Gal p-(1-->4)-D-Glc (6'-N- acetylglucosaminyllactose) was prepared by beta-D-galactosidase digestion of beta-D-Gal p-(1-->3)[beta-D-Glc pNAc-(1-->6)]-beta-D-Gal p-(1-->4)-D-Glc (lacto-N-novotetraose) and characterized by one- and two-dimensional NMR spectroscopy at 600 MHz.

Two components of the sialyl oligosaccharides were separated from milk of the tammar wallaby (Macropus eugenii) by gel filtration and ion exchange chromatography. Their molecular weights, estimated by gel filtration on HPLC using 5 mM triethylamine-acetate buffer (pH 5.0), were approx. 3,000. Their monosaccharide compositions, determined by GC analysis after methanolysis and by colorimetric assay, were (Glc)1(Gal)9(GlcNAc)2(Neu5Ac)1, and (Glc)1(Gal)8(GlcNAc)2(Neu5Ac)2. Their chemical structures were further elucidated by 1H-NMR and methylation analysis. The results suggest that their approximate structures are: [formula: see text]

We performed laboratory and clinical evaluation of meropenem (SM-7338, MEPM), a new carbapenem antibiotics, in pediatric field. Pharmacokinetics of MEPM was examined with 5 patients, at a dose of 10 mg/kg via 30 minutes drip infusion. Mean plasma concentrations at 30 minutes, 1, 1.5, 2.5, 3.5 and 5.5 hours after dose were 18.8, 6.97, 3.62, 1.14, 0.43 and 0.12 micrograms/ml, respectively, with a half life of 0.96 hour. The urine recovery rate in 6 hours was 70.4%. Clinical efficacy of MEPM was evaluated in 36 patients with various infectious diseases. MEPM was administered at doses ranging 9.5 to 30.6 mg/kg/dosage, 3 to 4 times a day, 21/3 to 10 days. Clinical effects were excellent in 24, good in 11, fair in 1, with an efficacy rate of 97.2%. Bacteriologically, all causative organisms except one each of Haemophilus influenzae and Salmonella enteritidis were eradicated, an eradication rate for Gram-positive and Gram-negative bacteria were 100% and 93.3%, respectively. No side effects were observed. Elevations of GOT and/or GPT were noted in 2 patients. From the above results, we believe that MEPM is a highly effective and safe drug for patients with various infectious diseases in pediatric fields.

Pharmacokinetic and clinical studies in pediatrics were performed on panipenem/betamipron (PAPM/BP), a combined drug of a carbapenem antibiotic (panipenem) and organic ion inhibitor (betamipron) at a weight ratio of 1:1. 1. Plasma levels and urinary excretion were studied when PAPM/BP, at 10 mg/10 mg/kg (4 cases) or 20 mg/20 mg/kg (5 cases), was administered using intravenous drip infusion in 30 minutes to 9 children (4-14 years old). The plasma PAPM level at the end of drip infusion was 30.75 +/- 4.98 micrograms/ml in the cases administered with 10 mg/10 mg/kg and 68.72 +/- 5.73 micrograms/ml in the cases administered with 20 mg/20 mg/kg. Drug concentrations then gradually decreased with half-lives of 1.08 +/- 0.09 hours and 0.98 +/- 0.02 hour, and reached 0.39 +/- 0.14 micrograms/ml and 0.62 +/- 0.06 micrograms/ml, respectively, after 5.5 hours. Plasma BP levels at the end of drip infusion was 18.93 +/- 3.75 micrograms/ml in the cases administered 10 mg/10 mg/kg and 37.09 +/- 2.68 micrograms/ml in the cases administered 20 mg/kg, and half-lives were 0.55 +/- 0.07 hour and 0.61 +/- 0.03 hour, respectively; the plasma BP level could not be determined in any cases after 5.5 hours. Mean urinary recovery rates of PAPM in the first 6 hours after the start of intravenous drip infusion were 33.0 +/- 6.1% in the cases administered 10 mg/10 mg/kg and 21.8 +/- 2.3% in the cases administered 20 mg/20 mg/kg and those of BP were 77.0 +/- 2.4% and 76.6 +/- 7.3%, respectively. 2. When PAPM/BP, was administered at 31.3 mg/31.3 mg/kg thought by intravenous drip infusion in 30 minutes to 1 case of purulent meningitis, PAPM levels were 0.76 micrograms/ml at the end of drip infusion but varied between 0.80 to 1.97 micrograms/ml 30 minutes after the end of drip infusion during 8 days of treatment. 3. PAPM/BP was administered to 43 cases, 47 diseases of bacterial infections in the domain of pediatrics to study its clinical efficacy, bacteriological efficacy and adverse reactions. Single doses were 5.2mg/5.2mg to 31.3 mg/31.3 mg/kg; frequencies of administration were 3 to 4 times a day, and durations of administration were 3 1/3 to 11 days; and total dosages ranged between 1.125 g/1.125 g and 11.0 g/11.0 g.(ABSTRACT TRUNCATED AT 400 WORDS)

An 11-year-old boy with subaortic stenosis due to parashute accessory mitral valve tissue was treated successfully with surgery. He had a mild left ventricular-aortic pressure gradient associated with mild aortic regurgitation. The abnormal subaortic tissue was attached to the anterior leaflet of the mitral valve and was complicated with discrete subaortic stenosis. This tissue had five chordae connecting to the anterior papillary muscle and the anterior leaflet of the mitral valve. By resection of this accessory tissue and the part of the septal discrete stenotic tissue, stenosis of the left ventricular outflow tract was relieved completely.

Flomoxef sodium (FMOX) was evaluated experimentally and clinically in neonates. 1. Serum concentrations and urinary excretions of the drug were examined after a bolus intravenous injection at 20 mg/kg to 22 neonates 1-30 days after birth (durations of pregnancy 31-43 weeks, weights at birth 1,650-4,040 g) and 5 infants 50-95 days after birth (durations of pregnancy 33-40 weeks, weights at birth 1,720-3,308 g). Serum concentrations were 10.8-67.6 micrograms/ml (mean 32.7 +/- 2.8 micrograms/ml) and 25.1-52.0 micrograms/ml (mean 38.9 +/- 4.3 micrograms/ml) in the neonates and the infants, respectively, at their peaks (0.5 hour value), decreased thereafter with half-lives of 0.96-5.59 hours (mean 2.20 +/- 0.26 hours value), and 0.97-1.54 hours (mean 1.22 +/- 0.12 hours value), respectively. Serum levels decreased to 0.2-17.1 micrograms/ml (mean 2.9 +/- 0.6 micrograms/ml) and N.D. -1.1 micrograms/ml (mean 0.4 +/- 0.2 micrograms/ml) after 8 hours, respectively. The urinary recovery rates of the drug in the first 8 hours after administration were 15.0-96.0% (mean 53.7 +/- 4.9%) and 29.9-73.3% (mean 62.4 +/- 9.4%) in the neonates and in the infants, respectively. 2. FMOX was administered to 78 neonates (durations of pregnancy 31-42 weeks, weights at birth 1,420-3,860 g) in whom bacterial infections were established or suspected, and clinical, bacteriological, and side effects were evaluated. In 47 neonates examined (1 with sepsis, 3 with acute upper respiratory infections, 18 with acute pneumonia, 1 with umbilical infection, 1 with impetigo, 4 with acute urinary tract infections, 1 with acute otitis externa, 1 with periproctal abscess, and 17 with intrauterine infections), the treatment was markedly effective in 41, and effective in 6, with an overall efficacy rate of 100%. The bacterilogical effects of the drug on 3 strains of Staphylococcus aureus, 1 strain of Streptococcus pneumoniae, 1 strain of Streptococcus agalactiae, 9 strains of Escherichia coli, and 2 strains of Haemophilus influenzae which were responsible for these infections were all rated as "eradicated". Moreover, the drug, administered with or without prophylactic intentions showed complete prophylactic effects in all 27 cases tested. No side effects were observed in any of the patients. Concerning abnormal clinical laboratory results, increases in GOT were noted in 2, eosinophilia in 1, and thrombocytosis in 1, but these abnormalities were invariably mild and the normalized in 1 patient without treatment. The results suggest that FMOX is useful and safe also in neonates.

Clinical evaluation in pediatrics on cefdinir (CFDN, FK482) (5% fine granules), a new oral cephem, was performed. 1. CFDN was administered to 112 pediatric patients with ages between 1 month to 13 years with various infections. Dose levels used were 3.0-8.9 mg/kg (mean 5.1 mg/kg) t.i.d. for 3-14 days (mean 6.7 days). The studied patients included 2 patients with scarlet fever, 6 with acute pharyngitis, 6 with acute rhinopharyngitis, 52 with acute purulent tonsillitis, 8 with acute bronchitis, 24 with acute pneumonia, 7 with acute urinary tract infections, 1 with acute vaginitis, and 6 with impetigo. Total doses ranged from 0.6 to 4.05 g. One hundred eleven of the 112 patients were evaluated for clinical efficacy and all the patients were evaluated for safety. 2. Clinical effects were excellent in 51 cases, good in 57, and fair in 3 with an extremely high efficacy rate of 97.3%. Efficacy rates were 100% in scarlet fever, acute pharyngitis, acute purulent tonsillitis, acute bronchitis, acute vaginitis and impetigo, and 83.3%, 95.7%, 85.7% in acute rhinopharyngitis, acute pneumonia, and acute urinary tract infections, respectively. Good clinical effects were observed regardless of diseases. 3. Causative organisms were identified in 79 cases, of which 71 were found to be monobacterial infections and 8 were found to be multi-bacterial infections. In mono-bacterial infections, clinical efficacies were 100% for those caused by Staphylococcus aureus/Streptococcus pyogenes/Streptococcus pneumoniae/beta-Streptococcus except those in A and B groups with an overall efficacy of 100% against Gram-positive cocci (GPC) and they were 89.5%, 100%, 100% for those caused by Haemophilus influenzae, Haemophilus parainfluenzae, and Escherichia coli, respectively, with an overall efficacy of 90.3% in Gram-negative rods (GNR). In multi-bacterial infections also, a clinical efficacy of 100% was obtained. 4. Bacteriological effects were studied for 89 strains in the 79 cases. The eradication rate for a few strains of S. pneumoniae was low, 25%, but it was 100% for S. aureus, with the same results for S. pyogenes, and beta-Streptococcus. The eradication rate on GPC was high 94.1%. Among GNR, 66.7% of E. coli, 50.0% of H. influenzae, and 71.4% of H. parainfluenzae was eradicated. The overall eradication rate for GNR was 55.3%, lower than that for GPC. Microbial substitutions were observed in 13 cases, with Haemophilus sp. replacing other bacteria. 5. Diarrhea and soft stools were noted in 4 and 2 patients, respectively. The severity of these side effects, however, was slight and it was possible to continue the CFDN treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Cefpirome (HR 810, CPR), a new cephem antibiotic, was investigated for its experimental and clinical studies in pediatrics. The results obtained are summarized as follows. 1. Plasma and urinary levels of CPR were determined in 2 children (age 5 and 7 years) after the one shot intravenous injection of the drug at 20 mg/kg. Average plasma levels of the drug were 44.7 micrograms/ml, 28.5 micrograms/ml, 10.5 micrograms/ml, 4.6 micrograms/ml and 1.5 micrograms/ml at 1/2 hour, 1 hour, 2 hours, 4 hours and 6 hours, respectively, and the average half life was 1.57 hours. Average urinary levels of the drug were 1,785 micrograms/ml, 545 micrograms/ml and 198 micrograms/ml at 0-2 hours, 2-4 hours, 4-6 hours, respectively and the average urinary elimination rate was 52.0%. The results were nearly equivalent to those in adults except for urinary elimination rate which tended to be slightly lower than that in adults. 2. Cerebrospinal fluid levels in 3 cases of purulent meningitis treated with CPR were investigated. Cerebrospinal fluid levels in a case of Neisseria meningitidis were 11.5-23.1 micrograms/ml at 1 hour and 0.94 microgram/ml at 5 hours after intravenous injection of 44.4 mg/kg, 4 times a day. Cerebrospinal fluid levels in a case of Streptococcus pneumoniae were 1.01-4.23 micrograms/ml at 1 hour after intravenous injection of 49.0 mg/kg, 6 times a day, and in the other case with Streptococcus pneumoniae, the levels were 16.8-37.1 micrograms/ml at 1 hour, 11.3 and 3.60 micrograms/ml at 3 and 4 hours after intravenous injection 52.2 mg/kg, 6 times a day. These results are not inferior to those with cefotaxime or ceftriaxone. These levels appear to be higher than MIC90 values against Escherichia coli, Streptococcus agalactiae, S. pneumoniae or Haemophilus influenzae which are the major pathogens of these diseases. 3. CPR was given to 62 patients and clinical efficacy, bacteriological response and adverse reactions were evaluated. Evaluated cases for clinical efficacy included 3 cases of purulent meningitis, 1 case of acute purulent otitis media, 2 cases of acute purulent tonsillitis, 1 case of acute bronchitis, 49 cases of acute pneumoniae, 1 case of scarlet fever, 1 case of acute osteomyelitis, 1 case of acute enterocolitis, and 2 cases of acute UTI, totalling 61 cases. Clinical efficacies were excellent in 38 cases, good in 22 cases and fair in 1 case with an efficacy rete of 98.4% (excellent + good).(ABSTRACT TRUNCATED AT 400 WORDS)

A survey of purulent meningitis in infancy and childhood from 1980 through 1986 was made by sending questionnaires to 32 pediatric institutions in Aichi, Gifu and Shizuoka prefectures. Case cards of 125 patients were collected and analyzed. The results are summarized as follows: 1. The sex ratio (male/female) was 1.78. The age distribution for all patients was as follows: younger than 1 month, 24.8%; 1-12 months, 32.8%; 1 year, 19.2%; 2-5 years, 16.0%; older than 6 years, 7.2%. Nearly 3/4 of all purulent meningitis cases occurred in infancy. 2. The isolation rate of causative organisms was 71.2%. The 4 major causative organisms were Haemophilus sp. (28 cases), Streptococcus pneumoniae (14 cases), Streptococcus agalactiae (13 cases), and Escherichia coli (12 cases). Haemophilus sp. was dominant in patients over 3 months of age, and S. pneumoniae was noted in all age groups. The latter 2 were dominant under 3 months of age. 3. The outcome of 125 cases was as follows: cured, 73 cases (58.4%); improved, 26 cases (20.8%); dead, 15 cases (12.0%); unknown, 11 cases (8.8%). As to the outcome by age, the mortality of infants within 1 month old was the highest, 29.0%, and then decreased with increasing age. As to the outcome by causative organisms, Haemophilus sp. and E. coli were associated with good outcome, whereas S. pneumoniae and S. agalactiae with poor outcome. 4. Among several antibiotics, ampicillin was the most frequently used in 94 cases, followed by cefotaxime in 50 cases. 5. As to the initial antibiotic treatment, 51 cases were treated with penicillins (PCs) (including PCs + aminoglycosides (AGs], 9 cases with cephalosporins group I, II, IV, (CEPs I, II, IV) (including CEPs I, II, IV + AGs), 25 cases with CEPs V (including CEPs V + AGs) and 31 cases with CEPs V + PCs (including CEPs V + PCs + AGs). No significant differences were observed in the outcome among these initial treatment group. 6. Compared with the initial treatments of CEPs V or CEPs V + PCs groups, other antibiotics were used more frequently in those of PCs + AGs and CEPs I, II, IV groups. In the light of this analysis, the initial treatments of purulent meningitis with PCs + AGs or CEPs I, II, IV were not so effective as those with CEPs V or CEPs V + PCs.

Cefixime (CFIX) was evaluated clinically in pediatric respiratory tract infections, particularly those caused by Haemophilus influenzae: 1. The total number of children in this study treated with CFIX was 232, out of which 215 cases were evaluated for clinical efficacy and 224 cases were investigated for safety. A daily dosage of 3-6 mg/kg/day was given divided into 2 to 3 times daily for 3-15 days. 2. Causative organisms were identified in 146 cases, out of which 128 cases were found to be single microbial infections and 18 cases were mixed infections. In single microbial infections, clinical efficacy was 100% for those caused by H. influenzae/Haemophilus parainfluenzae, and was 95% for Streptococcus pyogenes with an overall efficacy of 96.9%. In mixed infections, the clinical efficacy was 100% for those caused by a combination of H. influenzae and Streptococcus pneumoniae, and the overall rate was 94.4%. An involvement of H. influenzae was observed in 108 cases with a clinical efficacy rate of 99.1%, and definite involvement of beta-lactamase secreting strains of H. influenzae was found in 32 cases with a clinical efficacy of 96.9%. 3. Bacteriological effect was studied for 164 strains identified in 146 cases, and eradication rates were 89.5% for H. influenzae, 100% for H. parainfluenzae and S. pyogenes, and 71.4% for S. pneumoniae. The overall eradication rate was 91.4%. Superinfection was observed in 21 cases. MICs against 78 strains of H. influenzae were in a range of less than or equal to 0.10 microgram/ml regardless of beta-lactamase production, and far superior to cefaclor and amoxicillin. MICs against S. pyogenes and S. pneumoniae were in ranges of less than or equal to 0.10 microgram/ml and 0.39 micrograms/ml, respectively. 4. Clinical efficacy was 93.0% in 215 cases (excellent: 136, good: 64, fairly good: 10, poor: 5). CFIX attained a high efficacy in the range of 89.4-95.7% in acute pharyngitis, acute tonsillitis, acute bronchitis and acute pneumonia. 5. Safety was monitored in 224 cases and there were only one case of loose stool and another of diarrhea as side effects. There were no abnormal findings in 31 cases of the laboratory test. In conclusion, it was confirmed that CFIX is excellent and safe in the treatment of the respiratory tract infections.