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A 55-year-old man with hypertrophic cardiomyopathy and a pacemaker was admitted with coronavirus disease 2019 (COVID-19). Before admission, the patient's medications included amiodarone, diltiazem, bisoprolol, atorvastatin, etizolam, and warfarin (WF). After admission, dexamethasone (DXM) and remdesivir (RDV) were initiated for treating COVID-19. The international normalized ratio (INR) on admission was 1.8, which increased to 3.4 on day 5 and to 6.9 on day 10 after admission. Although there have been reports that RDV may occasionally prolong prothrombin time and that the degree of prolongation is often less severe, the mechanism of action has not been elucidated till date. There are reports of prolonged INR when WF is co-administered with RDV and DXM, suggesting that drug interactions may be a potential cause for the prolongation. A similar drug interaction may have potentially occurred in the case reported here. In addition, this case used amiodarone (AMD), and it has been reported that the RDV concentration increases when used in combination with AMD. Further investigations are needed to elucidate the cause of INR prolongation. Thus, close monitoring of the patient is recommended when RDV is co-administered with high-risk agents to avoid unnecessary side effects.

Introduction For medication adherence, pill counting has higher accuracy in objective assessment. However, previous reports have shown that factors such as psychological bias and other people’s involvement in managing and helping patients take their medications may influence the outcomes. In Japan, all prescription medicines of patients are checked by medical reconciliation, and a pill count is performed during hospitalization. This study investigated factors affecting the medication adherence of patients with type 2 diabetes mellitus (T2DM), including patient- and medication-related factors, by pill counting using medical reconciliation in a situation where the patient’s psychological bias is low. Methods This study included 103 patients with T2DM who had been treated with oral hypoglycemic agents (OHAs) for at least 24 weeks. Patients whose OHAs were managed by another person were excluded. We calculated medication adherence values (MAVs) according to the following formula: MAV = (total prescription days − prescription days of OHAs brought when admitted)/(days from the start of OHAs to hospitalization). The relationship between MAVs and patient- and medication-related factors was analyzed. Results On multiple linear regression analysis of patient-related factors with P

The impact of overlapping risk factors on coronavirus disease (COVID-19) severity is unclear. To evaluate the impact of type 2 diabetes (T2D) and obesity on COVID-19 severity, we conducted a cohort study with 28,095 anonymized COVID-19 patients using data from the COVID-19 Research Database from January 1, 2020 to November 30, 2020. The mean age was 50.8 ± 17.5 years, and 11,802 (42%) patients were male. Data on age, race, sex, T2D complications, antidiabetic medication prescription, and body mass index ≥ 30 kg/m2 (obesity) were analysed using Cox proportional hazard models, with hospitalization risk and critical care within 30 days of COVID-19 diagnosis as the main outcomes. The risk scores were 0–4 for age ≥ 65 years, male sex, T2D, and obesity. Among the participants, 11,294 (61.9%) had obesity, and 4445 (15.8%) had T2D. T2D, obesity, and male sex were significantly associated with COVID-19 hospitalization risk. Regarding hospitalization risk scores, compared with those for hospitalization risk score 0 and critical care risk score 0, hazard ratios [95% confidence intervals] were 19.034 [10.470–34.600] and 55.803 [12.761–244.015] (P P

Aims/Introduction Research has proved a correlation between glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) and gastrointestinal adverse events. Predominantly, nausea and vomiting are frequent gastrointestinal adverse events that lead to the discontinuation of GLP‐1 RAs treatment. The present study aims to investigate clinical factors related to nausea and vomiting, considering diabetic complications and agents affecting the gastrointestinal tract, such as proton pump inhibitors (PPIs) and histamine‐2 receptor antagonists (H2RAs), in patients with type 2 diabetes treated with GLP‐1 RAs. Materials and Methods This retrospective study included Japanese patients with type 2 diabetes who started receiving GLP‐1 RAs therapy. We assessed nausea and vomiting up to 48 weeks after treatment with GLP‐1 RAs and used Fine–Gray's proportional hazards model to investigate clinical factors related to nausea and vomiting. Results A total of 130 patients were included in this study. Patients with PPIs or H2RAs showed a higher incidence of nausea and vomiting at 48 weeks than those without PPIs or H2RAs. The multivariate analysis revealed that female sex, retinopathy and treatment with PPIs or H2RAs were statistically significant risk factors for nausea and vomiting. Analysis of patients without PPIs or H2RAs showed that female sex and retinopathy were also statistically significant risk factors. Conclusions The present study showed a significant correlation of PPIs or H2RAs, female sex, and diabetic retinopathy with nausea and vomiting in patients with type 2 diabetes treated with GLP‐1 RAs. Hence, the occurrence of nausea and vomiting in patients with these factors warrants attention.

Objective: Coronavirus disease (COVID-19) in 2019 is highly prevalent among patients with type 2 diabetes (T2D). Several factors, such as the older and obesity have been reported to be risks of COVID-19 infection, but little is known about the clinical factors limited to patients with T2D. Here, we aimed to identify clinical factors linked to hospitalization with COVID-19 infection in T2D. Research Design and Methods: We used data from Electronic Medical Record (EHR) registered in the Healthjump database provided by the COVID-19 Research Database consortium. Primary outcomes were to determine clinical factors linked to COVID-19 infection-associated hospitalization. Results: Of 4,445 T2D patients with COVID-19, hospitalization occurred in 228 (5.1%). The risk of Covid-19 infection-related hospitalization was higher with ≥65years old (hazard ratio [HR] 1.45; 95% confidence interval [CI], 1.30-1.63), high in patients with a body-mass index (BMI) ≥30 kg/m2 (HR 1.59; 95% CI, 1.10-2.31), and Blacks than in Caucasians (HR 1.39; 95% CI, 1.04-1.85). The risk was lower in Metformin users (HR 0.56; 95% CI, 0.34-1394) and SGLT2inhibitors users (HR 0.45; 95% CI, 0.22-0.91). Asians tended to be at increased risk, but there was no significant difference due to the small number of cases (HR 1.88; 95% CI, 0.59-5.96). Conclusions: We revealed that the risk of hospitalization may be higher with older, obesity and blacks. Furthermore, we discovered a low risk of hospitalization in patients with treated SGLT2 inhibitors and/or metformin. These findings can help inform patient-centered care decision making for people with T2D at risk for COVID-19. Disclosure T. Horii: None. W. Ando: None. K. Otori: None. K. Atsuda: None.

The immunosuppressant azathioprine (AZA) is classified as a hazardous drug. AZA contamination during tablet-splitting increases exposure risk. However, there is no study on contamination and exposure during AZA tablet splitting and dispensing. AZA tablet splitting and dispensing methods were classified based on whether tweezers are used during splitting and packaging. In Dispensing Method (1), no tweezers were used in either step. In Dispensing Method (2), no tweezers were used during tablet splitting, but were used during packaging. In Dispensing Method (3), tweezers were used in both steps. After AZA half-tablet split-dispensing, we quantified the adherent AZA removed from the tools, packaging machines, and dispensing counters by three consecutive wipings with water-dampened polypropylene cloths. A large amount of AZA adhered to the gloves used in Dispensing Methods (1) and (2), wherein tablets were placed with gloved hands, compared with Dispensing Method (3), wherein tablets were held with tweezers. Thus, the gloves must be replaced before touching the packaging paper during the final step. After three consecutive wipings, AZA was not detected at most of the sites in the third round. Thus, we recommend that (1) AZA tablet splitting should be performed while wearing gloves, (2) the gloves should be changed before packaging the half tablets, and (3) the tools, packaging machines, and dispensing counters should be wiped twice or thrice with a water-dampened cloth after dispensing.

Background In clinical practice, a mixed suspension of clopidogrel bisulfate and magnesium oxide (MgO) tablets is administered frequently via a feeding tube. However, there is no report on the changes occurring when suspensions of these two drugs are combined, including the effects or potential decrease in dose following tube administration. Thus, the purpose of our study was to investigate the (i) changes caused by mixing clopidogrel bisulfate (ion form) and MgO tablets and (ii) effects on the administered clopidogrel dose after passing through a feeding tube. Methods The molecular structure of clopidogrel generated in a mixture of clopidogrel bisulfate and a basic compound, such as sodium bicarbonate or MgO tablet, was determined by 1H-NMR after extraction and purification. The suspension of clopidogrel bisulfate tablet alone and the mixed suspension of clopidogrel bisulfate tablet and MgO tablet were passed through a feeding tube. We compared the yield of the molecular form of clopidogrel from each passed fraction. Results The substance obtained from the mixture of clopidogrel bisulfate tablet and sodium bicarbonate or MgO tablet was identified as the molecular form of clopidogrel, and chemical degradation did not occur under these conditions. In the tube passage test, the yield of clopidogrel (molecular form) from the mixture of clopidogrel bisulfate and MgO tablets was lower than that from the suspension of clopidogrel bisulfate tablet alone. Conclusions The mixture of clopidogrel bisulfate and MgO tablets caused a considerable reduction in the administered dose passed through the feeding tube. Therefore, it is recommended to administer the suspensions of clopidogrel bisulfate and MgO tablets separately for safe and effective pharmacotherapy.

Isao Okazaki,1,* Shinsuke Shibata,2,3,* Wataru Ando,4,* Takayo Yanagawa,5,6 Hiroaki Yokomori,7 Akira Sonoda,8 Norihiko Suzuki,9 Eigoro Yamanouchi,10 Shinya Okada,11 Shinichi Kamikura,11 Kazuaki Hachimura,11 Takashi Takaki,12 Katsuya Otori,4 Yutaka Suzuki,9 Hideyuki Okano,2 Yutaka Inagaki5,6 1Department of Internal Medicine, International University of Health and Welfare (IUHW) Hospital, Nasu-Shiobara City, Tochigi Prefecture, Japan; 2Department of Physiology, Keio University School of Medicine, Shinjuku-Ku, Tokyo, Japan; 3Electron Microscope Laboratory, Keio University School of Medicine, Shinjuku-Ku, Tokyo, Japan; 4Department of Clinical Pharmacy, Kitasato University School of Pharmacy, Minato-Ku, Tokyo, Japan; 5Center for Matrix Biology and Medicine, Tokai University Graduate School of Medicine, Isehara City, Kanagawa Prefecture, Japan; 6Department of Innovative Medical Science, Tokai University School of Medicine, Isehara City, Kanagawa Prefecture, Japan; 7Department of Internal Medicine, Kitasato University Medical Center, Kitamoto City, Saitama Prefecture, Japan; 8Collaborative Research Resources, Core Instrumentation Facility, Keio University School of Medicine, Shinjuku-Ku, Tokyo, Japan; 9Department of Surgery; 10Deparment of Radiology; 11Department of Pathology, IUHW Hospital, Nasu-Shiobara City, Tochigi Prefecture, Japan; 12Division of Electron Microscopy, Showa University School of Medicine, Shinagawa-Ku, Tokyo, Japan*These authors contributed equally to this workCorrespondence: Isao OkazakiHigashi Nippon International University, Iwaki City, Fukushima Prefecture, JapanTel +81-246-35-0001Fax +81-246-25-9188Email okazakiisao@hotmail.co.jpBackground/Aims: Matrix metalloproteinase-1 (MMP-1) is a key enzyme in collagen metabolism and tissue remodeling. We previously reported that MMP-1 expression in monocytes and other types of cells in the liver is associated with disease progression in patients with nonalcoholic steatohepatitis (NASH). To further implicate MMP-1 up-regulation in NASH pathogenesis, we examined dynamic and sequential MMP-1 expression in peripheral blood monocytes and cells in steatotic liver, and attempted to elucidate the mechanism of MMP-1 induction.Methods: Twenty-nine NASH patients and 26 non-NASH subjects were recruited in the study. Their peripheral blood mononuclear cells were isolated and analyzed by fluorescence-activated cell sorting, and liver specimens were subjected to confocal laser-scanning and immunoelectron microscopic examinations. Peripheral blood monocytic lineage cells were co-cultured with steatotic hepatocytes obtained from biopsy specimens to examine MMP-1 induction.Results: Infiltrating monocytes were the earliest to acquire an MMP-1-expressing phenotype among all investigated cell types in early-stage NASH liver. On the other hand, circulating monocytes did not express significant levels of MMP-1 mRNA or protein before infiltrating steatotic liver. Co-culture with steatotic hepatocytes induced MMP-1 expression in otherwise MMP-1-negative peripheral blood monocytic lineage cells. As disease progressed, MMP-1 was sequentially expressed by other types of cells in NASH liver. Notably, clusters of OV-6- or CK19-positive hepatic progenitor cells with a morphological feature of ductular reaction showed strong MMP-1 staining in advanced-stage NASH.Conclusion: MMP-1 up-regulation in infiltrating monocytic lineage cells represents an initial event in early-stage NASH and, together with the subsequent expression in other types of cells, modulates pathophysiological aspects of NASH.Keywords: matrix metalloproteinase-1, nonalcoholic steatohepatitis, monocytic progenitor cells, hepatic progenitor cells, liver fibrosis

Background: For medication adherence, pill count is a reliable objective for evaluation. In Japan, at the time of hospitalization, all prescription medicines of patients are checked by medical reconciliation and a pill count is done. This study investigated factors affecting medical adherence by pill count using medical reconciliation. Methods: This retrospective study included 76 patients (mean age 65.6±12.6 years, 60.5% of men) with type 2 diabetes mellitus who had been taking oral hypoglycemic agents (OHAs) for more than 48 weeks. Patients whose OHAs were managed by another person or those who were taking psychotropic drugs were excluded. To evaluate medication adherence, medication adherence value (MAV) was calculated: (total prescription days-prescription days of OHAs brought when admitted)/(days from start of OHAs to hospitalization). The relationship between MAV and patient characteristics was analyzed. Results: Subjects were divided into MAV of ≤ 0.86 (those who forgot to take medicine on one or more days per week), > 0.86 ≤ 0.93 (who forgot to take on one or more days in two weeks and less than one day per week), and > 0.93 (who forgot less than one day in two weeks). HbA1c showed a significantly higher value in the group of ≤ 0.86 compared with the group of > 0.93 (P = 0.02). The patients were divided into good (MAV > 0.86) and poor (MAV ≤ 0.86) adherence groups. On multivariate analysis of patient characteristics with P < 0.2 in the univariate analysis as explanatory variables, lower age and no insulin therapy were independent factors for poor adherence (P = 0.004; P = 0.02). Dosing period, Dosing time, number of doses, and types of OHAs were non-independent factors. However, in the poor adherence group, taking 3 doses a day was an independent factor (P = 0.03). Conclusion: Our findings suggest that poor adherence was independently associated with lower age and no insulin therapy in type 2 diabetes patients. In poor adherence patients, taking 3 doses a day was a factor for reduced adherence. Disclosure M. Shiomi: None. Y. Tanaka: None. M. Kurobuchi: None. T. Takada: None. K. Otori: None.

Few studies have examined the relationship between the use of antidepressants and the onset of hyperglycemia and diabetes mellitus in Japan. We herein explored the possibility of this relationship using the Japanese Adverse Drug Event Report database (JADER). The present study included 20 individual antidepressants, consisting of 6 subclasses, which have been approved for use in Japan. We used Standardized MedDRA Queries 20000041 to extract patients who developed hyperglycemia/new onset diabetes mellitus (NODM) in JADER between April 2004 and September 2016. We calculated reporting odds ratios (RORs) with 95% confidence intervals (CI). We also calculated odds ratios defined as the ratio of odds of hyperglycemia/NODM to all other adverse drug events (ADEs) by the age cut-off group or sex in the cases of antidepressants. The lower limit of 95%CI of RORs for 13 antidepressants (imipramine, clomipramine, nortriptyline, amitriptyline, amoxapine, maprotiline, mianserin, sertraline, paroxetine, escitalopram, duloxetine, mirtazapine, and trazodone), which included all subclasses, exceeded 1. Younger age group was associated with hyperglycemia/NODM for 5 antidepressants (imipramine, amitriptyline, maprotiline, duloxetine, and trazodone), and female was associated with the ADEs for trazodone, although these results should be interpreted cautiously. Healthcare personnel need to be aware that the use of antidepressants may lead to hyperglycemia/NODM.

Background/Aims: Nonalcoholic steatohepatitis (NASH) is prevalent in both economically developed and developing countries. Twenty percent of NASH progresses to cirrhosis with/without hepatocellular carcinoma, and there is an urgent need to find biomarkers for early diagnosis and monitoring progression of the disease. Using immunohistochemical and immunoelectron microscopic examination we previously reported that expression of matrix metalloproteinase-1 (MMP- 1) increased in monocytes, Kupffer cells and hepatic stellate cells in early stage NASH. The present study investigated whether serum MMP-1 levels reflect disease activity and pharmaceutical effects in NASH patients. Methods: We measured the serum levels of MMPs, tissue inhibitors of metalloproteinases (TIMPs), and several cytokines/ chemokines in patients with histologically proven early and advanced stages of NASH and compared them with those in healthy controls. Results: Serum MMP-1 levels in stage 1 fibrosis, but not in the more advanced fibrosis stages, were significantly higher than in healthy controls (P=0.019). There was no correlation between serum MMP-1 level and fibrosis stage. Serum MMP- 1 levels in NASH patients represented disease activity estimated by serum aminotransferase values during the followup period. In contrast, MMP-2, MMP-9 and TIMPs did not change with disease activity. Consistent with the finding that MMP-1 is expressed predominantly in monocytes and Kupffer cells, serum levels of monocyte chemotactic protein-1 and granulocyte-colony stimulating factor were significantly increased in NASH with stage 1 fibrosis. Conclusions: These results suggest that serum MMP-1 levels represent disease activity and may serve as a potential biomarker for monitoring the progression of NASH. (Clin Mol Hepatol 2018;24:61-76)

The handling of medical bags in high temperature disaster sites has not been fully evaluated. In this study, medical bags were assessed in the closed, semi-opened, and opened state, with and without heat insulating material (HIM) and a coolant. The bags were heated for 300 minutes at 35 or 40°C, and the internal temperature was measured. closed and semi-opened bags were able to limit temperature increases in the central part of the bag at both 35 and 40°C to a greater extent than opened bags. When coolant and HIM were used in closed and semi-opened bags, the internal temperature was significantly lower than that seen in the opened state at 40°C (P < 0.01 and P < 0.001, respectively). In conclusion, in high temperature disaster sites, medical bags should be maintained in a semi-opened or closed state using a HIM and coolant.

Serum and tissue miR-21 expression in patients with breast cancer (BC) is a useful biomarker for cancer diagnosis, progression, and treatment. Matrix metalloproteinase-1 (MMP-1) is also important in breast cancer carcinogenesis. However, miR-21 and MMP-1/CD63 in urine exosomes in these patients have not been examined. Urine samples were collected from patients with BC and 26 healthy females. Urinary exosomes were isolated and confirmed by western blotting with anti-CD63 antibody and electron microscopy observation. MiR-21 and MMP-1/CD63 expression was examined by quantitative RT-PCR and western blotting, respectively. Patients with very early stage breast cancer were evaluated. MiR-21 expression in the patients was 0.26 [95% CI: 0.20–0.78], which was significant lower than in the 26 controls (1.00 [95% CI: 1.01–3.37], p = 0.0947). MMP-1/CD63 expression in patients was significantly higher than in controls (1.74 [95% CI: 0.86–5.08] vs 0.535 [95% CI: −0.01–2.81], p = 0.0001). Sensitivity and specificity were 0.708 and 0.783 for miR-21 and 0.792 and 0.840 for MMP-1/CD63, respectively. Sensitivity and specificity of combined expression were 95% and 79%, respectively. The sensitivity of MMP-1/CD63 expression in urinary exosomes was better than that of miR-21 expression. Thus, miR-21 and MMP/CD63 may be useful markers for BC screening.

BACKGROUND Ribavirin (RBV) is an antiviral drug that is part of the current standard therapy for chronic hepatitis C (CHC). It is enzymatically converted to ribavirin triphosphate (RTP) that inhibits the activity of viral RNA polymerase, thereby preventing viral replication. However, one of its adverse effects includes hemolytic anemia that limits its application. The variant of ITPA (inosine triphosphatase), which dephosphorylates inosine triphosphate to inosine monophosphate, is a protective factor for RBV-induced anemia. RTP is an important metabolite required for ribavirin action. This study evaluated the time-dependent association of RTP concentrations in erythrocytes, RBV-induced toxicity, and virological response to RBV treatment for hepatitis C. METHODS A total of 28 Japanese patients with CHC were treated with RBV/peg-interferon/simeprevir or RBV/sofosbuvir and were genotyped for ITPA variants (rs1127354 and rs7270101). We measured RTP concentrations in erythrocytes in a total of 76 samples collected at 4, 8, and 12 weeks from the initiation of treatment. RESULTS The ITPA rs1127354 variant was found in 7 patients. This was associated with significantly higher RTP concentrations in erythrocytes than in the wild-type patients (P < 0.001). Moreover, a significant correlation was observed between RTP concentrations and decline in hemoglobin (Hb) levels from baseline values in ITPA wild type and rs1127354 variant 12 weeks after treatment initiation (P < 0.01; r = -0.618 and -0.967, respectively). Multiple regression analysis revealed that ITPA genotype and erythrocyte RTP concentrations were major factors associated with reduced Hb levels in RBV therapy for CHC. However, we did not find any association between erythrocyte concentrations and virological response. CONCLUSIONS The increased tolerability to RTP concentrations in erythrocytes in the ITPA variant rs1127354 plays a role in preventing RBV-induced severe anemia in this ITPA variant.

Background: One quarter of global adults by overeating and reduced physical activity cause nonalcoholic fatty liver, and progress to nonalcoholic steatohepatitis (NASH), in which 10% of cases lead to liver cirrhosis and/or hepatocellular carcinoma. Adequate therapeutic option is urgent. We previously reported that matrix metalloproteinase-1 (MMP-1) expression in monocytes (MCs) and other types of cells in NASH livers is associated with disease progression. To test the hypothesis that bone marrow-derived monocytes (BMMCs) secrete exosomes with MMP-1 before their infiltration into steatosis liver, we examined MMP-1 mRNA and protein expression in circulating BMMCs. Methods: Twenty-nine NASH patients and 26 non-NASH patients were recruited in this study. Confocal laser scanning microscopic (CLSM) and immune-electron microscopic examinations (IEM), and fluorescence-activated cell sorting of CD34+ BMMCs were performed. Peripheral CD45+CD14+CD34+ cells were co-cultured with steatosis hepatocytes (HCs) isolated from NASH liver. Findings: IEM revealed that MCs were the earliest to acquire an MMP-1-expressing phenotype amongst all investigated cell types. CLSM showed that MMP-1 expression in Kupffer cells, hepatic stellate cells, progenitor cells, HCs, and endothelial cells were observed in subsequent to MCs. In advanced stage of NASH, OV-6- or CK19-positive hepatic progenitor cells around lethal HCs showed strong staining for MMP-1. These results suggested that MMP-1 expressed in progenitor cells may contribute to regeneration of injured liver, while MMP-1 up-regulation in hepatic stellate cells caused their activation leading to fibrosis. Unlike our initial hypothesis, circulating BMMCs did not express significant amounts of MMP-1 mRNA or protein before their infiltration into steatosis liver. By contrast, co-culture with steatosis HCs induced MMP-1 expression in otherwise MMP-1-negative CD34+ BMMCs. This phenotypic change in MMP-1 expression was the most pronounced in CD45+CD14+CD34+ cells. Interpretation: The results of the present study implicated MMP-1 expression by the monocyte progenitor cell population after their migration into steatosis liver in NASH pathogenesis. Funding Statement: This work is supported by grant no. IUHW 2016-24 and -25 from Mr. Takeshi Mori and Mrs. Eiko Mori to Dr. Okazaki. Declaration of Interests: The authors have declared that no conflict of interest exists. Ethics Approval Statement: The study protocol was approved by the Ethics Committee of IUHW (13-B-136, February 22, 2016; 13-B-205, November 24, 2016; 13-B-229, April 27, 2017). All patients provided written formal informed consent for participation in this study.

Ribavirin (RBV) is an antiviral agent and the primary component for chronic hepatitis C (CHC) therapy. Hemolytic anemia is limitation for RBV treatment. Inosine triphosphatase (ITPA) activity has been associated with severity of RBV-induced anemia. However, changes in ITPA activity during CHC therapy are unknown. The aim of this study was to measure the time-dependent change in ITPA activity over the RBV treatment.Forty-two patients with CHC were evaluated for ITPA activity over the course of RBV treatment.The median value of ITPA activity at start of RBV treatment was 134.2 μmol/h/g hemoglobin (Hb; range, 26.3-251.0 μmol/h/g Hb). The ITPA activity values at 4, 8, and 12 weeks during RBV treatment were 143.2, 202.2, and 225.7 μmol/h/g Hb, respectively, and these ITPA values were significantly elevated compared with the start of treatment (p 0.001). In patients with ITPA variants, patients with anemia (Hb 10 g/dL) had greater elevated ITPA activities compared with patients without anemia at 12 weeks.Our findings indicate that ITPA activities are elevated with RBV therapy, and this elevation may be a risk of anemia in late therapeutic phase in patients that began with low ITPA activity.

Background: Non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis and inflammation with or without fibrosis. The apelin receptor (APJ) is related to angiotensin-like-receptor 1 (AGTRL1). The present study aimed to evaluate APJ as an indicator of the pathophysiology of early-stage NASH. Methods: APJ expression was evaluated in six tissue samples with histologically proven early-stage NASH using immunohistochemistry (IHC) and immunoelectron microscopy (IEM). Results: On IHC, in control liver tissue, APJ was mainly localized in the aortic artery, although APJ was detected only slightly in the sinusoids. In early NASH liver tissue, on IEM, APJ was observed mainly at the sites of sinusoidal lining cells around the central vein and periportal regions, and at arterial capillaries in the portal tract. With regard to endothelial cells (ECs), one sample showed a hematopoietic stem cell (HSC)/progenitor cell (HPC) partially wrapped with an EC. Conclusion: HSCs/HPCs expressing APJ may contribute to the angiogenesis of liver tissue in early-stage NASH. J Clin Med Res. 2017;9(9):809-811 doi: https://doi.org/10.14740/jocmr3103w

Elcatonin injection is used for the treatment of osteoporosis in Japan.In order to compare the original product with generic versions, we measured the elcatonin content and amounts of impurities in both using high performance liquid chromatography, and observed changes in content with time under the conditions of light exposure and shaking.We found that elcatonin content and amounts of impurities varied among the generics and that changes in content with time under the above conditions for some generics were greater than the changes for the original product.These results suggest that some generic products should not be considered to be equivalent to the original product.

We studied the quality and stability of generic sodium ozagrel solution products for injection. Through the use of inspection apparatus, we noted exfoliation of the surface layer of glass ampoules filled with sodium ozagrel solution drug products for injection. Also, foreign insoluble matter, such as oil droplets, which was assumed to be silicone that had been applied to the internal surface of syringe barrels, was observed in pre-filled syringe products. In a stability study performed under accelerated conditions (40°C/75% RH) the generic sodium ozagrel solutions yielded a degradation product that was not detected in the lyophilized original product. The degradation product content of some of the generic products was over 16 mg/mL of sodium ozagrel, exceeding the specification for the original lyophilized product. These results indicate that some of the generic products are inferior in quality and stability to the original lyophilized drug.

With a recent progress in biotechnology, mass production of various kinds of cytokines became possible. At present, recombinant human granulocyte-colony stimulating factor, rhG-CFG is widely applied to clinical areas, and its good efficacy has been confirmed.rhG-CSF is administered by drip infusion or by subcutaneous injection, which is chosen depending on the indications. We previously indicated that the adsorption of rhG-CSF onto an end-line filter used for preventing compromised hosts from the infection or the infusion route was a serious problem for its use, because the administration dose was extremely low, in an order of μg.Since we obtaind a newly developed filter (PDl), we made a comparative study on the adsorption of rhG-CSF to two kinds of filters which are frequently used for infusion; ELD-096LL and IVEX-II.The drug was used at a half of the ordinary adult dose of 150μg/100ml. The adsorption of rhG-CSF was found for the conventional filters but almost not for the new fluter tested. Its adsorption to the infusion route was estimated to be 10-20%.