Pharmacokinetics of CuGTSM, a Novel Drug Candidate, in a Mouse Model of Menkes Disease.

PURPOSE: Menkes disease is a rare hereditary disease in which systemic deficiency of copper due to mutation of the ATP7A gene causes severe neurodegenerative disorders. The present parenteral drugs have limited efficacy, so there is a need for an efficacious drug that can be administered orally. This study focused on glyoxal-bis (N(4)-methylthiosemicarbazonato)-copper(II (CuGTSM), which has shown efficacy in macular mice, a murine model of Menkes disease, and examined its pharmacokinetics. In addition, nanosized CuGTSM (nCuGTSM) was prepared, and the effects of nanosizing on CuGTSM pharmacokinetics were investigated. METHODS: CuGTSM or nCuGTSM (10 mg/kg) was administered orally to male macular mice or C3H/HeNCrl mice (control), and plasma was obtained by serial blood sampling. Plasma concentrations of CuGTSM and GTSM were measured by LC-MS/MS and pharmacokinetic parameters were calculated. RESULTS: When CuGTSM was administered orally, CuGTSM and GTSM were both detected in the plasma of both mouse strains. When nCuGTSM was administered, the Cmax was markedly higher, and the mean residence time was longer than when CuGTSM was administered for both CuGTSM and GTSM in both mouse strains. With macular mice, the AUC ratio (GTSM/CuGTSM) was markedly higher and the plasma CuGTSM concentration was lower than with C3H/HeNCrl mice when either CuGTSM or nCuGTSM was administered. CONCLUSION: Absorption of orally administered CuGTSM was confirmed in macular mice, and the nano-formulation improved the absorption and retention of CuGTSM in the body. However, the plasma concentration of CuGTSM was lower in macular mice than in control mice, suggesting easier dissociation of CuGTSM.

Trace element levels in mature breast milk of recently lactating Japanese women.

BACKGROUND: Many trace elements are essential for infant growth and development during early life. Their concentrations in breast milk vary depending on social and economic factors. Nonetheless, the present available values in Japan were derived from lactating mothers approximately 15 years ago. METHODS: Healthy mothers who gave birth to a single infant after 37 weeks of gestation at Teikyo University Hospital were recruited between July 2016 and December 2017. They were encouraged to collect breast milk samples and a self-administered food frequency questionnaire at 1 and 3 months postpartum. Anthropometric data for the mothers and their infants were also collected. Overall, 79 subjects were analyzed after excluding subjects with inadequate data in the food frequency questionnaire, insufficient breast milk samples, and medication that could affect dietary intakes. Trace element concentrations were determined by inductively coupled plasma mass spectrometry, and their correlation with several factors were investigated. RESULTS: Trace element concentrations were widely distributed as previously reported. Median concentrations of Cr, Mn, Fe, Cu, Zn, Se, and Mo were 0.8, 0.8, 98, 50, 272, 2.2, and 0.7 µg/dL at 1 month postpartum and 0.6, 0.7, 55, 33, 177, 2.1, and 0.7 µg/dL at 3 months postpartum, respectively. There were no correlations between trace element concentrations and either mothers' intakes or infants' growth. In contrast, there were significant correlations between several trace elements and macronutrients in addition to inter-element correlations among almost all trace elements. CONCLUSIONS: Trace element concentrations in mature breast milk were determined from recently lactating mothers in Japan.

Policy statement of enteral nutrition for preterm and very low birthweight infants.

For preterm and very low birthweight infants, the mother's own milk is the best nutrition. Based on the latest information for mothers who give birth to preterm and very low birthweight infants, medical staff should encourage and assist mothers to pump or express and provide their own milk whenever possible. If the supply of maternal milk is insufficient even though they receive adequate support, or the mother's own milk cannot be given to her infant for any reason, donor human milk should be used. Donors who donate their breast milk need to meet the Guideline of the Japan Human Milk Bank Association. Donor human milk should be provided according to the medical needs of preterm and very low birthweight infants, regardless of their family's financial status. In the future, it will be necessary to create a system to supply an exclusive human milk-based diet (EHMD), consisting of human milk with the addition of a human milk-derived human milk fortifier, to preterm and very low birthweight infants.

Japan's Practical Guidelines for Zinc Deficiency with a Particular Focus on Taste Disorders, Inflammatory Bowel Disease, and Liver Cirrhosis.

Zinc deficiency is common in Japan, yet awareness on this disorder is lacking. The Japanese Society of Clinical Nutrition recently issued the Japan's Practical Guideline for Zinc Deficiency 2018 setting forth criteria for diagnosing zinc deficiency, i.e., (a) one or more symptoms of zinc deficiency or low serum alkaline phosphatase, (b) ruling out other diseases, (c) low serum zinc, and (d) alleviation of symptoms upon zinc administration. Serum zinc <60 µg/dL and 60-80 µg/dL indicate zinc deficiency and marginal deficiency, respectively. Zinc deficiency symptoms vary and include dermatitis and taste disorders among others. Zinc administration improves taste in 50-82% of patients suffering from taste disorders (a common symptom of zinc deficiency). Effects of zinc administration do not appear immediately, and therapy should be continued for at least three months. Zinc deficiency often accompanies various diseases and conditions. Here, we focus on inflammatory bowel diseases and liver cirrhosis. As zinc deficiency enhances intestinal inflammation via macrophage activation, we discuss the pathological mechanism for inflammation and zinc deficiency in the context of IBD. Zinc deficiency can also lead to a nitrogen metabolic disorder in patients with liver cirrhosis. Zinc supplementation can improve not only the ammonia metabolism, but also the protein metabolism. We also discuss directions for future studies of zinc deficiency.

[The impact of support from medical professionals on families' decision-making during end-of-life care].

Families are involved in decision-making regarding end-of-life (EOL) care in Japan. However, how support from medical professionals toward families' decision-making affects families' satisfaction with EOL care has not been adequately studied. We aimed to examine the impact of support from medical professionals considering the care recipients' preferences on families' overall satisfaction with EOL care and the mediating effect of fulfilling care recipients' preferences.We administered self-report questionnaires through home-nursing providers to bereaved families (n=753), who lost loved ones between April 2015 and March 2016. Analyses were conducted with 237 of these bereaved families whose loved ones had been ≥65 years old, and had no missing values in key variables. We asked whether the families had received any support from medical professionals in determining the care recipients' EOL preferences, in discussing how to honor the care recipients' own interests, and in supporting the families' decision-making. We also collected data measuring the overall satisfaction with EOL care, families' perceptions that the care recipients' preferences were honored during EOL care, and demographic characteristics of care recipients and caregivers.Data from 58 male and 179 female family members were analyzed. The average age was 65.8 (standard deviation [SD]=11.9) years. Care recipients were 113 men and 124 women, and their average age was 83.0 (SD=9.1) years old at the time of death. A path analysis revealed that support for families from medical professionals was related to families' satisfaction with EOL care through the mediating factor of fulfilling care recipients' preferences.Support from medical professionals considering care recipients' preferences will help families' involvement in EOL decision-making.

ATP7A mutations in 66 Japanese patients with Menkes disease and carrier detection: A gene analysis.

BACKGROUND: Menkes disease (MNK; MIN 309400) is an X-linked recessive lethal disorder of copper metabolism caused by mutations in ATP7A (MIM 300011), which encodes a transmembrane copper-transporting P-type ATPase. This study assessed mutations in ATP7A in Japanese patients with MNK and their families using gene analysis. METHODS: A total of 66 patients with MNK born between 1975 and 2013 in Japan were investigated in this study. Definite diagnosis of MNK was carried out on polymerase chain reaction (PCR) amplification and direct sequencing of each exon. Genetic analysis was also performed on 39 women for carrier diagnosis, and on nine fetuses and 10 neonates for the diagnosis of MNK. RESULTS: We detected 55 different mutations, of which 20 were de novo mutations. The mutations were located around the six copper binding sites, first to third and six transmembrane domains, and the ATP binding site. Of 30 mothers, 23 (76.7%) were carriers. Approximately half of the male siblings of patients with MNK were also diagnosed with MNK. CONCLUSION: Mutations in ATP7A varied widely across patients, although approximately half of the mutations were located in exons 4, 9, 10, and 15. Approximately 23% of patients did not inherit the mutations from their mothers, but had de novo mutations. An early definite diagnosis is necessary for the early treatment of MNK, and gene analysis serves as an effective method for detecting mutations in ATP7A.

Menkes disease: Oral administration of glyoxal-bis(N(4)-methylthiosemicarbazonato)-copper(II) rescues the macular mouse.

BACKGROUND: Menkes disease is a copper metabolism disorder caused by mutations in ATP7A, a copper-transporting P-type ATPase. In this study, oral copper supplementation via glyoxal-bis(N(4)-methylthiosemicarbazonato)-copper(II) (CuGTSM), a lipophilic copper complex, was investigated in male hemizygous macular (MoMl/y) mice, a mouse model of Menkes disease. METHODS: CuGTSM was administered by oral gavage on postnatal days 5, 8, 11, 17, 23, and 32. The copper levels in the organs and serum, copper-dependent enzyme activities in the brain, and ceruloplasmin (Cp) activity in the serum were measured at 15 days and 3 and 8 months of age. Histological analysis of the intestines and the rotarod test were also performed. RESULTS: CuGTSM treatment extended the lifespan of MoMl/y mice and partly restored the copper concentrations and cytochrome oxidase and DBH activities in the brain; however, the rotarod test showed impaired motor performance. The treatment also increased copper concentrations and Cp activity in the serum. In suckling MoMl/y mice, CuGTSM treatment transiently induced diarrhea accompanied by copper accumulation and altered villus morphology in the ileum. CONCLUSION: Oral administration of CuGTSM extended the lifespan of MoMl/y mice. Oral administration is attractive, but pharmaceutical studies are needed to reduce the adverse enteral effects.

Disulfiram enhanced delivery of orally administered copper into the central nervous system in Menkes disease mouse model.

INTRODUCTION: Menkes disease (MD) is an X-linked recessive disorder caused by dysfunction of a copper-transporting protein, leading to severe neurodegeneration in early childhood. We investigated whether a lipophilic copper chelator, disulfiram, could enhance copper absorption from the intestine and transport copper across the blood-brain barrier in MD model mice. METHODS: Wild type and MD model mice were pretreated with disulfiram for 30 min before oral administration of 64CuCl2. Each organ was sequentially analyzed for radioactivity with γ counting. Copper uptake into the brain parenchyma was assessed by ex vivo autoradiography. RESULTS: In wild type mice, orally administered copper was initially detected in the intestine within 2 h, reaching a maximum level in the liver (19.6 ± 3.8 percentage injected dose per gram [%ID/g]) at 6 h. In MD model mice, the copper reached the maximum level in the liver (5.3 ± 1.5 %ID/g) at 4 h, which was lower than that of wild type mice (19.0 ± 7.4 %ID/g) (P < 0.05). Pretreatment of disulfiram in MD model mice increased the copper level in the brain (0.59 ± 0.28 %ID/g) at 24 h compared with MD model mice without disulfiram (0.07 ± 0.05 %ID/g) (P < 0.05). Ex vivo autoradiography revealed that high levels of copper uptake was observed in the cerebral cortex upon disulfiram pretreatment. CONCLUSION: Our data demonstrated that disulfiram enhanced the delivery of orally administered copper into the central nervous system in MD model mice. The administration of disulfiram will enable patients to avoid unpleasant subcutaneous copper injection in the future.

Zinc monotherapy for young children with presymptomatic Wilson disease: A multicenter study in Japan.

BACKGROUND AND AIM: Few studies of zinc monotherapy for presymptomatic Wilson disease have focused on young children. We therefore evaluated long-term efficacy and safety of zinc monotherapy for such children and established benchmarks for maintenance therapy. METHODS: We retrospectively and prospectively examined children under 10 years old with presymptomatic Wilson disease who received zinc monotherapy from time of diagnosis at 12 participating pediatric centers in Japan. RESULTS: Twenty-four patients met entry criteria. Aspartate aminotransferase and alanine aminotransferase decreased significantly beginning 1 month after initiation of treatment and usually remained under 50 U/L from 1 to 8 years of treatment. Twenty four-hour urinary copper decreased significantly at 6 months and usually remained under 75 µg/day and between 1 and 3 µg/kg/day for the remainder of the study. All patients continued to take zinc, and none became symptomatic. In patients under 6 years old who received 50 mg/day of zinc as an initial dose, aspartate aminotransferase and alanine aminotransferase significantly decreased at 1 month after initiation of treatment, as did γ-glutamyltransferase and 24-h urinary copper at 6 months. CONCLUSIONS: To our knowledge, this is the first multicenter study of zinc monotherapy for young children with presymptomatic Wilson disease. Such monotherapy proved highly effective and safe. Maintaining normal transaminase values (or values under 50 U/L when normalization is difficult) and 24-h urinary copper excretion between 1 and 3 µg/kg/day and under 75 µg/day is a reasonable goal. An initial dose of 50 mg/day is appropriate for patients under 6 years old.

Novel mutations in SLC30A2 involved in the pathogenesis of transient neonatal zinc deficiency.

BACKGROUND: Infants are vulnerable to zinc deficiency. Thus, abnormally low breast milk zinc levels cause transient neonatal zinc deficiency (TNZD) in breast-fed infants. TNZD has been considered to be rare because of a paucity of citations in the published literature. However, recent studies of affected mothers identified four missense mutations in the solute carrier family 30 member 2 gene (SLC30A2), which encodes the zinc transporter, ZnT2. METHODS: Genetic analyses of SLC30A2/ZnT2 in three Japanese mothers secreting low-zinc milk (whose infants developed TNZD) were performed. The effects of identified mutations were examined in a cell-based assay. Furthermore, 31 single-nucleotide polymorphisms (SNPs) in SLC30A2/ZnT2 were evaluated for their potential involvement in low-zinc levels in milk. RESULTS: Each mother had a different novel heterozygous mutation in SLC30A2/ZnT2. One mutation reduced splicing efficiency of the SLC30A2/ZnT2 transcript, and all ZnT2 mutants were defective in zinc transport and were unstable in cells. Moreover, four SNPs caused a significant loss of zinc-transport activity, similar to that in disease-causing ZnT2 mutants. CONCLUSION: Our results indicate that many SLC30A2/ZnT2 mutations cause or potentially cause TNZD. Genetic information concerning TNZD pathogenesis is limited, and our results suggest that the TNZD frequency may be higher than previously thought.

Low serum biotin in Japanese children fed with hydrolysate formula.

BACKGROUND: Given that nutritional biotin deficiency in Japanese infants has been reported, a straightforward method for estimating biotin level is needed. The biotin content in infant formula, breast milk, and the sera of infants fed with various types of formula were measured using avidin-binding assay. METHODS: A commercially available ELISA kit was used for the measurement of biotin in 54 types of formula, including hydrolysate formulas for milk allergy, as well as in breast milk and in the sera of 27 infants fed with these formulas. RESULTS: The biotin content reached the recommended value in only five formulas. All of the hydrolysate formulas and more than half of the special formulas contained biotin <0.1 µg/dL. Serum biotin was low in infants fed only with the hydrolysate formulas, and one of them had alopecia related to biotin deficiency. CONCLUSION: While many were asymptomatic, infants fed with formulas lacking biotin are at risk of developing symptomatic disease. The addition of biotin to breast milk substitutes was finally approved in the middle of 2014, however pediatricians in Japan should still be vigilant with regard to nutritional biotin deficiency in infants for the time being.

Serum biotin in Japanese children: Enzyme-linked immunosorbent assay measurement.

BACKGROUND: Biotin deficiency has been reported in Japanese infants fed special formulas for medical reasons, including those with milk allergy and congenital metabolic diseases, because these formulas contain little biotin. Serum biotin measurement is useful for diagnosing biotin deficiency. We applied a simple and rapid method to analyze serum biotin, and established normal ranges for children and adults. METHODS: Serum biotin in 188 healthy Japanese children aged 0-4 years and in 25 healthy adults was analyzed using a Biotin ELISA Kit (immundiagnostik). The effects of various conditions on the measurement of serum biotin were also examined. RESULTS: Median biotin in children aged 0-4 years was 10.4 ng/dL (IQR, 7.9-13.4 ng/dL), and that in adults was 12.9 ng/dL (IQR, 10.8-15.8 ng/dL). Normal range was 4.7-22.0 ng/dL in children and 8.4-20.5 ng/dL in adults (calculated using two-sided 95%CI). Measurements obtained with this method were not affected by frozen storage, freeze-thaw, or hemolysis, indicating that serum biotin can be analyzed accurately under these conditions, with a possible application to plasma samples. CONCLUSIONS: Serum biotin was significantly lower in children than in adults, with the normal range being 4.7-22.0 ng/dL in children and 8.4-20.5 ng/dL in adults. This simple and accurate enzyme-linked immunosorbent assay method is useful for diagnosing biotin deficiency.

Severe hypoglycemic encephalopathy due to hypoallergenic formula in an infant.

A 7-month-old girl was brought to hospital due to vomiting. Upon admission, she was in a convulsive state and stupor with extremely low blood glucose. Head computed tomography showed brain edema, and comprehensive treatment for acute encephalopathy was initiated immediately. Severe hypoglycemia, metabolic acidosis, elevation of ammonia and serum transaminases and creatine kinase suggested metabolic decompensation. Infusion of a high-glucose solution containing vitamins, biotin, and l-carnitine resolved the metabolic crisis quickly, but brain damage was irreversible. She was found to have been fed exclusively on a hypoallergenic formula (HF) for 7 months, although she was found later to be non-allergic. Evidence of inborn metabolic diseases was absent, therefore biotin deficiency and carnitine deficiency were concluded to be a consequence of reliance on a HF for a prolonged period. Health-care professionals should warn parents of the consequences of using HF.

Lactate and pyruvate levels in blood and cerebrospinal fluid in patients with Menkes disease.

OBJECTIVE: To examine levels of lactate (LA) and pyruvate (PA) in both blood and cerebrospinal fluid (CSF) in patients with Menkes disease (MNK). STUDY DESIGN: A nationwide survey involving a retrospective review of medical records or medical record summaries of 42 male patients with MNK born between 1993 and 2008 were performed, and the genetic analysis of their ATP7A gene was reviewed. RESULTS: In these patients, LA and PA levels and the lactate vs pyruvate ratio (L/P ratio) at diagnosis in both blood and CSF were abnormally high. There were no significant differences in LA levels, PA levels, and the L/P ratio between blood and CSF at diagnosis (P > .05). There was also no correlation between LA levels, PA levels, and the L/P ratio, and age at measurement (P > .05). There was no or slight metabolic acidosis, as analyzed by blood gas analysis, in 7 patients. During treatment with subcutaneous injections of copper-histidine, LA and PA levels and the L/P ratio in both the blood and CSF decreased. CONCLUSION: Our findings suggest that LA and PA levels, and in particular, the L/P ratio, and blood gas analysis can be used to guide the diagnosis and management of MNK.

[Deficiency of some nutrients due to use of enteral and special milk formulas].

The importance of nutritional management has recently been at the forefront of medicine. This also applies to the pediatric field, in which patients are often treated with special milk and enteral nutrient formulas. To meet this demand, various types of formula have been developed. However, some of these products lack sufficient levels of some necessary nutrients, and severe nutritional deficiencies have been reported in patients treated with these special milk and enteral formulas. Milk used to treat patients with inborn metabolic disorders, as well as those with milk allergies and ketogenic formulas, and some enteral nutrient formulas lack sufficient amounts of biotin, carnitine, selenium, and iodine. This suggests that special care to avoid a deficiency of nutrients must be taken when treating patients with special milk or enteral nutrient formulas.

[Clinical manifestations of three neonates with family histories of Menkes disease].

OBJECTIVE: To examine indications for the early diagnosis of Menkes disease (MD). METHODS: We compared clinical examination results of 3 neonate males with family histories of MD who were at risk of being affected (1 infant was affected and 2 were unaffected). RESULTS: Kinky hair, a characteristic shown by MD patients, was observed just after birth in the affected infant; however, this characteristic was extremely mild and easy to miss. In the first month after birth, serum copper level declined over time in the affected infant,while it increased in the unaffected infants. Urine homovanillic acid/vanillylmandelic acid (HVA/VMA) ratio, which is typically high in MD patients, was observed to be 4.9-8.0 (cut-off, 4.0) in the affected infant. In the unaffected infants, the urine HVA/MVA ratio showed a high value of 11.0 during catecholamine administration, but this decreased to below the cut-off value when catecholamine was not administered. CONCLUSIONS: Variations in the serum copper level and urine HVA/VMA ratio over time were considered as useful indicators for the early diagnosis of MD.

Longitudinal and regional association between dietary factors and prevalence of Crohn's disease in Japan.

Although a Western diet has been identified as a risk factor for Crohn's disease (CD), there is still controversy surrounding the specific foods that may contribute to the development of the disease. In this study, we examined the association between food intake and the prevalence of CD in Japan, as Japanese patients with CD are known to have limited genetic involvement. We identified changes in food intake associated with an increase in the number of patients with CD by analyzing the per capita consumption of food types from 1981 to 2014. Additionally, we examined the association between CD prevalence and food intake in each prefecture. Finally, the relationship between food intake and estimated age at CD onset was also investigated. Between 1981 and 2014, we observed Increased consumption of meat, eggs, milk and dairy products, oil, and potatoes and decreased consumption of grains, beans, vegetables, fruit, fish, sugar, and seaweed. The annual incidence of CD increased by 1388% over the same period. We found that meat consumption was significantly associated with CD prevalence (ß = 0.503, p = 0.0003), while a significant negative correlation was observed between CD prevalence and fruit and vegetable consumption (fruit, ß = 0.464, p = 0.0012; vegetables, ß = 0.404, p = 0.0023). Furthermore, we estimated that the peak consumption of more meat and less fruit and vegetables and the peak age of CD onset occurred within the age range of 20-24 years. Our study identified a clear correlation between the consumption of meat, fruits, and vegetables and the prevalence of CD in Japan. Additionally, we found an association between meat, fruit, and vegetable consumption and the age at CD onset.

Copper-trafficking efficacy of copper-pyruvaldehyde bis(N4- methylthiosemicarbazone) on the macular mouse, an animal model of Menkes disease.

BACKGROUND: Menkes disease (MD) is a disorder of copper transport caused by ATP7A mutations. Although parenteral copper supplements are partly effective in treating MD, the copper level in the brain remains insufficient, whereas copper accumulates in the kidney. We investigated the copper-trafficking efficacy of copper-pyruvaldehyde bis(N4-methylthiosemicarbazone) (Cu-PTSM), a lipophilic copper complex, in macular mice, an animal model of MD. METHODS: Macular mice were treated with cupric chloride (CuCl2) or Cu-PTSM on postnatal days 4, 10, and 17. At 4 wk of age, the copper levels in major organs and cytochrome oxidase (CO) activity in brain tissue were measured. Hematology, blood biochemistry, and urinary ß2-microglobulin (ß2-M) secretion were also assessed. RESULTS: The copper levels in the brains of the Cu-PTSM-treated group remained low, but CO activity in the cerebral and cerebellar cortices in the Cu-PTSM-treated group were higher than those in the CuCl2-treated group. There were no significant differences in hematological or biochemical findings or in urinary ß2-M secretion among the groups. CONCLUSION: Although the copper-trafficking efficacy of Cu-PTSM was limited, the improved CO activity in the brain suggests that Cu-PTSM delivered copper more effectively to neuronal CO than did CuCl2. Reduced renal copper accumulation may be beneficial in prolonged copper supplementation.

[Efficacy and safety of sitafloxacin in patients with urinary tract infections].

Sitafloxacin (STFX, Gracevit 50mg, fine granules 10%), a new quinolone antibacterial agent, was approved in January 2008, and the use-results survey was carried out over the 2 years between December 2008 and November 2010. We studied the efficacy and safety of STFX in 1,452 patients with urinary tract infections (cystitis, pyelonephritis, urethritis). The total efficacy rate for urinary tract infections was 91.4% (1,235/1,351 patients). Efficacy rates, classified by the type of infection, were: uncomplicated cystitis 95.9% (466/486 patients), complicated cystitis 87.2% (511/586 patients), uncomplicated pyelonephritis 96.1% (49/51 patients), complicated pyelonephritis 93.5% (145/155 patients), and urethritis 87.7% (64/73 patients). Efficacy rates were 86.0% (49/57 patients) for non-responders to cephems and 77.4% (48/62 patients) for non-responders to quinolones. The eradication rate of indicated strains was 90.5% (545/602 strains). The eradication rates of major causative bacteria were; Escherichia coli 92.7% (294/317 isolates), Enterococcus faecalis 86.0% (43/50 isolates), Pseudomonas aeruginosa 66.7% (16/24 isolates), Klebsiella pneumoniae 95.2% (20/21 isolates), and Chlamydia trachomatis 88.9% (8/9 isolates). The incidence of adverse drug reactions (ADRs) was 2.71% (37/1,365 cases). Major ADRs were diarrhoea (0.88%, 12 cases) and hepatic function disorders (0.51%, 7 cases). A serious ADR (hepatic function abnormality) was observed in 1 case, and the hepatic function in this patient returned to normal after treatment with STFX was discontinued. In conclusion, these results suggest that STFX is a useful antibacterial agent with an efficacy rate of 91.4% against urinary tract infections, with a minimum efficacy rate of 87.2% (against complicated cystitis), and has no serious problems in its safety profile.

Selenium Associates With Response to Erythropoiesis-Stimulating Agents in Hemodialysis Patients.

Introduction: Impaired response to erythropoiesis-stimulating agents (ESAs) is associated with increased mortality in patients with end-stage kidney disease. However, the underlying mechanisms are not fully elucidated. Accumulating data reveal that selenium (Se), a trace element, plays a key role in stress erythropoiesis and erythrocyte homeostasis. We evaluated the relationship between serum Se levels and the response to ESAs in hemodialysis patients. Methods: In this cross-sectional study, we determined serum Se levels in 173 hemodialysis patients. We analyzed the association of serum Se with ESA responsiveness, as defined by ESA resistance index. Results: Of the study participants, 50% had lower Se levels than the population-based reference values. We found that serum Se levels were significantly and inversely correlated with erythropoiesis resistance index (ERI) but not transferrin saturation (TSAT) or ferritin levels. Multiple regression analyses confirmed the association between Se levels and ESA hyporesponsiveness, independently of other known factors, such as iron status, being female, and dialysis vintage (ß = -0.11, P < 0.001). When patients were divided according to Se levels and iron status, both low serum Se (<10.5 µg/dl) and iron deficiency significantly affected the response to ESA. Conversely, serum Se levels were significantly different among groups when patients were divided according to ERI quartiles. The association of low serum Se with ESA hyporesponsiveness persisted after adjustment of confounding variables. Conclusion: Serum Se levels are associated with the response to ESAs and can predict ESA resistance independently of iron status in Japanese hemodialysis patients. These data open the possibility to test whether Se supplementation reduces ESA demand.