Population pharmacokinetics and limited sampling strategy for therapeutic drug monitoring of mycophenolate mofetil in Japanese patients with lupus nephritis.

BACKGROUND: Mycophenolate mofetil (MMF), a prodrug of the immunosuppressive agent mycophenolic acid (MPA), is difficult to administer because of the pharmacokinetic complexity of MPA. Although dosage adjustment according to the 12-h area under the concentration-time curve (AUC0-12) is thought to be desirable, multiple blood samplings for AUC calculation may pose a clinical challenge. A limited sampling strategy (LSS) would provide a solution; however, little is known about MPA pharmacokinetics in lupus nephritis patients, especially in those with Asian backgrounds, or few, if any, LSSs are reported for them. METHODS: Thirty-four adult Japanese patients receiving MMF for lupus nephritis were examined retrospectively. MPA pharmacokinetics were investigated, and a PPK model was developed using Phoenix® NLME™ software. Single and double blood sampling strategies from Bayesian estimation using the PPK model and from multiple linear regression were compared. Tolerability was also evaluated. RESULTS: In the pharmacokinetic analysis, renal function and serum albumin had significant effects on dose-normalized AUC0-12; and serum albumin, concomitant proton pump inhibitor (PPI) and iron/magnesium oxide did on dose-normalized maximum concentration. As a PPK model, a two-compartment model was developed with a transit absorption model and first-order elimination, in which creatinine clearance and serum albumin were covariates for MPA clearance. The double sampling strategy at 1 and 4 h by multiple linear regression showed the best agreement with the observed AUC0-12 (r2 = 0.885). Of the single sampling strategies, the one at 6 h by Bayesian estimation performed best (r2 = 0.769). The tolerability evaluation showed that correlations were suggested for gastrointestinal involvement. CONCLUSIONS: The present study developed the first PPK model of MPA for Japanese lupus nephritis patients. As for LSSs, a double sampling strategy at 1 and 4 h by multiple linear regression would work best; when only a single blood sampling is allowed, a strategy at 6 h by Bayesian estimation using the PPK model developed in this study would be best. The LSSs good enough for clinical use may facilitate safer, more effective, and individualized therapy.

Risk factors of first recurrence of Clostridioides difficile infection.

OBJECTIVES: Clostridioides difficile infection (CDI) often recurs. Approximately 25% of patients have recurrences after the initial treatment, and patients who have relapsed once are more likely to relapse. We aimed to identify the risk factors for initial CDI recurrence. METHODS: We performed a retrospective survey of patient backgrounds and treatment-related factors. Risk factors were analyzed using single and multiple logistic regression analyses. RESULTS: A total of 134 patients were included in the study. Prophylactic probiotic use and nasogastric tube feeding were independent risk factors for the initial recurrence of CDI. Patients using prophylactic probiotics had significantly higher recurrence rates than those not using prophylactic probiotics. CONCLUSION: Prophylactic probiotic use and nasogastric tube placement may be risk factors for the initial recurrence of CDI. It is noteworthy that CDI that occurs during the use of prophylactic probiotics may be prone to recurrence.

Conexivisphaera calida gen. nov., sp. nov., a thermophilic sulfur- and iron-reducing archaeon, and proposal of Conexivisphaeraceae fam. nov., Conexivisphaerales ord. nov., and Conexivisphaeria class. nov. in the phylum Thaumarchaeota.

A thermoacidophilic, anaerobic, and iron- and sulfur-reducing archaeon, strain NAS-02T, was isolated from a terrestrial hot spring in Japan, as previously reported. This organism is the first non-ammonia-oxidizing isolate in the phylum Thaumarchaeota. Here, we propose Conexivisphaera calida gen. nov., sp. nov. to accommodate this strain. The type strain of the type species is NAS-02T (=JCM 31663T=DSM 105898T). The values of 16S rRNA gene similarity and average amino acid identity between NAS-02T and its closest relatives are <86 and <42 %, respectively. Based on the phylogeny and physiology, we propose the family Conexivisphaeraceae fam. nov., the order Conexivisphaerales ord. nov. and the class Conexivisphaeria class. nov. to accommodate the novel genus.

Interferon-γ-induced HLA Class II expression on endothelial cells is decreased by inhibition of mTOR and HMG-CoA reductase.

In organ transplantation, donor-specific HLA antibody (DSA) is considered a major cause of graft rejection. Because DSA targets primarily donor-specific human leukocyte antigen (HLA) expressed on graft endothelial cells, the prevention of its expression is a possible strategy for avoiding or salvaging DSA-mediated graft rejection. We examined the effect of various clinically used drugs on HLA class II expression on endothelial cells. Interferon-γ (IFN-γ)-induced HLA class II DR (HLA-DR) was downregulated by everolimus (EVR, 49.1% ± 0.8%; P < 0.01) and fluvastatin (FLU, 33.8% ± 0.6%; P < 0.01). Moreover, the combination of EVR and FLU showed a greater suppressive effect on HLA-DR expression. In contrast, cyclosporine, tacrolimus, mycophenolic acid, and prednisolone did not exhibit any significant suppressive effect. FLU, but not EVR, suppressed mRNA of HLA-DR. Imaging analysis revealed that HLA-DR expressed in cytosol or on the cell surface was repressed by EVR (cytosol: 58.6% ± 4.9%, P < 0.01; cell surface: 80.9% ± 4.0%, P < 0.01) and FLU (cytosol: 19.0% ± 3.4%, P < 0.01; cell surface: 48.3% ± 4.8%, P < 0.01). These data indicated that FLU and EVR suppressed IFN-γ-induced HLA-DR expression at the transcriptional and post-translational level, respectively, suggesting a potential approach for alleviating DSA-related issues in organ transplantation.

[A Study on the Status of End-of-Life Chemotherapy for Solid Cancer after the Introduction of New Anti-Cancer Drugs].

BACKGROUND: In recent years, the decision to discontinue chemotherapy has become more difficult, and there is a tendency for chemotherapy to continue until just before death. We investigated the current state of end-of-life(EOL)chemotherapy for solid cancer patients. METHODS: Patients who died of cancer during hospitalization between January and November 2018 were included. Patients were divided into 2 groups, those who received EOL chemotherapy within 30 days of death(Near group: NG)and those who did not receive it(Far group: FG). The contents of each treatment were compared retrospectively. RESULTS: The number of patients were 46(32%)in the NG and 96(68%)in the FG. As EOL chemotherapy, the number of patients received cytotoxic drugs were 27(59%)and 68(71%), molecular targeted drugs were 6(13%)and 16(16%), immune-checkpoint inhibitors were 8(18%)and 12(12%), and hormone drugs were 0(0%)and 5(5%)in patients with NG and FG respectively(p<0.05). DISCUSSION: Minimally invasive drugs were often selected for EOL chemotherapy. It was suggested that the advent of new drugs has expanded the options for EOL chemotherapy.

Isolation and characterization of a thermophilic sulfur- and iron-reducing thaumarchaeote from a terrestrial acidic hot spring.

A deep-branching clade of Thaumarchaeota, conventionally called Terrestrial hot spring creanarchaeotic group (THSCG), is a missing link between thaumarchaeotic ammonia oxidizers and the deeper-branching non-ammonia oxidizers, such as Crenarchaeota and Candidatus Korarchaeota. Here, we report isolation of the first cultivated representative from the THSCG, named as NAS-02. Physiological characterization demonstrated that the isolate was a thermoacidophilic, sulfur- and iron-reducing organoheterotroph, which was supported by gene contents encoded in its complete genome. There was no evidence for ammonia oxidation by the isolate. Members in THSCG are likely thermophiles, and may play roles in degrading cell debris as a scavenger and in biogeochemical cycling of sulfur and iron in the hot environments, as suggested by the physiological characteristics of the isolate and the geographical distribution of the 16S rRNA gene sequences of THSCG in terrestrial hot springs and marine hydrothermal fields. Phylogenetic analysis suggests that the THSCG lineage represented by NAS-02 has gained the ability of sulfur reduction via horizontal gene transfer. Based on the phylogeny and physiology, we propose the name Conexivisphaera calidus gen. nov., sp. nov. to accommodate the isolate.

Examining the relationships between attention deficit/hyperactivity disorder and developmental coordination disorder symptoms, and writing performance in Japanese second grade students.

The purpose of this study was to explore the relationships between attention deficit/hyperactivity disorder and developmental coordination disorder symptoms and writing performance in Japanese second grade students from regular classrooms. The second grade students (N=873) in Japanese public elementary schools participated in this study. We examined a variety of writing tasks, such as tracing, copying, handwriting (Hiragana and Katakana), and spelling (Hiragana, Katakana, and Kanji). We employed the Japanese version of the home form ADHD-rating scale (ADHD-RS) and the Japanese version of the Developmental Coordination Disorder Questionnaire (DCDQ-J) to assess the developmental characteristics of the participating children. Seven writing performance scores were submitted to a principal component analysis with a promax rotation, which yielded three composite scores (Spelling Accuracy, Tracing and Copying Accuracy, and Handwriting Fluency). A multiple regression analysis found that inattention predicted Spelling Accuracy and Handwriting Fluency and that hyperactive-impulsive predicted Handwriting Fluency. In addition, fine motor ability predicted Tracing and Copying Accuracy. The current study offered empirical evidence suggesting that developmental characteristics such as inattention and fine motor skill are related to writing difficulties in Japanese typical developing children.

[Relationship among inattentive and hyperactive-impulsive behavior, aggression, and depression in Japanese elementary and junior high school students].

The present study examines the relationship among inattentive, and hyperactive-impulsive behavior, aggression, and depression in elementary school and junior high school students. The participants were 3,885 children and their teachers and caregivers. Children's inattentive and hyperactive-impulsive behavior was rated by their teachers and caregivers (ADHD-RS). Children rated aggression (HAQ-C) and depression (DSRS-C) themselves. Inattentive and hyperactive-impulsive behavior rated by teachers and caregivers were positively related to aggression and depression. Inattention predicted higher levels of aggression and depression. Inattentive and hyperactive-impulsive behavior as rated by teachers was more highly related to depression than those behaviors as rated by caregivers. The relationships among inattentive, and hyperactive-impulsive behavior, aggression, and depression were almost the same for both elementary school and junior high school students. This study suggests the importance of assessing inattentive and hyperactive-impulsive behavior from multiple views to examine the relationship between inattentive and hyperactive-impulsive behavior and mental health problems.

Reliability and validity of autism diagnostic interview-revised, Japanese version.

To examine the inter-rater reliability of Autism Diagnostic Interview-Revised, Japanese Version (ADI-R-JV), the authors recruited 51 individuals aged 3-19 years, interviewed by two independent raters. Subsequently, to assess the discriminant and diagnostic validity of ADI-R-JV, the authors investigated 317 individuals aged 2-19 years, who were divided into three diagnostic groups as follows: autistic disorder (AD), pervasive developmental disorder not otherwise specified, and other psychiatric diagnosis or no diagnosis, according to the consensus clinical diagnosis. As regards inter-rater reliability, intraclass correlation coefficients of greater than 0.80 were obtained for all three domains of ADI-R-JV. As regards discriminant validity, the mean scores of the three domains was significantly higher in individuals with AD than in those of other diagnostic groups. As regards diagnostic validity, sensitivity and specificity for correctly diagnosing AD were 0.92 and 0.89, respectively, but sensitivity was 0.55 for individuals younger than 5 years. Specificity was consistently high regardless of age and intelligence. ADI-R-JV was shown to be a reliable tool, and has sufficient discriminant validity and satisfactory diagnostic validity for correctly diagnosing AD, although the diagnostic validity appeared to be compromised with respect to the diagnosis of younger individuals.

[Development of a Japanese version of Child Social Preference Scale].

This study developed a Japanese version of the Child Social Preference Scale, which measures children's social withdrawal. In addition, we examined developmental changes of children's withdrawal and the relationships between withdrawal and problematic behaviors. The participants were 7 012 mothers of preschool, elementary school, and middle school children. A factor analysis revealed a two-factor solution of shyness and social disinterest, which is consistent with previous studies. Shyness decreased as children's grade level increased. Social disinterest changed in a quadratic manner. The shyness score was lowest in the lower grades of elementary school. Shyness was related to more emotional symptoms, more peer relationship problems, and less prosocial behavior. Social disinterest was related to peer relationship problems. The importance of the distinction between shyness and social disinterest is discussed.

Japanese version of school form of the ADHD-RS: an evaluation of its reliability and validity.

Using the Japanese version of school form of the ADHD-RS, this survey attempted to compare the scores between the US and Japan and examined the correlates of ADHD-RS. The classroom teachers of 7414 children (3842 males and 3572 females) evaluated all the children's behaviors. A confirmed factor analysis of ADHD-RS confirmed the two-factor solution (Inattentive and Hyperactive-Impulsive) same as previous studies. ADHD-RS scores were not related to IQ, but were associated with standardized achievement test scores. Males showed stronger ADHD tendencies than did the females, and the males tended to score lower as they grew older. Our comparison of the scores between the US and Japan found the Japanese children scored lower than did their US children. Japanese version of school form of the ADHD-RS with good reliability and validity was developed. More researches of ADHD in Japanese children are required.

Japanese version of home form of the ADHD-RS: an evaluation of its reliability and validity.

Using the Japanese version of home form of the ADHD-RS, this survey attempted to compare the scores between the US and Japan and examined the correlates of ADHD-RS. We collected responses from parents or rearers of 5977 children (3119 males and 2858 females) in nursery, elementary, and lower-secondary schools. A confirmed factor analysis of ADHD-RS confirmed the two-factor solution (Inattentive and Hyperactive-Impulsive) same as previous studies. ADHD-RS scores were not related to IQ, but were negatively associated with standardized achievement test scores. Males showed stronger ADHD tendencies than did the females, and the scores ended to decline as the children grew older. Japanese children scored lower than did their US children in Hyperactive-Impulsive among all of the sex-age groups. Japanese version of home form of the ADHD-RS was developed with good reliability and validity. More researches of ADHD in Japanese children are required.

Effect of a Kampo preparation, byakkokaninjinto, on pharmacokinetics of ciprofloxacin and tetracycline.

The effect on the bioavailability of the antimicrobial agents (ciprofloxacin and tetracycline), which are well known to form chelates with cationic metals such as calcium, was evaluated in 20 healthy male volunteers according to an open, random crossover fashion using a Kampo preparation, byakkokaninjinto (TJ-34) which contains various cationic metals including calcium. Each subject received a single oral dose of tetracycline (250 mg) alone or ciprofloxacin (200 mg) alone along with a single coadministration of one pack (3 g) of the Kampo preparation, at one-week intervals. Concentrations of the drugs in plasma and urine were analyzed by HPLC. Concomitant administration of the Kampo preparation significantly decreased the peak plasma concentration (C(max)) and area under the plasma concentration-time curves (AUC), but not time to reach C(max) (T(max)), of ciprofloxacin and tetracycline. However, the decrease in bioavailability of ciprofloxacin was slight (15%) compared with that of tetracycline (30%). The Kampo preparation significantly decreased the urinary recovery of tetracycline, but not ciprofloxacin, and it had no effect on the renal clearance of either ciprofloxacin or tetracycline. These results indicate that the Kampo preparation tested in this study reduces the extent of bioavailability of ciprofloxacin and tetracycline, but not renal excretion, by decreasing the gastrointestinal absorption due to the formation of insoluble chelates with calcium. We recommend that the dose timing of the Kampo preparation should be carefully controlled to avoid therapeutic failure especially for patients receiving the treatment with tetracycline.

[Trait guilt discriminate between anthropophobic tendency and social anxiety in adolescents].

This study examined the role of trait guilt in discriminating between anthropophobic tendency and social anxiety. 212 University and technical college students (103 males and 109 females) were administered a questionnaire with a trait guilt scale, an anthropophobic tendency scale, and a social anxiety scale. Trait guilt showed a positive correlation with anthropophobic tendency when the influence of social anxiety was controlled. When the influence of Anthropophobic tendency was controlled, trait guilt did not correlate as highly with social anxiety. These results were discussed related to cultural views of the self. Japanese culture is a "shame culture" because interdependent view of the self (seeing themselves as essentially connected with others) is dominant. People worry about appearances and how others see them, and are ashamed of their own deficiency or negative side, which leads to a sense of betrayal of others and thus guilt becomes a prominent trait.

Role of plasma proteins in pharmacokinetics of micafungin, an antifungal antibiotic, in analbuminemic rats.

There were no significant differences in the pharmacokinetics of micafungin and expression of hepatic multidrug resistance-associated protein 2 (ABCC2/Mrp2) between analbuminemic and Sprague-Dawley rats. Micafungin bound strongly to high-density lipoprotein (HDL) and moderately to gamma globulin. These results suggest that HDL and gamma globulin contribute to the pharmacokinetics of micafungin.

Usefulness of collagen gel droplet embedded culture drug sensitivity testing in ovarian cancer.

Due to the emergence of new anticancer agents for the treatment of ovarian cancer, methods to determine which agents will be most effective in individual patients are required. In order to investigate the potential for tailor-made chemotherapy, the drug sensitivities of various ovarian cancers were examined using collagen gel droplet embedded culture drug sensitivity testing (CD-DST), and the results were correlated with clinical outcomes. Sensitivities to paclitaxel, cisplatin, doxorubicin, etoposide, and SN-38, which is an active metabolite of irinotecan, were examined. Eight out of 22 samples failed to grow colonies and thus, their cell sensitivities could not be determined. Out of the 14 cases from which CD-DST results were obtained, seven patients then received chemotherapy aimed at inducing remission, while four received adjuvant, and three did not receive any chemotherapy. Three of the four tumors subsequently treated with adjuvant chemotherapy showed sensitivity to TXL and CDDP on CD-DST analysis, while one did not. None of these patients experienced recurrent disease from 24 to 36 months. Five of the seven tumors subsequently treated with chemotherapy aimed at inducing remission showed sensitivity to the relevant anticancer agents upon CD-DST analysis, while two did not. Among the five cases that showed tumor cell sensitivity, three experienced complete responses, one achieved a partial response and one had progressive disease. For the remaining two cases that demonstrated tumor cell resistance, one had stable disease and one had progressive disease following chemotherapy. Thus, six out of the seven cases (85.7%) that received chemotherapy aimed at inducing remission had clinical outcomes in keeping with the results of CD-DST. In conclusion, CD-DST results reflect clinical outcomes and may be a useful means by which to select drugs to which ovarian cancer cells are chemosensitive.

Synthetic study of optically active 3-azabicyclo[3.3.0]octane-2,6,8-tricarboxylic acid.

Synthesis of (1R,2S,5S,6R,8S)-3-azabicyclo[3.3.0]octane-2,6,8-tricarboxylic acid (2) from trans-4-hydroxy-L-proline (5) was attempted. A Diels-Alder reaction of 3,4-dehydroproline derivative 9 and cyclopentadiene afforded a single stereoisomer 11. The Diels-Alder adduct was smoothly converted to the hydrochloride of 2 (24) via RuO(4) oxidation. Although some racemization of the material or product was observed during the synthetic processes, the amino acid 24 proved to be optically pure.

Growth inhibitory effect of paradicsompaprika in cancer cell lines.

We investigated whether components of paradicsompaprika have direct antitumor effects or inhibitory effects on cancer growth, using its water extract. We applied collagen gel droplet embedded culture drug sensitivity test (CD-DST) as a screening method, which was developed based on the characteristics of cell culture on collagen matrix. Colon adenocarcinoma cells, epithelial cells of lung cancer, and cervical cancer cells were used. Paradicsompaprika is classified as Capsiucum annume L. var. grossum of Solanaceae. It is the first of the Hungarian species that was planted in Japan. It is available as TOMA-P in Japan. TOMA-P contains abundant carotenoids including capsanthin and beta-carotene. Water extract of paradicsompaprika was added to each cell at each concentration, and the mixture was cultured for 24 h and 7 days. The inhibitory effects against lung cancer and cervical cancer were observed concentration- and time-dependently. The effect was more prominent against lung cancer. The growth of bowel cancer cells was observed after the 7-day exposure of paradicsompaprika at the concentrations below the highest concentration compared to the control. At the highest concentration, the growth inhibition was not different between the 24-h exposure and the 7-day exposure, which suggests that tumor dormancy was induced. Results of the present study suggest that the water extract of paradicsompaprika can be a candidate of a new anticancer agent. Fat soluble component of paradicsompaprika, capsanthin is regarded as an anti-promoter of cancer. Thus, paradicsompaprika possesses chemopreventive and inhibitory effects on cancer cells.

Prediction of cell kill kinetics of anticancer agents using the collagen gel droplet embedded-culture drug sensitivity test.

A vital component of chemotherapy is selecting effective anticancer agents for the patient and determining an appropriate dose and administration regimen. Prediction of the drug sensitivity of each patient and cell kill kinetics of the drug may improve the outcome of treatment and avoid unnecessary dosing of the drug. For this reason, the development and clinical application of anticancer drug sensitivity tests and cell kill kinetics tests which successfully reflect clinical outcomes are required. In the present study, we tried to establish a cell kill kinetics test through the use of new anticancer agents: paclitaxel, docetaxel, SN-38, vinorelbine, and gemcitabine. These agents were studied at concentrations close to their clinical doses using a collagen gel droplet embedded-culture drug sensitivity test (CD-DST). It is thought that the mechanism, by which the anticancer agents used in this study exert their effects is dependent on the cell cycle; however, the cell kill kinetics of these agents at clinical concentrations has not yet been clarified in vitro. We investigated the drug sensitivity and cell kill kinetics of these new anticancer agents against a human colon cancer strain. Results of this study suggest that the test method established by us can predict drug sensitivity and cell kill kinetics of the agents, and can be a useful tool in deciding appropriate treatment regimen for individual patients.