Plasma prolactin axis shift from placental to pituitary origin in late prepartum mice.

The placenta secretes a prolactin (PRL)-like hormone PRL3B1 (placental lactogen II), a luteotropic hormone essential for maintaining pregnancy until labor in mice. A report from 1984 examined the secretion pattern of PRL3B1 in prepartum mice. In the current study, we found contradictory findings in the secretion pattern that invalidate the previous report. By measuring maternal plasma PRL3B1 and PRL every 4 hrs from gestational day 17 (G17), we newly discovered that maternal plasma PRL3B1 levels decrease rapidly in prepartum C57BL/6 mice. Interestingly, the onset of this decline coincided with the PRL surge at G18, demonstrating a plasma prolactin axis shift from placental to pituitary origin. We also found that maternal plasma progesterone regression precedes the onset of the PRL shift. The level of Prl3b1 mRNA was determined by RT-qPCR in the placenta and remained stable until parturition, implying that PRL3B1 peptide production or secretion was suppressed. We hypothesized that production of the PRL family, the 25 paralogous PRL proteins exclusively expressed in mice placenta, would decrease alongside PRL3B1 during this period. To investigate this hypothesis and to seek proteomic changes, we performed a shotgun proteome analysis of the placental tissue using data-independent acquisition mass spectrometry (DIA-MS). Up to 5,891 proteins were identified, including 17 PRL family members. Relative quantitative analysis between embryonic day 17 (E17) and E18 placentas showed no significant difference in the expression of PRL3B1 and most PRL family members except PRL7C1. These results suggest that PRL3B1 secretion from the placenta is suppressed at G18 (E18).

Increased c­SRC expression is involved in acquired resistance to lenvatinib in hepatocellular carcinoma.

Lenvatinib, a multi-kinase inhibitor, serves a crucial role in the treatment of unresectable hepatocellular carcinoma (HCC). However, >50% of patients receiving lenvatinib therapy experience tumor growth or metastasis within 1 year, highlighting the need to address acquired resistance as a critical clinical challenge. To elucidate the factors associated with acquired resistance to lenvatinib, a lenvatinib-resistant HCC cell line (JHH-7_LR) was established by exposing a lenvatinib-sensitive HCC cell line, JHH-7, to lenvatinib. The changes in protein expression associated with the development of resistance were analyzed using a proteomic approach, detecting 1,321 proteins and significant changes in the expression of 267 proteins. Using Ingenuity Pathway Analysis bioinformatics software, it was revealed that the activity of multiple signaling pathways varied alongside the changes in expression of these proteins, and c-SRC was identified as a protein involved in a number of these signaling pathways, with its activity varying markedly upon the acquisition of resistance. When co-administering dasatinib, a c-SRC inhibitor, the partial restoration of lenvatinib sensitivity in the JHH-7_LR cell line was observed. The present study demonstrated that increased c-SRC expression was partially associated with HCC resistance to lenvatinib, suggesting that c-SRC inhibition could reduce the resistance of HCC to lenvatinib.

Blood Concentration of Cabazitaxel in a Patient Whose General Condition Worsened with Concomitant Use of Clarithromycin.

We encountered a case in which the general condition of a patient receiving cabazitaxel worsened with concomitant use of clarithromycin. Cabazitaxel is metabolized mainly by CYP3A4, and the frequency of adverse events is known to increase with increasing exposure. Although these drugs are not often quantified in daily practice, we quantified them because we considered it possible that the blood concentration of cabazitaxel had increased due to CYP3A4 inhibition of clarithromycin and that cabazitaxel-related adverse events had occurred. However, the concentration of cabazitaxel was not increased and we attributed the patient's deterioration to decreased tolerability of cabazitaxel. At least at a trough concentration of 70 ng/mL, which is the trough concentration when a normal dose of clarithromycin is administered, clarithromycin does not appear to have a significant effect on the blood concentration of cabazitaxel. This case suggests that the administration of the normal dose of clarithromycin might be relatively safe in patients receiving cabazitaxel.

Risk of exposure of patients' family members to lenalidomide at home.

OBJECTIVES: Lenalidomide, a hazardous drug, has strict distribution controls. However, the risk of contamination with lenalidomide when patients take the drug has not been studied and the risk of drug exposure to people in the patient's living environment is unknown. Thus, we investigated the amount of lenalidomide that could be dispersed during the period between removal of the capsule and returning the used blister packages, and we considered the conditions under which lenalidomide could be dispersed and countermeasures. METHODS: The amount of lenalidomide contamination was measured on the outside of the unused blister packages returned by the patients, on the surface of the capsule, and on the inside of the package immediately after removal of the capsule. In addition, the amount of contamination was measured on the blister packages used by the patients and on the gloves worn by the pharmacists on receipt of the packages. Lenalidomide was analysed by liquid chromatography-tandem mass spectrometry. RESULTS: Lenalidomide amounts on the outside of the unused blister packages returned by the three patients were <10, <10, and 26.8 ng/pack, those on the capsule surface immediately after removal from the packages were 297, 388, and 297 ng/capsule, and those on the inside of packages immediately after removal of all capsules were 143, 184, and 554 ng/pack, respectively. A median of 15.6 ng/pack lenalidomide was detected on the surface of packages used by the patients (n=18). The lenalidomide remaining in the packages immediately after capsule removal (~200 ng/pack), except for the 15.6 ng/pack detected in the packages used by the patients, may have been dispersed in the patient's living environment (~90% or more). The maximum amount of lenalidomide on the surface of the packages used by the patients was over 2500 ng/pack. CONCLUSIONS: The amount of lenalidomide contamination per package was found to be at least 100 ng less after collection by the pharmacist than immediately after removal of the capsules. Therefore, it is recommended to clean the surrounding area and wash one's hands after taking the capsules.

Target concentration achievement for efficacy and safety of patients with osteosarcoma treated with high-dose methotrexate based on individual pharmacokinetics: A retrospective study.

In the high-dose methotrexate (HD-MTX) treatment of patients with osteosarcoma, a dose-adjustment method using individual pharmacokinetic parameters (PK method) to optimize the concentration was developed in 2010. However, to the best of our knowledge, the clinical usefulness of the PK method has not been verified until now. In the present retrospective study, to assess the usefulness of the PK method, the achievement rate of an effective and safe concentration range was evaluated. A total of 43 patients with osteosarcoma who were administered HD-MTX therapy (43 first courses and 200 subsequent courses) were enrolled. The MTX dose in the first course was determined using a common method based on body surface area (BSA method); a total of 8-12 g/m2 was administered as an initial dose for 1 h and a maintenance dose for 5 h. In the subsequent courses, loading and maintenance doses were calculated by the PK method based on the serum MTX concentration profile of the previous course. The effective target concentration during 1-6 h after the start of MTX administration was 700-1,000 µmol/l, whereas the target safe MTX level was less than 10, 1 and 0.1 µmol/l at 24, 48 and 72 h, respectively. Notably, the rate of achieving the effective target concentration was significantly higher when using the PK method as compared to that when using the BSA method. The achievement rate of the safe target concentration at 24, 48 and 72 h when using the PK method was significantly higher. Additionally, the incidence of abnormal laboratory values of aspartate aminotransferase and alanine aminotransferase was significantly lower when using the PK method. Therefore, the PK method was suggested to be very useful in HD-MTX therapy for patients with osteosarcoma.

Prevention of Postoperative Cognitive Dysfunction by Minocycline in Elderly Patients after Total Knee Arthroplasty: A Randomized, Double-blind, Placebo-controlled Clinical Trial.

BACKGROUND: There are no effective pharmacologic interventions for preventing postoperative cognitive dysfunction in daily practice. Since the antibiotic minocycline is known to suppress postoperative neuroinflammation, this study hypothesized and investigated whether minocycline might have a preventive effect on postoperative cognitive dysfunction after noncardiac surgery. METHODS: This study included patients aged more than 60 yr undergoing total knee arthroplasty under general anesthesia. They were randomly assigned to minocycline and placebo groups, to orally receive 100 mg of minocycline or placebo twice daily from the day before surgery until the seventh day after surgery. Cognitive function was evaluated before surgery, and 1 week and 3 months after surgery, using a battery of four cognitive function tests, including Visual Verbal Learning Test, Trail Making Test, Stroop Color and Word Test, and Letter-Digit Coding Task. Additionally, 30 healthy volunteers were subjected to the same tests as the patients to examine the learning effect of repeated tests. The occurrence of postoperative cognitive dysfunction was judged from the results of the neurocognitive test battery, with consideration of the learning effect. The secondary endpoints were the effects of minocycline on postoperative delirium and postoperative pain. RESULTS: A total of 100 patients were randomized to the minocycline group, and 102 were randomized to the placebo group. The average age of patients was 75 yr. Evaluation showed no significant difference in the incidence of postoperative cognitive dysfunction between the minocycline and placebo groups at both 1 week (8 of 90 [8.9%] vs. 4 of 95 [4.2%]; odds ratio, 2.22 [95% CI, 0.64 to 7.65]; P = 0.240) and 3 months (15.3 of 90 [17.0%] vs. 15.3 of 95 [16.1%]; odds ratio, 1.07 [95% CI, 0.49 to 2.32]; P = 0.889) postoperatively. Missing data 3 months after surgery were corrected by the multiple imputation method. There were no differences between the two groups in postoperative delirium and postoperative pain. CONCLUSIONS: Minocycline is likely to have no preventive effect on postoperative cognitive dysfunction.

Surface Engineering of Top7 to Facilitate Structure Determination.

Top7 is a de novo designed protein whose amino acid sequence has no evolutional trace. Such a property makes Top7 a suitable scaffold for studying the pure nature of protein and protein engineering applications. To use Top7 as an engineering scaffold, we initially attempted structure determination and found that crystals of our construct, which lacked the terminal hexahistidine tag, showed weak diffraction in X-ray structure determination. Thus, we decided to introduce surface residue mutations to facilitate crystal structure determination. The resulting surface mutants, Top7sm1 and Top7sm2, crystallized easily and diffracted to the resolution around 1.7 Å. Despite the improved data, we could not finalize the structures due to high R values. Although we could not identify the origin of the high R values of the surface mutants, we found that all the structures shared common packing architecture with consecutive intermolecular ß-sheet formation aligned in one direction. Thus, we mutated the intermolecular interface to disrupt the intermolecular ß-sheet formation, expecting to form a new crystal packing. The resulting mutant, Top7sm2-I68R, formed new crystal packing interactions as intended and diffracted to the resolution of 1.4 Å. The surface mutations contributed to crystal packing and high resolution. We finalized the structure model with the R/Rfree values of 0.20/0.24. Top7sm2-I68R can be a useful model protein due to its convenient structure determination.

The influence of Javanese turmeric (Curcuma xanthorrhiza) on the pharmacokinetics of warfarin in rats with single and multiple-dose studies.

CONTEXT: Co-administration between warfarin (WF) and Curcuma xanthorrhiza Roxb. (Zingiberaceae) (CX) is found in Indonesian patients and need to be evaluated. OBJECTIVE: This study assesses the effect of concomitant administration of CX extract on the pharmacokinetics of WF in rats. MATERIALS AND METHODS: Wistar rats were divided into 4 groups (n = 6) and administered with 2% Pulvis Gummi Arabicum (PGA, control), fluconazole (FZ, 6 mg/kg), CX-1 (6 mg/kg) or CX-2 (18 mg/kg BW) for 7 days. For the single-dose study, at the 8th day, WF (1 mg/kg) was administered to all groups and blood samples were taken from 0.25 to 72 h. For the multiple-dose study, daily dose of WF was administered to all groups of rats and at the 7th to 9th day, the rats were treated with PGA, CX-1, CX-2 and FZ. Blood samples were withdrawn daily at 4 h after administration of WF from the 1st to 11th day. RESULTS: The area under the curve (AUC) of R- and S-WF in the CX-2 group was a significantly higher value compared to the control (77.54 vs. 35.27 mg.h/L for R-WF and 316.26 vs. 40.16 mg.h/L for S-WF; p < 0.05; Kruskal-Wallis method). The CX-2 administration also caused the increasing in the concentration level of R-WF (16%) and S-WF (27%) from the 7th to 9th day of administration. DISCUSSION AND CONCLUSIONS: The CX administration in a higher dose caused alteration on WF pharmacokinetics suggesting the need for clinical evaluation of the interaction between CX and WF.

Endosperm cell size reduction caused by osmotic adjustment during nighttime warming in rice.

High night temperature (HNT) often reduces yield in field crops. In rice, HNT during the ripening stage diminishes endosperm cell size, resulting in a considerable reduction in final kernel weight; however, little is known about the underlying mechanisms at cell level. In this study, we performed picolitre pressure-probe-electrospray-ionization mass spectrometry to directly determine metabolites in growing inner endosperm cells of intact seeds produced under HNT conditions, combining with 13C feeding and water status measurements including in situ turgor assay. Microscopic observation in the inner zone suggested that approximately 24.2% of decrease in cell expansion rate occurred under HNT at early ripening stage, leading to a reduction in cell volume. It has been shown that HNT-treated plants were subjected to mild shoot water deficit at night and endosperm cell turgor was sustained by a decline in osmotic potential. Cell metabolomics also suggests that active solute accumulation was caused by a partial inhibition of wall and starch biosynthesis under HNT conditions. Because metabolites were detected in the single cells, it is concluded that a partial arrest of cell expansion observed in the inner endosperms was caused by osmotic adjustment at mild water deficit during HNT conditions.

Fast and Inexpensive Phenotyping and Genotyping Methods for Evaluation of Barley Mutant Population.

To further develop barley breeding and genetics, more information on gene functions based on the analysis of the mutants of each gene is needed. However, the mutant resources are not as well developed as the model plants, such as Arabidopsis and rice. Although genome editing techniques have been able to generate mutants, it is not yet an effective method as it can only be used to transform a limited number of cultivars. Here, we developed a mutant population using 'Mannenboshi', which produces good quality grains with high yields but is susceptible to disease, to establish a Targeting Induced Local Lesions IN Genomes (TILLING) system that can isolate mutants in a high-throughput manner. To evaluate the availability of the prepared 8043 M3 lines, we investigated the frequency of mutant occurrence using a rapid, visually detectable waxy phenotype as an indicator. Four mutants were isolated and single nucleotide polymorphisms (SNPs) were identified in the Waxy gene as novel alleles. It was confirmed that the mutations could be easily detected using the mismatch endonuclease CELI, revealing that a sufficient number of mutants could be rapidly isolated from our TILLING population.

FLEND (nelarabine, fludarabine, and etoposide) for relapsed T-cell acute lymphoblastic leukemia in children: a report from Japan Children's Cancer Group.

Nelarabine is a key drug for T-cell acute lymphoblastic leukemia (T-ALL). Fludarabine and etoposide might have synergistic effect with nelarabine by inhibiting ribonucleotide reductase and by preparing cell cycle for G1/S phase, respectively. We had started phase 1/2 multicenter clinical trial of combination chemotherapy consisted of nelarabine, fludarabine, and etoposide (FLEND therapy) for children with relapsed/refractory T-ALL which has been conducted since October 2011. Although we could not complete this trial because of recruitment difficulties, we treated five children with first-relapsed T-ALL which were enrolled in the phase 1 dose escalation study of fludarabine and etoposide with nelarabine. No dose-limiting toxicity occurred, and frequent grade 3-4 toxicity was hematological toxicity and febrile neutropenia, as expected. There was no neurotoxicity. All 2 patients who received the target dose of FLEND, in which nelarabine (650 mg/m2), fludarabine (30 mg/m2), and etoposide (100 mg/m2) were administered for 5 consecutive days, were induced to complete remission. We concluded that FLEND might be safe and one of the promising combination chemotherapies to relapsed/refractory T-ALL.

New insights into the heat of adsorption of water, acetonitrile, and n-hexane in porous carbon with oxygen functional groups.

Isosteric heat of adsorption is exquisitely sensitive to structural changes in carbon surfaces based on the energetic behavior of the interactions between adsorbates and carbon materials. We discuss the relationships between porous structures, oxygen functional groups, and heat of adsorption based on the behavior of the heat of adsorption of polar and non-polar fluids on porous carbon materials with oxygen functional groups. The porosity and functional groups of porous carbon materials were estimated from N2 adsorption isotherms at 77 K and temperature-programmed desorption. High-resolution adsorption isotherms of water, acetonitrile (polar fluid), and n-hexane (non-polar fluid) were measured on porous carbon materials with different pore size distributions and amounts of oxygen functional groups at various temperatures. The heats of adsorption were determined by applying the Clausius-Clapeyron equation to the adsorption isotherms. The heat of adsorption curves directly reflect the effects of interactions of fluid-oxygen functional groups, fluid-basal planes of pore walls, and fluid-fluid interfaces. In particular, the heat of adsorption curve of water is very sensitive to surface oxygen functional groups. This finding indicates the possibility of estimating the relative amounts of oxygen functional groups on porous carbon materials based on the amounts of water adsorbed at specific relative pressures.

L-Lactate dehydrogenase B may be a predictive marker for sensitivity to anti-EGFR monoclonal antibodies in colorectal cancer cell lines.

Recently, proteins derived from cancer cells have been widely investigated as biomarkers for predicting the efficacy of chemotherapy. In this study, to identify a sensitive biomarker for the efficacy of anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR mAbs), proteins derived from 6 colorectal cancer (CRC) cell lines with different sensitivities to cetuximab, an anti-EGFR mAb, were analyzed. Cytoplasmic and membrane proteins extracted from each CRC cell line were digested using trypsin and analyzed comprehensively using mass spectrometry. As a result, 148 and 146 peaks from cytoplasmic proteins and 363 and 267 peaks from membrane proteins were extracted as specific peaks for cetuximab-resistant and -sensitive CRC cell lines, respectively. By analyzing the proteins identified from the peptide peaks, cytoplasmic L-lactate dehydrogenase B (LDHB) was detected as a marker of cetuximab sensitivity, and it was confirmed that LDHB expression was increased in cetuximab-resistant CRC cell lines. Furthermore, LDHB expression levels were significantly upregulated with the acquisition of resistance to cetuximab in cetuximab-sensitive CRC cell lines. In conclusion, LDHB was identified as an important factor affecting cetuximab sensitivity using comprehensive proteome analysis for the first time.

Darunavir concentration in PBMCs may be a better indicator of drug exposure in HIV patients.

PURPOSE: The clinical efficacies of some antiretroviral drugs are known to not depend on its concentration in blood. To establish a method of dosage adjustment for darunavir (DRV) based on pharmacokinetic theory, we analyzed the correlation between DRV levels in peripheral blood mononuclear cells (PBMCs) and plasma. METHODS: The concentrations of DRV and ritonavir (RTV) in plasma and PBMCs of 31 samples obtained from 19 patients were analyzed. An in vitro kinetic study using MOLT-4 cells was performed to assess the contribution of RTV to the intracellular accumulation of DRV. RESULTS: DRV levels in PBMCs varied between 7.91 and 29.36 ng/106 cells (CV 37.5%), while those in plasma were greater. No significant correlation was found between the trough level of DRV in plasma and that in PBMCs (p = 0.575). The inter-day difference in DRV levels in PBMCs seemed smaller than that in plasma (- 41.6-23.0% vs - 83.3-109.1%). In the in vitro study, the elimination half-life of cellular efflux of DRV was 15.7 h in the absence of RTV and extended to 47.6 h in the presence of RTV. CONCLUSIONS: We found a poor correlation between intracellular DRV and plasma DRV levels in patients receiving highly active antiretroviral therapy. The efflux rate of DRV from cells was slow; therefore, the concentration of DRV in PBMCs may reflect average exposure to the drug and clinical efficacy.

Dynamic Analysis of Photosynthate Translocation Into Strawberry Fruits Using Non-invasive 11C-Labeling Supported With Conventional Destructive Measurements Using 13C-Labeling.

In protected strawberry (Fragaria × ananassa Duch.) cultivation, environmental control based on the process of photosynthate translocation is essential for optimizing fruit quality and yield, because the process of photosynthate translocation directly affects dry matter partitioning. We visualized photosynthate translocation to strawberry fruits non-invasively with 11CO2 and a positron-emitting tracer imaging system (PETIS). We used PETIS to evaluate real-time dynamics of 11C-labeled photosynthate translocation from a 11CO2-fed leaf, which was immediately below the inflorescence, to individual fruits on an inflorescence in intact plant. Serial photosynthate translocation images and animations obtained by PETIS verified that the 11C-photosynthates from the source leaf reached the sink fruit within 1 h but did not accumulate homogeneously within a fruit. The quantity of photosynthate translocation as represented by 11C radioactivity varied among individual fruits and their positions on the inflorescence. Photosynthate translocation rates to secondary fruit were faster than those to primary or tertiary fruits, even though the translocation pathway from leaf to fruit was the longest for the secondary fruit. Moreover, the secondary fruit was 25% smaller than the primary fruit. Sink activity (11C radioactivity/dry weight [DW]) of the secondary fruit was higher than those of the primary and tertiary fruits. These relative differences in sink activity levels among the three fruit positions were also confirmed by 13C tracer measurement. Photosynthate translocation rates in the pedicels might be dependent on the sink strength of the adjoining fruits. The present study established 11C-photosynthate arrival times to the sink fruits and demonstrated that the translocated material does not uniformly accumulate within a fruit. The actual quantities of translocated photosynthates from a specific leaf differed among individual fruits on the same inflorescence. To the best of our knowledge, this is the first reported observation of real-time translocation to individual fruits in an intact strawberry plant using 11C-radioactive- and 13C-stable-isotope analyses.

Significant decreases in blood propofol concentrations during adrenalectomy for phaeochromocytoma.

AIM: The kinetics of propofol are influenced by cardiac output. The aim of this study was to examine changes in blood propofol concentrations during phaeochromocytoma surgery using target-controlled infusion (TCI) anaesthesia with propofol. METHODS: This is a prospective observational study. Ten patients with phaeochromocytoma who underwent unilateral adrenalectomy were included. Cardiac output was measured using an arterial pressure-based cardiac output analysis method. The target blood propofol concentrations were adjusted to maintain an approximate bispectral index (BIS) value of 40 before initiating surgery. The settings remained constant during surgery. Blood samples for propofol concentrations were collected from the radial artery at seven time points: two before tumour manipulation (T1, 2), two during tumour manipulation (T3, 4), and three after tumour vein ligation (T4-7). BIS values, the arterial pressure cardiac index (APCI) and haemodynamic parameters were measured at the same time points as the blood samples. The prop-ratio was calculated by dividing blood propofol concentrations by target concentrations of TCI. RESULTS: APCI increased during tumour manipulation and after tumour vein ligation. The prop-ratio was reduced significantly by approximately 40% and showed a significant negative correlation with APCI. BIS values increased significantly and showed a significant negative correlation with the prop-ratio. CONCLUSION: The increased APCI during tumour manipulation and after tumour vein ligation was associated with markedly reduced blood propofol concentrations. These results reveal that significant decreases in the anaesthetic effect may be observed in patients undergoing phaeochromocytoma surgery even if TCI anaesthesia is used with propofol.

A hairy-leaf gene, BLANKET LEAF, of wild Oryza nivara increases photosynthetic water use efficiency in rice.

BACKGROUND: High water use efficiency is essential to water-saving cropping. Morphological traits that affect photosynthetic water use efficiency are not well known. We examined whether leaf hairiness improves photosynthetic water use efficiency in rice. RESULTS: A chromosome segment introgression line (IL-hairy) of wild Oryza nivara (Acc. IRGC105715) with the genetic background of Oryza sativa cultivar 'IR24' had high leaf pubescence (hair). The leaf hairs developed along small vascular bundles. Linkage analysis in BC5F2 and F3 populations showed that the trait was governed by a single gene, designated BLANKET LEAF (BKL), on chromosome 6. IL-hairy plants had a warmer leaf surface in sunlight, probably due to increased boundary layer resistance. They had a lower transpiration rate under moderate and high light intensities, resulting in higher photosynthetic water use efficiency. CONCLUSION: Introgression of BKL on chromosome 6 from O. nivara improved photosynthetic water use efficiency in the genetic background of IR24.

Sex Differences in the Blood Concentration of Tacrolimus in Systemic Lupus Erythematosus and Rheumatoid Arthritis Patients with CYP3A5*3/*3.

The purpose of this study was to describe the impact of sex and cytochrome P450 3A5 (CYP3A5) variant on the blood concentration of tacrolimus in patients with systemic lupus erythematosus or rheumatoid arthritis. The blood concentration of tacrolimus (ng/mL) divided by the daily dose of tacrolimus (mg/day) and the patient's weight (kg) (C/D) was obtained from 55 patients. The C/D value was analysed according to genetic variation in CYP3A5 or ATP binding cassette subfamily B member 1 (ABCB1), sex, and age. The C/D value in the CYP3A5*3/*3 group was significantly higher than in the CYP3A5*1/*1 and *1/*3 groups (p < 0.05, effect size: d = 1.40). In the CYP3A5*3/*3 group, the concentration of tacrolimus was significantly higher in men than in women (p < 0.05, effect size: d = 1.78). Furthermore, in the CYP3A5*3/*3 group, the concentration of tacrolimus was significantly higher in women aged over 50 years than in women aged under 50 years (p < 0.05, effect size: d = 1.18). In contrast, ABCB1 genetic variations did not show any significant effect on the C/D value. Since the blood concentration of tacrolimus in patients with CYP3A5*3/*3 varies depending on sex and age, these factors should be considered when studying the difference of sex in CYP3A.

Factors influencing trough and 90-minute plasma dabigatran etexilate concentrations among patients with non-valvular atrial fibrillation.

INTRODUCTION: Dabigatran etexilate, a direct oral anti-coagulation agent, is used in the prevention of thromboembolism in patients with non-valvular atrial fibrillation (NVAF). However, for reasons that are not fully understood, plasma dabigatran etexilate concentrations (PDC) vary significantly among patients. METHODS: We measured trough and 90min PDC in 98 patients with NVAF. To elucidate the cause of variations in PDC, we determined correlations between PDC and various factors including renal function, co-administration of a P-glycoprotein inhibitor, and the effects of three single nucleotide polymorphisms (SNPs) of the P-glycoprotein intestinal efflux transporter. To further determine the cause of PDC variations, we examined the relationship between PDC, activated partial prothrombin time (APTT), and D-dimer (DD) levels, which are surrogate markers for thrombotic risk. RESULTS: Multivariate analysis showed significant relations among creatinine, creatinine clearance, and CHA2D2-VaSc scores (p=0.04, p=0.01, and p=0.04, respectively). In addition, creatinine and creatinine clearance were significantly correlated with trough and 90min PDC (p<0.01), respectively. There was a clear linear relation between PDC and APTT, but not DD levels. However, higher DD levels (>0.5µg/mL) were associated with lower trough and 90min PDCs. CONCLUSIONS: Renal function and CHA2D2-VaSc scores affect PDC, suggesting these may be primary factors influencing the wide variation observed in PDCs under these conditions. Variations in APTT can primarily be explained by variations in PDC; patients with lower PDCs may have a higher risk of thromboembolism events.