Kinetic-pharmacodynamic model of warfarin for prothrombin time-international normalized ratio in Japanese patients.

AIMS: Genotype-guided dosing algorithms can explain about half of the interindividual variability in prothrombin time-international normalized ratio (PT-INR) under warfarin treatment. This study aimed to refine a published kinetic-pharmacodynamic model and guide warfarin dosage for an optimal PT-INR based on renal function. METHODS: Using a retrospective cohort of adult patients (>20 years) who were administered warfarin and underwent PT-INR measurements, we refined the kinetic-pharmacodynamic model with age and the genotypes of cytochrome P450 2C9 and vitamin K epoxide reductase complex subunit 1 using the PRIOR subroutine in the nonlinear-mixed-effect modelling programme. We searched the significant covariates for parameters, such as the dose rate for 50% inhibition of coagulation (EDR50 ), using a stepwise forward and backward method. Monte Carlo simulation determined a required daily dose of warfarin with a target range of PT-INR (2.0-3.0 or 1.6-2.6) based on the significant covariates. RESULTS: A total of 350 patients with 2762 PT-INR measurements were enrolled (estimated glomerular filtration rate [eGFR]: 47.5 [range: 2.6-199.0] mL/min/1.73 m2 ). The final kinetic-pharmacodynamic model showed that the EDR50 changed power functionally with body surface area, serum albumin level and eGFR. Monte Carlo simulation revealed that a lower daily dose of warfarin was required to attain the target PT-INR range as eGFR decreased. CONCLUSIONS: Model-informed precision dosing of warfarin is a valuable approach for estimating its dosage in patients with renal impairment.

Pharmacokinetic/Pharmacodynamic Modeling and Simulation of the Analgesic Effects of Pentazocine Using Perioperative Real-World Data.

Pentazocine (PTZ) is a widely used drug for postoperative pain. It should be administered at appropriate dosing intervals not only because of its morphine-like side effects but also because frequent inappropriate dosing can lead to dependence. Although perioperative patients reportedly have nonnegligible effects on placebo drugs and postoperative wound healing, no pharmacokinetic (PK)/pharmacodynamic (PD) model has been established and simulated using real-world data for the perioperative period. This study aimed to perform PTZ modeling and simulation and to establish an indicator of the timing of drug efficacy evaluation in clinical practice. Participants were in-hospital orthopedic surgery patients who received 15 mg of PTZ within 48 h postoperatively. Pain severity was assessed using the numerical rating scale (NRS). A two-compartment model was selected for the population PK model and an indirect response model for the PK/PD model. Using these models, a virtual population of 1000 patients with Painbase NRS of 5 and 6 and body weights of 40, 80, and 120 kg were treated with single and multiple PTZ administrations (4, 8, and 24 h apart) of 15 mg. Simulation results indicate that its analgesic efficacy should be evaluated within 1 h after administration of 15 mg of PTZ. Additional doses should be considered every 8-12 h in postoperative patients with Painbase NRS of 5 weighing 40-80 kg. Simulation using the PK/PD model developed in this study may provide useful information for determining the analgesic effects and timing of the dosing interval after PTZ administration in perioperative patients.

External Evaluation of a Bayesian Warfarin Dose Optimization Based on a Kinetic-Pharmacodynamic Model.

Warfarin is a representative anticoagulant with large interindividual variability. The published kinetic-pharmacodynamic (K-PD) model allows the prediction of warfarin dose requirement in Swedish patients; however, its applicability in Japanese patients is not known. We evaluated the model's predictive performance in Japanese patients with various backgrounds and relationships using Bayesian parameter estimation and sampling times. A single-center retrospective observational study was conducted at Tokyo Women's Medical University, Medical Center East. The study population consisted of adult patients aged >20 years who commenced warfarin with a prothrombin time-international normalized ratio (PT-INR) from June 2015 to June 2019. The published K-PD model modified by Wright and Duffull was assessed using prediction-corrected visual predictive checks, focusing on clinical characteristics, including age, renal function, and individual prediction error. The external dataset included 232 patients who received an initial warfarin daily dose of 3.2 ± 1.28 mg with 2278 PT-INR points (median [range] follow-up period of 23 d [7-28]). Prediction-corrected visual predictive checks carried a propensity for underprediction. Additionally, age >60 years, body mass index ≤25 kg/m2, and estimated glomerular filtration rate ≤60 mL/min/1.73 m2 had a pronounced tendency to underpredict PT-INR. However, Bayesian prediction using four prior observations reduced underprediction. To improve the prediction performance of these special populations, further studies are required to construct a model to predict warfarin dose requirements in Japanese patients.

Optimization of prediction methods for risk assessment of pathogenic germline variants in the Japanese population.

Predicting pathogenic germline variants (PGVs) in breast cancer patients is important for selecting optimal therapeutics and implementing risk reduction strategies. However, PGV risk factors and the performance of prediction methods in the Japanese population remain unclear. We investigated clinicopathological risk factors using the Tyrer-Cuzick (TC) breast cancer risk evaluation tool to predict BRCA PGVs in unselected Japanese breast cancer patients (n = 1,995). Eleven breast cancer susceptibility genes were analyzed using target-capture sequencing in a previous study; the PGV prevalence in BRCA1, BRCA2, and PALB2 was 0.75%, 3.1%, and 0.45%, respectively. Significant associations were found between the presence of BRCA PGVs and early disease onset, number of familial cancer cases (up to third-degree relatives), triple-negative breast cancer patients under the age of 60, and ovarian cancer history (all P < .0001). In total, 816 patients (40.9%) satisfied the National Comprehensive Cancer Network (NCCN) guidelines for recommending multigene testing. The sensitivity and specificity of the NCCN criteria for discriminating PGV carriers from noncarriers were 71.3% and 60.7%, respectively. The TC model showed good discrimination for predicting BRCA PGVs (area under the curve, 0.75; 95% confidence interval, 0.69-0.81). Furthermore, use of the TC model with an optimized cutoff of TC score ≥0.16% in addition to the NCCN guidelines improved the predictive efficiency for high-risk groups (sensitivity, 77.2%; specificity, 54.8%; about 11 genes). Given the influence of ethnic differences on prediction, we consider that further studies are warranted to elucidate the role of environmental and genetic factors for realizing precise prediction.

Method of Determining Pyrrole-Imidazole Polyamide in Rat Plasma Using Ultra-Fast Liquid Chromatography-Ultraviolet Spectrometry.

To improve the efficiency of drug-discovery research on pyrrole-imidazole polyamides (PIs), a more rapid method for quantitative and qualitative measurement of PI in rat plasma samples was developed here using ultra-fast liquid chromatography-ultraviolet spectrometry (UFLC-UV) in order to shorten the measurement time. A measurement method of PIs by HPLC developed until now takes 45 min for one sample measurement. This method was inefficient to investigate extraction conditions from biological samples and measurement of animal experimental samples. In the developed method of this study, PI and phenacetin (internal standard, IS) were separated with an ACQUITY UPLC HSS T3 (1.8 µm, 2.1 × 50 mm; Nihon Waters K.K., Japan) column using a mobile phase of 0.1% acetic acid (mobile phase A) and acetonitrile (mobile phase B) at a flow rate of 0.3 mL/min with a linear gradient. The detection wavelength was 310 nm. The calibration curve was linear in the range of 0.225-4.5 µg/mL (correlation coefficients ≥0.9995, n = 5). The intra- and inter-day accuracies were in the range of -6.04 to 12.2%, and the precision was less than 2.99%. The measurement time of this method (7 min per injection) was markedly shortened to about one-sixth of the previous measurement time (45 min per injection). This is the first report describing the quantitative and qualitative measurement of PI in plasma using UFLC-UV. The present method will be very useful for the drug-discovery research of PIs.

Preoperative vascular mapping for anterolateral thigh flap surgeries: A clinical trial of photoacoustic tomography imaging.

BACKGROUND: Photoacoustic tomography (PAT) is a noninvasive vascular imaging modality that uses near-infrared pulse laser beams and ultrasound (US) to visualize vessels. We previously demonstrated the utility of PAT for visualizing anterolateral thigh (ALT) perforators in a clinical study of 10 thighs in 5 healthy adults. Evaluation of the correlation between PAT and US findings showed that PAT had comparable diagnostic potential but was superior in visualizing subcutaneous microvessels; however, there was no comparison with intraoperative findings. In this study, we used a newly developed technique to transfer a PAT image to a body-attachable transparent sheet to compare PAT and intraoperative findings. METHODS: Eight patients were recruited in this prospective study. Patient age ranged from 32 to 79 years (average 60). Seven ALT flaps were applied in head and neck reconstruction. One flap was elevated in chest wall reconstruction. Each PAT scan of an 18 cm × 13.5 cm region took approximately 5 min. Acquired data were processed three-dimensionally using a novel imaging software program. Perforator vessel data from PAT imaging were traced and corrected for projection onto medical film sheets. The correlation between the perforator stem portions predicted by PAT and the intraoperative findings at the level of the fascia-penetrating points was evaluated, and distal branching patterns were analyzed. RESULTS: PAT imaging showed 16 perforators in 8 thighs. Intraoperative surgical findings revealed that all the perforator penetrating points at the deep fascia level matched the PAT findings within 10 mm. None of the eight ALT flaps demonstrated postoperative complications. The perforator complexes were classified as type I in three cases (19%), type II in eight cases (50%), and type III in five cases (31%). CONCLUSIONS: PAT imaging matched the intraoperative findings within 10 mm. Preoperative vascular evaluation allows for the creation of a vascular map for facilitating ALT flap surgeries.

Sal-like 4 protein levels in breast cancer cells are post-translationally down-regulated by tripartite motif-containing 21.

Sal-like 4 (SALL4) is a transcription factor that enhances proliferation and migration in breast cancer cells. SALL4 expression therefore has the potential to promote cancer malignancy. However, the regulatory mechanisms involved in SALL4 protein expression have not been thoroughly elucidated. In this study, we observed that treating MCF-7 and SUM159 breast cancer cell lines with a proteasome inhibitor increases SALL4 protein levels, suggesting that SALL4 is degraded by the ubiquitin-proteasome system. Using immunoprecipitation to uncover SALL4-binding proteins, we identified an E3 ubiquitin-protein ligase, tripartite motif-containing 21 (TRIM21). Using an EGFP reporter probe of the major SALL4 isoform SALL4B, we observed that shRNA-mediated knockdown of TRIM21 increases cellular SALL4B levels. Immunostaining experiments revealed that TRIM21 localizes to the nucleus, and a K64R substitution in the nuclear localization motif in SALL4B increased SALL4B levels in the cytoplasm. These results suggested that TRIM21 is involved in nuclear SALL4 degradation. To identify the amino acid residue that is targeted by TRIM21, we fragmented the SALL4B sequence, fused it to EGFP, and identified Lys-190 in SALL4B as TRIM21's target residue. Amino acid sequence alignments of SALL family members indicated that the region around SALL4 Lys-190 is conserved in both SALL1 and SALL3. Because SALL1 and SALL4 have similar functions, we constructed a SALL1-EGFP probe and found that the TRIM21 knockdown increases SALL1 levels, indicating that TRIM21 degrades both SALL1 and SALL4. Our findings extend our understanding of SALL4 and SALL1 regulation and may contribute to the development of SALL4-targeting therapies.

The Measurement of Meloxicam and Meloxicam Metabolites in Rat Plasma Using a High-Performance Liquid Chromatography-Ultraviolet Spectrophotometry Method.

A high-performance liquid chromatography-ultraviolet spectrophotometry (HPLC-UV) method for the determination of meloxicam (MEL) and meloxicam metabolites (5'-hydroxy meloxicam (5-HMEL) and 5'-carboxy meloxicam (5-CMEL)) has been developed. After extraction of MEL, 5-HMEL, and 5-CMEL from rat plasma using Oasis HLB cartridges, the extracts were separated with a Luna C18 (2) 100 A column (5 µm, 4.6×150 mm, Phenomenex) using a mobile phase of 50 mM phosphate buffer (pH 2.15, solvent A) and acetonitrile (solvent B) at a flow rate of 0.8 mL/min in a linear gradient. The detection wavelength was 360 nm, and the internal standard (IS) was piroxicam. Each calibration curve was linear in the range of 40 to 1000 ng/mL (r2>0.999). The extraction rates of MEL, 5-HMEL, and 5-CMEL were greater than 86.9%. The intra- and inter-day accuracies were in the range of 95.0 to 119.0%, and the precision was 0.2 to 17.0%. To the best of our knowledge, this is the first report of the quantitative and qualitative measurement of meloxicam and each metabolite using an HPLC-UV method.

Study on rectal administration of azithromycin by suppository for pediatric use.

OBJECTIVE: Azithromycin (AZM) is widely used as a first-line treatment option for children with mycoplasma pneumonia. Although pharmacists perform medication counseling in the pediatric ward, children often experience vomiting as a result of oral AZM administration. Drugs that are administered rectally are generally considered to enter the circulation system without passing through the liver first. The aim of our study was to prepare an AZM suppository and investigate the pharmaceutical properties and well as pharmacokinetics of the rectal administration route in humans. MATERIALS AND METHODS: Five healthy volunteers were enrolled in the study. All subjects provided written informed consent before participating in the study. Subjects were randomly assigned to either oral administration of oral AZM 500-mg tablet or rectal administration of 125-mg, 250-mg, or 500-mg AZM suppository. Blood samples for preparation of serum were collected predose as well as at 1, 2, 3, 4, 6, 12, and 24 hours following the first rectal dose. Serum concentrations of AZM were determined by high-performance liquid chromatography (HPLC) with electrochemical detection. RESULTS AND CONCLUSION: The bioavailability of the AZM suppository through rectal administration was 20.3% compared to oral administration. We hypothesize that the surface area where AZM is absorbed also affects the absorption by rectal administration. Although further investigation is necessary to improve the absorption of AZM by the rectum and to ensure safety in children, the AZM suppository may be an effective preparation in cases where oral administration is not tolerated.

Involvement of a proton-coupled organic cation antiporter in the blood-brain barrier transport of amantadine.

The blood-to-brain transport of amantadine, a weak N-methyl-d-aspartate (NMDA) antagonist, has been shown previously to participate in the cationic drug-sensitive transport system across the mouse blood-brain barrier (BBB). The purpose of the present study was to characterize the influx transport system by means of both an in situ mouse brain perfusion technique and in vitro studies using rat immortalized brain capillary endothelial cells (GPNT). The observed concentration-dependent initial uptake rate of [(3) H]amantadine suggested the involvement of a carrier-mediated transport mechanism. The normal uptake at physiological pH 7.4 was decreased by 72.9% in acidic perfusate, while it was increased by 35.3% in alkaline perfusate. These results suggest that pH-dependent transport is regulated by utilizing an oppositely directed proton gradient as a driving force. In addition, the [(3) H]amantadine uptake was moderately inhibited by the adamantane structural analogs (rimantadine and memantine) and other cationic drugs (pyrilamine, clonidine, nicotine, etc.), but not by substrates or inhibitors of the well-characterized organic cation transporters (tetraethylammonium, l-carnitine and choline). A similar inhibition pattern was observed between the in vivo studies and the in vitro experiments. These results indicate that the influx transport for amantadine across the BBB involves a proton-coupled organic cation antiporter. Copyright © 2016 John Wiley & Sons, Ltd.

Reduction of Dimethylnitrosamine-Induced Liver Fibrosis by the Novel Gene Regulator PI Polyamide Targeting Transforming Growth Factor ß1 Gene.

Pyrrole-imidazole (PI) polyamide is a novel gene regulating agent that competitively inhibits transcription factor binding to the promoter of the specific target gene. Liver fibrosis is an integral stage in the development of chronic liver disease, and transforming growth factor ß (TGFß) is known to play a central role in the progression of this entity. The aim of this study was to evaluate the effect of PI polyamide targeting TGFß1 on rat liver fibrosis. PI polyamide was designed to inhibit activator protein 1 (AP-1) transcription factor binding to the TGFß1 gene promoter. The effect of PI polyamide on hepatic stellate cells was evaluated by real time polymerase chain reaction (PCR) in RI-T cells. To determine the effect of PI polyamide in vivo, PI polyamide was intravenously administered at a dose of 3 mg/kg/week in dimethylnitrosamine (DMN)-induced rat model of liver fibrosis. Treatment of RI-T cells with 1.0 µM PI polyamide targeting TGFß1 significantly inhibited TGFß1 mRNA expression. Azan staining showed that DMN treatment significantly increased areas of fibrous materials compared with controls. PI polyamide targeting TGFß1 significantly decreased the fibrous area compared with DMN group. mRNA expression levels of α-smooth muscle actin and matrix metalloproteinase-2 were significantly increased in DMN-treated group compared with control. Treatment with TGFß1 PI polyamide significantly decreased mRNA expression of these genes compared with DMN group. The novel gene regulator PI polyamide targeting TGFß1 may be a feasible therapeutic agent for the treatment of chronic liver disease.

Effects on serum uric acid by difference of the renal protective effects with atorvastatin and rosuvastatin in chronic kidney disease patients.

Hyperuricemia and hyperlipidemia have attracted attention as progression factors for chronic kidney disease (CKD). In the drug treatment of hyperuricemia and hyperlipidemia complications, Atorvastatin (ATV), which inhibits urinary protein, increases glomerular filtration rate (GFR) and has renal protective effects, and Rosuvastatin (ROS) were found be suitable because they promote serum uric acid (SUA) excretion. However, these drugs were administered at very high doses in previous studies. In this study, we have investigated the effects of ATV or ROS on renal protective effects and their SUA levels before and three months after each drug administration in CKD patients. We retrospectively investigated outpatients presenting with CKD (stages 3) on the basis of their electronic medical records as subjects. Estimated GFR (eGFR) was significantly increased after ATV administration, whereas no change in eGFR was observed following ROS administration. Furthermore, SUA levels significantly decreased after ATV administration, whereas no changes were observed following ROS administration. Therefore, it may be not necessary to administer drugs that lower the SUA levels to patients presenting with hyperuricemia and hyperlipidemia complications associated with moderate renal failure, such as patients with at least stage 3 CKD. We consider that, by selecting ATV, the renal protective effects and SUA-lowering effect would be sufficient.

Remarkable remission of symptomatic dermatomyositis after curative breast cancer surgery.

Dermatomyositis (DM) is an autoimmune disease that causes proximal muscle weakness in the extremities leading to severe immobility and dysphagia. Approximately 20% of patients with DM are positive for anti-TIF-1γ antibody and frequently accompanied by malignant tumors. Although DM remission after tumor resection has been reported, the indications for surgery in patients with severe DM are unknown. Herein, we report a case of a 79-year-old Japanese woman who presented with breast cancer and anti-TIF-1γ antibody-positive DM. She became bedridden shortly after DM onset. Although pulsed steroid therapy, intravenous immunoglobulin, tacrolimus, and endocrine therapy with fulvestrant did not improve her symptoms, tumor resection with axillary lymph node dissection resulted in complete remission of the DM after 8 months. Immunohistochemistry revealed high expression of TIF-1γ in cancer cells, both in the primary tumor and axillary lymph nodes. Since the serum levels of anti-TIF-1γ antibody decreased after the surgery, the existence of breast cancer with TIF-1γ expression may have contributed to the worsening of DM. The present case suggests that curative surgery should be considered as a treatment option even if the patient has severe symptoms, such as immobility and dysphagia. Careful discussions with patients and multidisciplinary collaboration are essential to make surgery feasible, particularly for those with severe symptomatic DM.

Comparison of the efficacy of anti-diabetic medications as add-on to metformin in type 2 diabetes mellitus from a real-world database.

BACKGROUND: Metformin is recommended as a first-line drug in the guidelines of the treatment for type 2 diabetes mellitus. However, high-quality evidence from clinical trials directly comparing the degree of hypoglycemic effect of combination therapy of metformin and a hypoglycemic agent with a different mechanism of action with that of monotherapy of a hypoglycemic drug is lacking. We aimed to examine whether combination therapy of hypoglycemic agents with metformin showed antagonism, addition, or synergism compared to monotherapy with hypoglycemic agents other than metformin regarding hemoglobin A1c levels. METHODS: This retrospective cohort study used a medical information database in Japan. Non-insulin anti-hyperglycemic agents with different mechanisms of action were classified into eight drug classes. A monotherapy cohort and a combination therapy added to the metformin cohort were defined. The change in hemoglobin A1c levels was evaluated to compare the treatment effect between the cohorts. RESULTS: A total of 13,359 patients with type 2 diabetes mellitus in the monotherapy cohort and 1,064 in the metformin combination therapy cohort were identified. A comparison of the change from baseline HbA1c level by drug class between the two cohorts showed a similar trend. Among those treated with dipeptidyl peptidase-4 inhibitor and sodium-glucose co-transporter-2 inhibitor, no clinically significant difference was observed between the two cohorts (0.00% and -0.07% for unadjusted, 0.15% and -0.03% for propensity score matching-adjusted, and 0.09% and -0.01% for inverse probability treatment weighting-adjusted analysis). CONCLUSIONS: According to the results of this study, the effect of dipeptidyl peptidase-4 inhibitor or sodium-glucose co-transporter-2 inhibitor added to metformin seems to be additive with respect to the reduction in hemoglobin A1c.

Reproducibility assessment of uptake on dedicated breast PET for noise discrimination.

OBJECTIVES: Dedicated breast PET (dbPET) systems have improved the detection of small breast cancers but have increased false-positive diagnoses due to an increased chance of noise detection. This study examined whether reproducibility assessment using paired images helped to improve noise discrimination and diagnostic performance in dbPET. METHODS: This study included 21 patients with newly diagnosed breast cancer who underwent [18F]FDG-dbPET and contrast-enhanced breast MRI. A 10-min dbPET data scan was acquired per breast, and two sets of reconstructed images were generated (named dbPET-1 and dbPET-2, respectively), each of which consisted of randomly allocated 5-min data from the 10-min data. Uptake spots higher than the background were indexed for the study with visual assessment. All indexed uptakes on dbPET-1 were evaluated using dbPET-2 for reproducibility. MRI findings based on the Breast Imaging-Reporting and Data System (BI-RADS) 2013 were used as the gold standard. Uptake spots that corresponded to BI-RADS 1 on MRI were considered noise, while those with BI-RADS 4b-6 were considered malignancies. The diagnostic performance of dbPET for malignancy was evaluated using four different criteria: any uptake on dbPET-1 regarded as positive (criterion A), a subjective visual assessment of dbPET-1 (criterion B), reproducibility assessment between dbPET-1 and dbPET-2 (criterion C), and a combination of B and C (criterion D). RESULTS: A total of 213 indexed uptake spots were identified on dbPET-1, including 152, 15, 6, 6, and 34 lesions classified as BI-RADS MRI categories 1, 2, 4b, 4c, and 5, respectively. Overall, 31.9% of the index uptake values were reproducible. All malignant lesions were reproducible, whereas 93.4% of noise was not reproducible. The sensitivities for malignancy for criteria A, B, C, and D were 100%, 91.3%, 100%, and 91.3%, respectively, with positive predictive values (PPVs) of 21.4%, 68.9%, 67.6%, and 82.4%, respectively. CONCLUSIONS: Our results demonstrated that reproducibility assessment helped reduce false-positive findings caused by noise on dbPET without lowering the sensitivity for malignancy. While subjective visual assessment was also efficient in increasing PPV, it occasionally missed malignant uptake.

Hyperkalemia by eplerenone or esaxerenone in the presence or absence of clarithromycin in hypertensive patients: a retrospective observational cohort study.

OBJECTIVE: Mineralocorticoid receptor antagonists (MRAs), eplerenone and esaxerenone, cause hyperkalemia dose-dependently. We investigated the cytochrome P450 3A4-mediated drug-drug interaction between the MRAs and clarithromycin. METHODS: This retrospective observational study included adult hypertensive patients with MRA plus clarithromycin or MRA alone with a propensity score matching (1:1). The difference in serum potassium level (ΔK, maximum level - baseline level) between groups was compared using the Mann-Whitney U -test. Linear regression analysis was used to detect variables that correlated with ΔK in patients with MRA plus clarithromycin. RESULTS: After propensity score matching (each nine patients), serum potassium level was elevated after treatment with MRA plus clarithromycin [4.3 (3.5 to 5.1) meq/l to 4.9 (4.0 to 5.5) meq/l, P  = 0.0234] and MRA alone [4.3 (4.0 to 4.7) meq/l to 4.6 (4.4 to 5.2) meq/l, P  = 0.0469]. Although there was no significant difference in ΔK between groups [MRA plus clarithromycin: 0.5 (0.1 to 1.1) meq/l vs. MRA alone: 0.3 (0.1 to 1.2) meq/l, P  = 0.7231], ΔK was significantly higher in esaxerenone plus clarithromycin than in esaxerenone alone [0.6 (0.5 to 1.1) meq/l vs. 0.1 (0.1 to 0.2) meq/l, P  = 0.0495]. Conversely, clarithromycin did not show a significant effect on ΔK in patients with eplerenone [0.4 (-0.2 to 1.2) meq/l vs. 0.8 (0.1 to 1.3) meq/l, P  = 0.5745]. A positive correlation was found between ΔK and age in patients with MRA plus clarithromycin ( y  = 0.03 ×  x - 1.38, r  = 0.71, P  = 0.0336). CONCLUSION: The drug-drug interaction between MRAs and clarithromycin was evident, particularly in esaxerenone. Serum potassium levels should be closely monitored in older patients.

Performance of dedicated breast PET in breast cancer screening: comparison with digital mammography plus digital breast tomosynthesis and ultrasound.

OBJECTIVE: To compare the diagnostic performance of dedicated breast positron emission tomography (dbPET) in breast cancer screening with digital mammography plus digital breast tomosynthesis (DM-DBT) and breast ultrasound (US). METHODS: Women who participated in opportunistic whole-body PET/computed tomography cancer screening programs with breast examinations using dbPET, DM-DBT, and US between 2016-2020, whose results were determined pathologically or by follow-up for at least 1 year, were included. DbPET, DM-DBT, and US assessments were classified into four diagnostic categories: A (no abnormality), B (mild abnormality), C (need for follow-up), and D (recommend further examination). Category D was defined as screening positive. Each modality's recall rate, sensitivity, specificity, and positive predictive value (PPV) were calculated per examination to evaluate their diagnostic performance for breast cancer. RESULTS: Out of 2156 screenings, 18 breast cancer cases were diagnosed during the follow-up period (10 invasive cancers and eight ductal carcinomas in situ [DCIS]). The recall rates for dbPET, DM-DBT, and US were 17.8%, 19.2%, and 9.4%, respectively. The recall rate of dbPET was highest in the first year and subsequently decreased to 11.4%. dbPET, DM-DBT, and US had sensitivities of 72.2%, 88.9%, and 83.3%; specificities of 82.6%, 81.4%, and 91.2%; and PPVs of 3.4%, 3.9%, and 7.4%, respectively. The sensitivities of dbPET, DM-DBT, and US for invasive cancers were 90%, 100%, and 90%, respectively. There were no significant differences between the modalities. One case of dbPET-false-negative invasive cancer was identified in retrospect. DbPET had 50% sensitivity for DCIS, while that of both DM-DBT and US was 75%. Furthermore, the specificity of dbPET in the first year was the lowest among all periods, and modalities increased over the years to 88.7%. The specificity of dbPET was significantly higher than that of DM-DBT (p < 0.01) in the last 3 years. CONCLUSIONS: DbPET had a compatible sensitivity to DM-DBT and breast US for invasive breast cancer. The specificity of dbPET was improved and became higher than that of DM-DBT. DbPET may be a feasible screening modality.

Quantitation of pyrrole-imidazole polyamide in rat plasma by high-performance liquid chromatography coupled with UV detection.

A simple and robust method using high-performance liquid chromatography with UV detection was developed and validated for the determination of six pyrrole-imidazole (PI) polyamides (HN.49, TGF-ß1f, TGF-ß1t, HN.50f, HN.50t, and LOX-1) in rat plasma. After the plasma proteins were precipitated with methanol containing phenacetin as an internal standard, the analytes were separated on a Luna C18 (2) (5 µm, 4.6 × 150 mm). Calibration curves were linear over the range of 0.5 to 200 µg/mL for HN.49, 0.25 to 200 µg/mL for TGF-ß1f, TGF-ß1t, HN.50t, and LOX-1, 1 to 200 µg/mL for HN.50f in rat plasma. The inter- and intraday precision were below 15%, and the accuracy was within 15% at the quality controls. The validated method was successfully applied to sample analysis for the pharmacokinetic study.

Evaluation of individual risk in nonvariceal gastrointestinal bleeding patients with NSAID administration: a multicenter study in Japan.

BACKGROUNDS: Gastrointestinal (GI) toxicity is an undesirable effect of nonsteroidal anti-inflammatory drugs (NSAIDs). We conducted a multicenter study in Japan to clarify the GI risk grade in patients with NSAID-induced GI bleeding. METHODS: Patients with emergent endoscopic hemostasis by nonvariceal bleeding were registered from 36 hospitals in Hiroshima. In cases with NSAID use, the GI risk grade (low, moderate, or high) was evaluated, and concomitant drugs were investigated. We asked 79 gastroenterologists and 234 orthopedists what concomitant drugs they would prescribe to 3 simulated patients. RESULTS: A total of 1,350 patients were registered. NSAIDs were used in 278 cases (21%). Concerning the risk grade in each patient, the largest group was the moderate-risk group (203 patients; 73%), while the high-risk group comprised 10% of all NSAID users with bleeding. A proton pump inhibitor (PPI) or misoprostol was administrated to only 20 patients (7%). A small number of the gastroenterologists and orthopedists who responded to the questionnaire would prescribe PPI or misoprostol to simulated patients with short-term loxoprofen use. CONCLUSIONS: In NSAID users with GI bleeding, the moderate-risk group was the largest group for GI toxicity in Japan. In these cases, PPI or misoprostol was not commonly medicated in clinical practice.