Controlled Sublimation Rate of Guest Drug from Polymorphic Forms of a Cyclodextrin-Based Polypseudorotaxane Complex and Its Correlation with Molecular Dynamics as Probed by Solid-State NMR.

Encapsulation of active pharmaceutical ingredients (APIs) in confined spaces has been extensively explored as it dramatically alters the molecular dynamics and physical properties of the API. Herein, we explored the effect of encapsulation on the molecular dynamics and physical stability of a guest drug, salicylic acid (SA), confined in the intermolecular spaces of γ-cyclodextrin (γ-CD) and poly(ethylene glycol) (PEG)-based polypseudorotaxane (PPRX) structure. The sublimation tendency of SA encapsulated in three polymorphic forms of the γ-CD/PEG-based PPRX complex, monoclinic columnar (MC), hexagonal columnar (HC), and tetragonal columnar (TC), was investigated. The SA sublimation rate was decreased by 3.0-6.6-fold and varied in the order of MC form > HC form > TC form complex. The 13C and 1H magic-angle spinning (MAS) solid-state nuclear magnetic resonance (NMR) spectra and 13C spin-lattice relaxation time (T1) indicated that the encapsulated SA molecules existed as the monomeric form, and its molecular mobility increased in the order of MC form > HC form > TC form complex. In the complexes, a rapid chemical exchange between two dynamic states of SA (free and bound) was suggested, with varying adsorption/desorption rates accounting for its distinct molecular mobility. This adsorption/desorption process was influenced by proton exchange at the interaction site and interaction strength of SA in the complexes, as evidenced by 1H MAS spectra and temperature dependency of the 13C carbonyl chemical shift. A positive correlation between the molecular mobility of SA and its sublimation rate was established. Moreover, the molecular mobility of γ-CD and PEG in the complexes coincided with that of SA, which can be explained by fast guest-driven dynamics. This is the first report on the stability improvement of an API through complexation in polymorphic supramolecular host structures. The relationship between the molecular dynamics and physical properties of encapsulated API will aid in the rational design of drug delivery systems.

The efficacy and safety of adaptive servo-ventilation therapy for heart failure with preserved ejection fraction.

It is unclear whether adaptive servo-ventilation (ASV) therapy for heart failure with preserved ejection fraction (HFpEF) is effective. The aim of this study was to investigate the details of ASV use, and to evaluate the effectiveness and safety of ASV in real-world HFpEF patients. We retrospectively enrolled 36 HFpEF patients at nine cardiovascular centers who initiated ASV therapy during hospitalization or on outpatient basis and were able to continue using it at home from 2012 to 2017 and survived for at least one year thereafter. The number of hospitalizations for heart failure (HF) during the 12 months before and 12 months after introduction of ASV at home was compared. The median number of HF hospitalizations for each patient was significantly reduced from 1 [interquartile range: 1-2] in the 12 months before introduction of ASV to 0 [0-0] in the 12 months after introduction of ASV (p < 0.001). In subgroup analysis, reduction in heart failure hospitalization was significantly greater in female patients, patients with a body mass index < 25, and those with moderate or severe tricuspid valve regurgitation. In patients with HFpEF, the number of HF hospitalizations was significantly decreased after the introduction of ASV. HFpEF patients with female sex, BMI < 25, or moderate to severe tricuspid valve regurgitation are potential candidates who might benefit from ASV therapy.

Successful treatment with bortezomib for POEMS syndrome, overcoming complicated severe heart block.

Cardiac bradyarrhythmia and conduction disorder may be rare, but recurrent adverse events caused by bortezomib. Here we report a case with POEMS syndrome presenting severe heart block after bortezomib plus dexamethasone therapy. After permanent pacemaker implantation, bortezomib was restarted and maintained, resulting in sustained complete response for POEMS syndrome.

Improved Liver Function After Sustained Virologic Response Enhanced Prognosis in Hepatitis C with Compensated Advanced Liver Fibrosis.

BACKGROUND AND AIM: Liver function can be improved in patients with chronic hepatitis C virus (HCV) infection who achieved sustained virologic response (SVR) with direct-acting antiviral (DAA) treatment. However, to our knowledge, the impact of liver function improvement after SVR on prognosis has not been investigated. METHODS: A total of 716 patients with chronic HCV infection and compensated advanced liver fibrosis who began receiving DAA treatment between September 2014 and August 2018 in 25 Japanese hospitals and achieved SVR were enrolled. RESULTS: The median age was 73 years, and 336 (47%) and 380 (53%) patients had albumin-bilirubin (ALBI) grade 1 and grade 2, respectively. Improvement to ALBI grade 1 at 1 year after the end of treatment (EOT) was observed in 76% of the patients with baseline ALBI grade 2. Among 380 patients with baseline ALBI grade 2, alanine aminotransferase (ALT) levels ≥ 40 U/L (p < 0.001) and modified ALBI (mALBI) grade 2a (p < 0.001) were significantly associated with improvement to ALBI grade 1 at 1 year after EOT in multivariate analysis. During the median observation period of 51.8 months, 4 and 10 patients with baseline ALBI grade 1 and 2, respectively, died. In patients with baseline ALBI grade 2, only the absence of improvement to ALBI grade 1 at 1 year after EOT was significantly associated with all-cause mortality in univariate analysis. CONCLUSIONS: Baseline ALT levels and mALBI grade were significantly associated with improvement in liver function after SVR. Patients whose liver function improved after SVR could have better prognosis.

Understanding the rod-to-tube transformation of self-assembled ascorbyl dipalmitate lipid nanoparticles stabilized with PEGylated lipids.

We previously established a nanoparticle-based drug delivery system (DDS) for high-dose ascorbic acid therapy by self-assembly of a lipid-modified ascorbic acid derivative, L-ascorbyl 2,6-dipalmitate (ASC-DP). The particles' morphology should be modified for effective DDSs. Here, we modulated the morphology of self-assembled ASC-DP nanoparticles using two different PEGylated lipids, distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG) and cholesterol-polyethylene glycol (Chol-PEG), with various PEG molecular weights. At the preparation molar ratio of 10 : 1 (ASC-DP/PEGylated lipid), rod-like nanoparticles emerged in the ASC-DP/DSPE-PEG system, whereas the ASC-DP/Chol-PEG system yielded tube-like nanoparticles. The internal structures of both rod-like ASC-DP/DSPE-PEG and tube-like ASC-DP/Chol-PEG nanoparticles were similar to that of repeated ASC-DP bilayers. The particles' surfaces featured PEGylated lipids, which stabilized the structure and dispersion of the nanoparticles. For both systems, the particle size increased slightly with increasing the PEGylated lipid's PEG molecular weight. Increasing the PEG molecular weight decreased the inner tunnel size of tube-like ASC-DP/Chol-PEG nanoparticles. A mechanism has been proposed for the rod-to-tube transformation. Surface-layer free-energy changes owing to the mixing of multiple lipids and PEG chain repulsion are thought to underlie the inner tunnels' formation. The rod-to-tube morphology of self-assembled ASC-DP nanoparticles can be modulated by controlling the PEGylated lipids' structure, including the lipid species and the PEG chain length.

Risk of hepatocellular carcinoma after sustained virologic response in hepatitis C virus patients without advanced liver fibrosis.

AIM: Hepatocellular carcinoma (HCC) after sustained virologic response (SVR) has been observed even in hepatitis C virus (HCV) patients without advanced liver fibrosis. Identifying predictors for HCC incidence in patients without advanced liver fibrosis will enable efficient post-SVR HCC surveillance. This study aimed to develop a scoring system to predict the incidence of HCC after SVR in HCV patients without advanced liver fibrosis. METHODS: A total of 1682 HCV patients without advanced liver fibrosis (defined as Fibrosis-4 index <3.25) with no history of HCC who initiated direct-acting antiviral treatment between September 2014 and October 2020 at 26 institutions, and achieved SVR24, were included. We divided 1682 patients into training (1122) and validation (560) cohorts. RESULTS: In the multivariate analysis, baseline age ≥ 65 years (p = 0.030), alanine aminotransferase (ALT) levels at SVR24 ≥ 30 U/l (p = 0.001), and α-fetoprotein (AFP) levels at SVR24 ≥ 5.0 ng/ml (p = 0.001) were independent predictors for HCC incidence in the training cohort. We developed a scoring system to predict HCC incidence after SVR24 using these three factors (1 point was added for each factor). The cumulative HCC incidence rates at 5 years were 7.1% in patients who scored 2 or 3, and no patients developed HCC in those who scored 0 in the validation cohort. CONCLUSIONS: Our scoring system using the three factors of baseline age, ALT levels at SVR, and AFP levels at SVR is useful for post-SVR HCC surveillance of patients without advanced liver fibrosis.

Transition from epoprostenol to selexipag in a patient with systemic sclerosis and pulmonary hypertension during the postoperative period of colon cancer surgery: A case report.

Introduction: Most pulmonary vasodilators are administered orally; however, in patients with pulmonary hypertension undergoing gastrointestinal surgery, a switch to parenteral drugs is needed. Parenteral pulmonary vasodilators carry a risk of infection and reduced quality of life owing to long-term central venous catheterization; therefore, it is preferable to switch them to oral vasodilators after surgery. Here, we present the case of a patient with systemic sclerosis complicated by pulmonary hypertension and colon cancer, for which treatment was successfully switched from epoprostenol to selexipag postoperatively. Case Description: A 59-year-old woman, who was diagnosed with mixed group I and III pulmonary hypertension and systemic sclerosis, was on oral triple pulmonary vasodilators for pulmonary hypertension and Raynaud's phenomenon. She was diagnosed as having colon cancer 3 months before admission. Despite the severe pulmonary condition and treatment with oral triple pulmonary vasodilators, colon cancer resection surgery was performed with the management for pulmonary hypertension through multidisciplinary treatments in collaboration with cardiology specialists. Medications for patients with pulmonary hypertension undergoing gastrointestinal surgery need to be switched from oral vasodilators to epoprostenol perioperatively. On postoperative day 19, 0.4 mg/day of selexipag was administered with epoprostenol. Subsequently, the epoprostenol dosage was gradually decreased, and selexipag was increased. On postoperative day 30, the dose of selexipag was increased to 1.2 mg/day and epoprostenol was discontinued. The patient was discharged on postoperative day 40. Conclusion: In our case, transition from epoprostenol to selexipag contributed to a more useful management strategy for systemic sclerosis and pulmonary hypertension in the postoperative period.

Chest computer tomography is safe without additional interrogation or monitoring for modern cardiac implantable electrical devices.

INTRODUCTION: Whether diagnostic computed tomography (CT) scans to cardiac implantable electronic devices (CIED) is safe in recent models remains unknown. METHODS: A two-centers observational study. Over 14 years, consecutive 2362 chest CT scans (1666 pacemakers [PMs], 145 cardiac resynchronization therapy PM, 316 implantable cardioverter-defibrillator, and 233 cardiac resynchronization therapy defibrillator) were interrogated and monitored upon imaging. RESULTS: Electromagnetic interference occurred only in a few old models: InSync 8040 (n = 14), InSync III Marquis (n = 1), and Kappa (n = 4), which resulted no adverse events. CONCLUSION: CIEDs, especially recent ones, are confirmed safe on chest CT.

Serum growth differentiation factor 15 predicts hepatocellular carcinoma occurrence after hepatitis C virus elimination.

BACKGROUND: After hepatitis C virus (HCV) elimination, patients should be followed up due to risk of hepatocellular carcinoma (HCC). Growth differentiation factor 15 (GDF15) is a cytokine induced by mitochondrial dysfunction or oxidative stress. Aim To evaluate the prognostic value of GDF15 for HCC occurrence after HCV elimination. METHODS: We measured GDF15 levels in stored serum from patients with chronic HCV infection without a history of HCC who had achieved sustained virological response with direct-acting antiviral agents (DAAs). The patients were randomly divided into derivation (n = 964) and validation (n = 642) cohorts. RESULTS: In the derivation cohort, serum GDF15 levels were higher in those with HCC occurrence after DAA treatment than in those without. Multivariate Cox proportional hazards analysis revealed baseline GDF15 (>1350 pg/mL, HR 2.54), AFP (>5 ng/mL, HR 2.00), and the FIB-4 index (>3.25, HR 2.69) to be independent risk factors for HCC. Scoring based on GDF15, AFP and the FIB-4 index stratified HCC occurrence risk. In the validation cohort, the cumulative HCC occurrence rate at 3 years was 0.64%, 3.27% and 15.3% in low-score (N = 171), medium-score (N = 300) and high-score (N = 166) groups, respectively. In the total cohort, scoring divided patients with a FIB-4 index ≤3.25, whose HCC occurrence rate was 2.0% at 3 years, into medium-score and low-score groups with HCC occurrence rates at 3 years of 3.76% and 0.24%, respectively. CONCLUSIONS: Serum GDF15 predicts de novo HCC occurrence. Scoring using GDF15, AFP, and the FIB-4 index can predict de novo HCC occurrence risk after HCV elimination.

Prediction model for hepatocellular carcinoma occurrence in patients with hepatitis C in the era of direct-acting anti-virals.

BACKGROUND: Several factors associated with hepatocellular carcinoma (HCC) occurrence after sustained virological response (SVR) in patients with hepatitis C have been reported. However, few validation studies have been performed in the era of direct-acting anti-virals (DAAs). AIMS: To develop a prediction model for HCC occurrence after DAA-mediated SVR and validate its usefulness. METHODS: We analysed 2209 patients with SVR and without a history of HCC who initiated DAA treatment at 24 Japanese hospitals. These patients were divided into a training set (1473 patients) and a validation set (736 patients). RESULTS: In the training set, multivariate Cox proportional hazards analysis showed that the baseline BMI (≥25.0 kg/m2 , P = 0.024), baseline fibrosis-4 (FIB-4) index (≥3.25, P = 0.001), albumin level at SVR (<4.0 g/dL, P = 0.010) and alpha-foetoprotein level at SVR (≥5.0 ng/mL, P = 0.006) were significantly associated with HCC occurrence. We constructed a prediction model for HCC occurrence with these four factors (2 points were added for the FIB-4 index, and 1 point was added for each of the other three factors). Receiver operating characteristics curve analysis identified a score of 2 as the optimal cut-off value for the prediction model (divided into 0-1 and 2-5). In the validation set, the sensitivity and negative predictive value for HCC occurrence were 87.5% and 99.7%, respectively, at 2 years and 71.4% and 98.0%, respectively, at 3 years. CONCLUSION: A prediction model combining these four factors contributes to an efficient surveillance strategy for HCC occurrence after DAA-mediated SVR.

The nanostructure of rod-like ascorbyl dipalmitate nanoparticles stabilized by a small amount of DSPE-PEG.

Previously, we reported the formation of 100-200 nm disk- and tube-like nanoparticles by hydration of L-ascorbyl 2,6-dipalmitate (ASC-DP) and distearoylphosphatidylethanolamine polyethylene glycol 2000 (DSPE-PEG) films prepared at an initial molar ratio of 2:1. This study investigated the feasibility of nanoparticle formation with higher ASC-DP loading. Although particle size distribution determined by dynamic light scattering showed a multimodal pattern including micro-sized particles at a molar ratio of 3:1, the mean particle size gradually decreased with a further increased molar ratio. Homogeneous ca. 240 nm nanoparticles with a unimodal size distribution were obtained at a molar ratio of 10:1. FE-TEM showed that the nanoparticles at a molar ratio of 10:1 were rod-shaped with a diameter of ca. 100 nm and a length of ca. 300 nm. After centrifugation, X-ray analysis of the nanoparticle precipitates showed that these rod-like nanoparticles were composed of a series of lamellar structures with 3.7 nm repeated units. The molar ratio of ASC-DP/DSPE-PEG in the nanoparticle precipitates determined by 1H NMR measurements was 68.8:1. The rod-like nanoparticles should be composed of a core-shell structure, where a small amount of DSPE-PEG covers the lamellar structure of ASC-DP. Further increase in the ASC-DP/DSPE-PEG molar ratio over 33:1 no longer provided nanoparticles. Hence, to prepare a stable ASC-DP nanoparticle suspension, it is necessary to prepare ASC-DP/DSPE-PEG films containing at least 3 mol% DSPE-PEG.

A Visual Analytics Framework for Reviewing Multivariate Time-Series Data with Dimensionality Reduction.

Data-driven problem solving in many real-world applications involves analysis of time-dependent multivariate data, for which dimensionality reduction (DR) methods are often used to uncover the intrinsic structure and features of the data. However, DR is usually applied to a subset of data that is either single-time-point multivariate or univariate time-series, resulting in the need to manually examine and correlate the DR results out of different data subsets. When the number of dimensions is large either in terms of the number of time points or attributes, this manual task becomes too tedious and infeasible. In this paper, we present MulTiDR, a new DR framework that enables processing of time-dependent multivariate data as a whole to provide a comprehensive overview of the data. With the framework, we employ DR in two steps. When treating the instances, time points, and attributes of the data as a 3D array, the first DR step reduces the three axes of the array to two, and the second DR step visualizes the data in a lower-dimensional space. In addition, by coupling with a contrastive learning method and interactive visualizations, our framework enhances analysts' ability to interpret DR results. We demonstrate the effectiveness of our framework with four case studies using real-world datasets.

Small-Bowel Lesions in Patients Taking Direct Oral Anticoagulants Detected Using Capsule Endoscopy.

METHODS: This study was a prospective, open-label, nonblinded, multicenter, and observational study. From September 2013 to March 2017, patients taking DOACs were enrolled. Patients underwent VCE. The type and location of small-bowel lesions were registered. Also, (1) the proportion of lesions detected between types of DOAC was evaluated and (2) the hemoglobin (Hb) and serum ferritin levels were compared between patients with and without small-bowel lesions. RESULTS: 33 patients were enrolled, but 4 patients withdrew their consent, and VCE was performed on 29 patients. Eight, 13, and 8 patients received dabigatran, rivaroxaban, and apixaban, respectively. Small-bowel transit was complete in 27 of 29 patients (93.1%). Small-bowel lesions were detected in 23 (79.3%), redness in 12 (41.4%), erosions in 14 (48.3%), and angioectasia in 3 (10.3%) patients, and 6 patients (20.7%) had no abnormalities. Redness and erosions were detected in the upper, middle, or lower portions, but erosions tended to be less frequent in the middle portion (p = 0.25, 0.06). Angioectasia was not detected in the lower portion. No patients had active bleeding. The findings did not differ according to the drug. The relationships between the endoscopic findings and the Hb and serum ferritin levels were not significant. CONCLUSION: Many patients taking DOACs had small-bowel lesions; however, most lesions were relatively mild. Observing small-bowel lesions over longer periods may be necessary in patients taking DOACs. This trial is registered with UMIN000011527.

Size Reduction Efficiency of Alpha-Mangostin Suspension Using High-Pressure Homogenization.

In this study, we aimed to investigate the effects of stabilizers and processing parameters on the size reduction of alpha-mangostin (AMG) using high-pressure homogenization (HPH). The solubility of AMG in various stabilizers was studied. Selected stabilizers were used to prepare AMG suspensions by HPH under different conditions. After HPH, the particle size of AMG suspensions with stabilizers significantly decreased to microns. Percent size reduction efficiency of all AMG suspensions with each stabilizer increased with the increase in the number of homogenization cycles. Sodium lauryl sulfate and poloxamer188 provided a greater extent of particle size reduction than polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. AMG suspensions with binary stabilizers at higher pressure were also prepared. The use of high pressure increased percent size reduction efficiency.

Molecular-level elucidation of saccharin-assisted rapid dissolution and high supersaturation level of drug from Eudragit® E solid dispersion.

In this work, the effect of saccharin (SAC) addition on the dissolution and supersaturation level of phenytoin (PHT)/Eudragit® E (EUD-E) solid dispersion (SD) at neutral pH was examined. The PHT/EUD-E SD showed a much slower dissolution of PHT compared to the PHT/EUD-E/SAC SD. EUD-E formed a gel layer after the dispersion of the PHT/EUD-E SD into an aqueous medium, resulting in a slow dissolution of PHT. Pre-dissolving SAC in the aqueous medium significantly improved the dissolution of the PHT/EUD-E SD. Solid-state 13C NMR measurements showed an ionic interaction between the tertiary amino group of EUD-E and the amide group of SAC in the EUD-E gel layer. Consequently, the ionized EUD-E could easily dissolve from the gel layer, promoting PHT dissolution. Solution-state 1H NMR measurements revealed the presence of ionic interactions between SAC and the amino group of EUD-E in the PHT/EUD-E/SAC solution. In contrast, interactions between PHT and the hydrophobic group of EUD-E strongly inhibited the crystallization of the former from its supersaturated solution. The PHT supersaturated solution was formed from the PHT/EUD-E/SAC SD by the fast dissolution of PHT and the strong crystallization inhibition effect of EUD-E after aqueous dissolution.