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Juyoung Khwarg,1 Soyoung Lee,1,2 In-Jin Jang,1 Won-Ho Kang,3 Hye Jung Lee,4 Kyu Yeon Kim,4 Ki-Sun Jeong,4 Chongho Won,4 Youn Woong Choi,5 Dae Chul Ha,5 RaeHoon Jung,5 Min-Gu Han,5 Won Tae Jung,6 Kyu-Yeol Nam,6 YeSeul Kim,6 Kyung-Sang Yu,1 Jaeseong Oh1,7 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea; 2Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, Republic of Korea; 3R&D Center, Korea United Pharm. Inc., Seoul, Republic of Korea; 4Caleb Multilab, Inc., Seoul, Republic of Korea; 5R&D Center, Korea United Pharm.Inc., Sejong, Republic of Korea; 6Global R&D, Korea United Pharm. Inc., Seoul, Republic of Korea; 7Department of Pharmacology, Jeju National University College of Medicine, Jeju, Republic of KoreaCorrespondence: Jaeseong Oh, Department of Pharmacology, Jeju National University College of Medicine, 15, Aran 13-gil, Jeju-si, Jeju-do, 63241, Republic of Korea, Email jaeseong5@jejunu.ac.krPurpose: Statins are widely used in combination with omega-3 fatty acids for the treatment of patients with dyslipidemia. The aim of this study was to compare the pharmacokinetic (PK) profiles of atorvastatin and omega-3-acid ethyl esters between fixed-dose combination (FDC) and loose combination in healthy subjects.Methods: A randomized, open-label, single-dose, 2-sequence, 2-treatment, 4-period replicated crossover study was performed. Subjects were randomly assigned to one of the 2 sequences and alternately received four FDC soft capsules of atorvastatin/omega-3-acid ethyl esters (10/1000 mg) or a loose combination of atorvastatin tablets (10 mg × 4) and omega-3-acid ethyl ester soft capsules (1000 mg× 4) for four periods, each period accompanied by a high-fat meal. Serial blood samples were collected for PK analysis of atorvastatin, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). PK parameters were calculated by a non-compartmental analysis. The geometric mean ratio (GMR) and its 90% confidence interval (CI) of the FDC to the loose combination were calculated to compare PK parameters.Results: A total of 43 subjects completed the study as planned. The GMR (90% CI) of FDC to loose combination for maximum concentration (Cmax) and area under the time-concentration curve from zero to the last measurable point (AUClast) were 1.0931 (1.0054– 1.1883) and 0.9885 (0.9588– 1.0192) for atorvastatin, 0.9607 (0.9068– 1.0178) and 0.9770 (0.9239– 1.0331) for EPA, and 0.9961 (0.9127– 1.0871) and 0.9634 (0.8830– 1.0512) for DHA, respectively. The intra-subject variability for Cmax and AUClast of DHA was 30.8% and 37.5%, respectively, showing high variability. Both the FDC and the loose combination were safe and well tolerated.Conclusion: The FDC of atorvastatin and omega-3-acid ethyl esters showed comparable PK characteristics to the corresponding loose combination, offering a convenient therapeutic option for the treatment of dyslipidemia. Keywords: pharmacokinetics, cardiovascular disease

Soyoung Lee,1,* Kyu-Yeol Nam,2,3,* Jaeseong Oh,1 SeungHwan Lee,1 Sang-Min Cho,3 Youn-Woong Choi,3 Joo-Youn Cho,1 Beom-Jin Lee,2,4,* Jang Hee Hong5,* 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea; 2College of Pharmacy, Ajou University, Suwon, Republic of Korea; 3Korea United Pharm Inc., Seoul, Republic of Korea; 4Institute of Pharmaceutical Science and Technology, Ajou University, Suwon, Republic of Korea; 5Department of Pharmacology, Chungnam National University Hospital and College of Medicine, Daejeon, Republic of Korea *These authors contributed equally to this work Background: Levodropropizine is a non-opioid antitussive agent that inhibits cough reflex by reducing the release of sensory peptide in the peripheral region. To improve patients’ compliance, a controlled-release (CR) tablet is under development. The aim of this study was to compare the pharmacokinetic (PK) profiles of the CR and immediate-release (IR) tablets of levodropropizine. In addition, the effect of food on the PK properties of levodropropizine CR tablet in healthy subjects was evaluated.Subjects and methods: A randomized, open-label, multiple-dose, three-treatment, three-period, six-sequence, crossover study was conducted on 47 healthy subjects. All subjects were randomly assigned to one of the six sequences, which involve combinations of the following three treatments: levodropropizine IR 60 mg three times in the fasted state (R), levodropropizine CR 90 mg two times in the fasted state (T), and levodropropizine CR 90 mg two times in the fed state (TF). Serial blood samples were collected up to 24 h after the first dose. Tolerability was assessed based on the vital signs, adverse events (AEs), and clinical laboratory tests.Results: Levodropropizine CR showed lower maximum drug concentration (Cmax) and similar total exposure compared to levodropropizine IR. The geometric mean ratios (GMRs) (90% confidence intervals [CIs]) of T to R for the Cmax and area under the concentration–time curve from the 0 to 24 h time points (AUC0–24h) were 0.80 (0.75–0.85) and 0.89 (0.86–0.93), respectively. In the fed group, levodropropizine CR showed exposure similar to that in the fasted group. The GMRs (90% CIs) of TF to T for the Cmax and AUC0–24h were 0.90 (0.85–0.97) and 1.10 (1.05–1.14), respectively. No serious AEs occurred with both levodropropizine CR and IR tablets.Conclusion: Total systemic exposure for levodropropizine was similar in subjects receiving the CR and IR formulations in terms of the AUC. Although food delayed the absorption of levodropropizine CR, systemic exposure was not affected. Keywords: pharmacokinetics, controlled-release, immediate-release, food effect

With the proliferation of smart embedded devices, cyber physical social computing and networking systems (CPSCN) are emerging as a next generation of social networks. Unlike traditional social networks that run on cloud-based infrastructure, CPSCN systems usually depend on a large number of distributed, heterogeneous devices, such as mobile phones, smart vehicles, or network access points. These computing resources, which are often referred to as fog computing systems, provide a gateway to the physical world, and thus offer new possibilities for social applications. Unfortunately, building CPSCN systems that leverage fog computing infrastructure is not straightforward. Significant challenges arise from the large scale distribution of computing resources over a wide area, and the dynamic nature of multiple, possibly mobile, hosts. In this paper, we extend our previous work on a distributed dataflow programming model and propose an application platform for realizing CPSCN systems. A key aspect of our work is the development of an exogenous coordination model, which exhibits a separation of concern between computation and communication activities, and helps resolve some of the challenges brought about by the dynamic and large scale nature of CPSCN systems.

YoonJung Choi,1 SeungHwan Lee,2 Sang-Min Cho,3 Won-Ho Kang,3 Kyu-Yeol Nam,4 In-Jin Jang,1 Kyung-Sang Yu1 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, 2Clinical Trials Center, Seoul National University Hospital, 3Research Institute, 4Global R&D, Korea United Pharm Inc., Seoul, Republic of Korea Background: A fixed-dose combination (FDC) of amlodipine and losartan has been used to reduce blood pressure in patients whose hypertension is not sufficiently controlled with either drug alone. The aim of this study was to evaluate the pharmacokinetic (PK) characteristics and tolerability of an FDC of 6.94 mg amlodipine besylate (5 mg as amlodipine)/50 mg losartan potassium compared to an FDC of 5 mg amlodipine camsylate/50 mg losartan potassium in healthy subjects. Subjects and methods: A randomized, open-label, single-dose, two-period, two-sequence crossover study was conducted on 46 healthy male subjects. Blood concentrations were measured by liquid chromatography–tandem mass spectrometry. Blood samples were collected up to 144 hours post dose for each period. PK parameters were calculated in each treatment group using a noncompartmental method. The 90% confidence intervals (CIs) of the geometric mean ratios of the two treatments for the maximum plasma concentration (Cmax) and the area under the concentration curve from time zero to the last quantifiable time point (AUC0–t) were estimated. Tolerability assessments were performed for all subjects who received the drug at least once. Results: The PK profiles of the two treatments were similar. For amlodipine, the geometric mean ratios (90% CIs) of amlodipine besylate to amlodipine camsylate for the Cmax and AUC0–t were 0.98 (0.94-1.01) and 0.97 (0.93-1.01), respectively. The corresponding values for losartan were 0.91 (0.81-1.02) and 1.05 (0.98-1.12), respectively. The incidence of adverse events was not significantly different between the two treatments, and both were well tolerated. Conclusion: An FDC of 6.94 mg amlodipine besylate (5 mg as amlodipine)/50 mg losartan potassium produced similar results to an FDC of 5 mg amlodipine camsylate/50 mg losartan potassium treatment with respect to the PK parameters of amlodipine and losartan based on Cmax and AUC0–t values. The amlodipine besylate/losartan potassium combination was well tolerated by healthy male subjects. Keywords: comparative pharmacokinetics, amlodipine, losartan, drug development

Objective of this study was to describe the morphological features of hypertrophic scars, categorize them, and evaluate the efficacy of triamcinolone injection therapy in treating these scars.Materials and Methods: A cross-sectional descriptive study of 80 patients with hypertrophic scars treated with triamcinolone intralesional injection at Can Tho University of Medicine and Pharmacy Hospital from 5/2018 to 5/2021.Results: There were 80 patients in all, with a male/female ratio of 1/1.05 and a median age of 15– 35. There were 129 scars in all, with scar age > 1 year accounting for 83%, keloid scars accounting for 64%, and hypertrophic scars accounting for the remaining 36%. Scars are most commonly seen on the trunk, accounting for 53.5% of all scars, particularly on the anterior chest wall. When the source of scars was discovered, trauma and acne accounted for 24% and 23%, respectively, while the rest were predominantly spontaneous scars, accounting for 49%. Scarring and discomfort of mild to moderate severity were common clinical symptoms; scars larger than 5cm in size had more symptoms than scars smaller than 5cm. Prior to the therapy, the mean Vancouver Score Scale-VSS was 6.55± 2.13. After 24 weeks of the therapy, 96.7% of patients had entirely improved itching symptoms, 75% had completely improved pain, and 25% still had minimal pain. After therapy, the mean Vancouver Score Scale-VSS was 2.55± 1.81 (p< 0.05). At week 24, 3.75% of patients experienced skin shrinkage, 3.75% experienced depigmentation, and 13.75% experienced vasodilation.Conclusion: Triamcinolone intralesional injection should be utilized as a first-line therapy for hypertrophic scarring.Plain Language Summary: This study looked at the effectiveness of triamcinolone injection (TAC) therapy in treating hypertrophic scars, which can cause significant cosmetic and psychological problems for patients. The study included 80 patients who had hypertrophic scars and were treated with triamcinolone injections over a period of 24 weeks. The majority of the scars were keloid scars (64%) and had an age of over one year (83%). Scars were most commonly found on the trunk, especially the anterior chest wall. The most common sources of scarring were trauma and acne. Mild to moderate scarring and discomfort were common symptoms, with larger scars having more symptoms. Before treatment, the mean Vancouver Score Scale-VSS was 6.55± 2.13. After 24 weeks of treatment, 96.7% of patients had improved itching symptoms, 75% had improved pain, and 25% still had minimal pain. The mean Vancouver Score Scale-VSS was also significantly reduced after treatment (2.55± 1.81). Some side effects were observed, such as skin shrinkage, depigmentation, and vasodilation, but these were experienced by a small percentage of patients. Based on these results, the study concludes that triamcinolone injection therapy should be considered as the first-line treatment for hypertrophic scarring. This therapy was found to be effective in reducing symptoms and the overall appearance of scars, with few side effects. This study provides valuable information for healthcare professionals who treat patients with hypertrophic scars, and may help improve the quality of life for those affected by this condition. [ABSTRACT FROM AUTHOR]

Background Programmed death ligand 1 (PD-L1) expression cannot currently be predicted through radiological findings. This study aimed to develop a prediction model capable of differentiating between positive and negative PD-L1 expression through a radiomics-based investigation of computed tomography (CT) images in patients with urothelial carcinoma. Methods Sixty-four patients with urothelial carcinoma who underwent immunohistochemical testing for PD-L1 were retrospectively reviewed. The number of patients in the positive and negative PD-L1 groups (PD-L1 expression >5%) was 14 and 50, respectively. CT images obtained 90 seconds after contrast medium administration were selected for radiomic extraction. For all tumors, 1,691 radiomic features were extracted from CT using a manually segmented three-dimensional volume of interest. Univariate and multivariate logistic regression analyses were performed to identify radiomic features that were significant predictors of PD-L1 expression. For the radiomics-based model, a receiver operating characteristic (ROC) analysis was performed. Results Among 64 patients, 14 were included in the PD-L1 positive group. Logistic regression analysis found that the following radiomic features significantly predicted PD-L1 expression: wavelet-low-pass, low-pass, and high-pass filters (LLH)_gray-level size-zone matrix (GLSZM)_SmallAreaEmphasis, wavelet-LLH_firstorder_Energy, log-sigma-0-5-mm-3D_GLSZM_SmallAreaHighGrayLevelEmphasis, original_shape_Maximum2DDiameterColumn, wavelet-low-pass, low-pass, and low-pass filters (LLL)_gray-level run-length matrix (GLRLM)_ShortRunEmphasis, and exponential_firstorder_Kurtosis. The radiomics signature was –4.0934+21.6224 (wavelet-LLH_GLSZM_SmallAreaEmphasis)+0.0044 (wavelet-LLH_firstorder_Energy)–4.7389 (log-sigma-0-5-mm-3D_GLSZM_SmallAreaHighGrayLevelEmphasis)+0.0573 (original_shape_Maximum2DDiameterColumn)–29.5892 (wavelet-LLL_GLRLM_ShortRunEmphasis)–0.4324 (exponential_firstorder_Kurtosis). The area under the ROC curve model representing the radiomics signature for differentiating cases that were deemed PD-L1 positive based on immunohistochemistry was 0.96. Conclusions This preliminary radiomics model derived from contrast-enhanced CT predicted PD-L1 positivity in patients with urothelial cancer.

Objective: Mitotically active cellular fibroma (MACF) of the ovary, characterized by relatively high mitotic activity without severe atypia, was first described in the WHO classification in 2014. However, due to its rarity, the clinicopathological characteristics of ovarian MACF have not been established. This study was performed to describe the clinical, radiological, and pathological features of MACF by analyzing 11 cases of ovarian MACF. Materials and methods: Between 2015 and 2022, 11 patients with ovarian MACFs underwent surgical treatment at our institution. Clinicopathologic data of the patients were retrospectively reviewed from their medical records. Results: Median patient age was 53.7 years (range 21–77 years), and median tumor diameter was 7.8 cm (range 4.3–14.0 cm). Preoperative CA125 was elevated in 4 cases. Four of the eleven patients had abdominal pain, and two presented with vulvar pain or a palpable abdominal mass, respectively. Preoperative radiological impressions included fibroma, fibrothecoma, stromal tumor, and cystadenocarcinoma. A laparoscopic approach was adopted in 7 cases (64%). Intraoperative frozen section was performed in 5 patients, and all demonstrated the presence of a benign, fibromatous stromal tumor. Three patients underwent fertility-sparing surgery, including laparoscopic ovarian cystectomy and unilateral salpingo-oophorectomy. Median follow-up was 37.7 months (range 2–84 months), and no patient experienced disease relapse or died of their disease. Conclusion: This study shows that ovarian MACF has a benign clinical course. Fertility-sparing surgery provides a safe therapeutic option for MACF, which can be managed safely by laparoscopy. Imaging findings and final pathological diagnosis were not well matched. Intraoperative frozen section is important for determining surgical extent in mitotically active cellular fibroma of the ovary.

Abstract Background During the pandemic period, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutated, leading to changes in the disease’s severity and the therapeutic effect of drugs accordingly. This study aimed to present the actual use of therapeutics and clinical outcomes based on the prevalence of each variant using real-world data. Methods We analyzed the electronic medical records of adult patients admitted to Busan Medical Center after confirming coronavirus disease 2019 (COVID-19) from February 1, 2020, to June 30, 2022. Patients with mild-to-moderate COVID-19 who were at a high risk of disease progression were selected as study subjects, and the time period was classified according to the variants as ancestral strain, Delta variant, or Omicron variant. We compared drug use status and clinical outcomes by time period. Results Among all 3,091 patients, corticosteroids were the most commonly used therapy (56.0%), being used most frequently in the Delta variant (93.0%), followed by the Omicron variant (42.9%) and ancestral strain (21.2%). Regdanvimab accounted for the majority of therapeutic use in the Delta variant (82.9%) and ancestral strain (76.8%), whereas remdesivir was most frequently used during the Omicron variant period (68.9%). The composite outcomes of death or disease aggravation were ranked in the order of the Delta variant, Omicron variant, and ancestral strain (14.5, 11.9, and 6.0%, respectively, P

Abstract This review article explores advanced surgical approaches and anatomical insights for tailoring rectal cancer surgery, particularly focusing on low‐lying rectal cancer. With the evolution of imaging technologies, precise preoperative planning has become possible, enhancing the visualization of anatomy surrounding the rectum and enabling more accurate assessments of circumferential resection margin (CRM) involvement. The article emphasizes the dynamic nature of rectal cancer treatment, advocating for individualized surgical planning based on comprehensive preoperative imaging and intraoperative assessment. This approach aims to optimize patient care by integrating recent advancements and anatomical insights into clinical practice for the management of low‐lying rectal cancer. Particularly, the article discusses the importance of customizing the excision of Denonvilliers' fascia (DVF) based on tumor characteristics for optimal oncologic and functional outcomes, especially for anteriorly located tumors. It highlights the need for precise dissection techniques to ensure a negative CRM while preserving critical anatomical structures. Additionally, the review addresses the surgical management of tumors at the anorectal ring and introduces the Gate Approach for deep anterolateral pelvic dissection. Special attention is given to tumors impacting the membranous and prostate urethra, emphasizing tailored surgical approaches to balance complete tumor resection with the preservation of urogenital functions.

Total mesorectal excision (TME) has greatly improved rectal cancer surgery outcomes by reducing local recurrence and enhancing patient survival. This review outlines essential knowledge and techniques for performing TME. TME emphasizes the complete resection of the mesorectum along embryologic planes to minimize recurrence. Key anatomical insights include understanding the rectal proper fascia, Denonvilliers fascia, rectosacral fascia, and the pelvic autonomic nerves. Technical tips cover a step-by-step approach to pelvic dissection, the Gate approach, and tailored excision of Denonvilliers fascia, focusing on preserving pelvic autonomic nerves and ensuring negative circumferential resection margins. In Korea, TME has led to significant improvements in local recurrence rates and survival with well-adopted multidisciplinary approaches. Surgical techniques of TME have been optimized and standardized over several decades in Korea, and minimally invasive surgery for TME has been rapidly and successfully adopted. The review emphasizes the need for continuous research on tumor biology and precise surgical techniques to further improve rectal cancer management. The ultimate goal of TME is to achieve curative resection and function preservation, thereby enhancing the patient’s quality of life. Accurate TME, multidisciplinary-based neoadjuvant therapy, refined sphincter-preserving techniques, and ongoing tumor research are essential for optimal treatment outcomes.