An extended-release (ER) fixed-dose combination (FDC) of tramadol 37.5 mg/acetaminophen 325 mg was developed due to the demand for varying dosages. This study aimed to evaluate the pharmacokinetics (PKs) for two tablets of the new developed tramadol 37.5 mg/acetaminophen 325 mg ER FDC (DW-0920, Wontran Semi ER®) as test formulation compared to one tablet of the tramadol 75 mg/acetaminophen 650 mg ER FDC (DW-0919, Wontran ER®) as reference formulation. A randomized, open-label, 2-way crossover study was conducted in 30 healthy subjects. Subjects were orally administered one of 2 formulations followed by an alternate formulation with a 7-day washout period. Blood samples were collected up to 36 hours post-dose. Plasma concentrations of tramadol and acetaminophen were determined using a validated high-performance liquid chromatography with tandem mass spectrometric method. The geometric mean ratios (GMRs) and their 90% confidence intervals (90% CIs) of test formulation to reference formulation were calculated for the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from zero to the last measurable time point (AUClast). The PK profiles of 2 formulations were comparable. The GMRs (90% CI) of Cmax and AUClast for tramadol were 1.086 (1.047–1.127) and 1.008 (0.975–1.042), respectively. The corresponding values for acetaminophen were 0.956 (0.897–1.019) and 0.986 (0.961–1.011), respectively. All the values were within the bioequivalence range of 0.80–1.25. Two tablets of DW-0920 were comparable to one tablet of DW-0919. The DW-0920 may be used for optimal pharmacotherapy for pain control with a lower dose.

UI026 is an expectorant and antitussive agent which is a new combination of Pelargonium sidoides extract andCoptis extract. The bioactive compounds of Pelargonium sidoides and Coptis extracts were identified as epicatechin and berberine, respectively. This study evaluated the effect of food on the pharmacokinetics (PKs) and safety of UI026. A randomized, openlabel, single-dose, 2-treatment, parallel study in 12 healthy male subjects was performed. Subjects received a single oral dose of UI026 (27 mL of syrup) under a fed or fasted condition according to their randomly assigned treatment. Blood samples for the PK analysis were obtained up to 24 hours post-dose for berberine and 12 hours post-dose for epicatechin. The PK parameters were calculated by non-compartmental analysis. In the fed condition, the mean maximum plasma concentration (C max ) and mean area under the plasma concentrationtime curve from time zero to the last observed time point (AUC last ) for berberine were approximately 33% and 67% lower, respectively, compared with the fasted condition, both showing statistically significant difference. For epicatechin, the mean C max and mean AUC last were about 29% and 45% lower, respectively, compared to the fasting condition, neither of which showed a statistically significant difference. There were no drug-related adverse events. This finding suggests that food affects the systemic exposure and bioavailability of berberine and epicatechin.

Venous thromboembolism (VTE), which includes pulmonary embolism and deep vein thrombosis, is a condition characterized by abnormal blood clot formation in the pulmonary arteries and the deep venous vasculature. It is often serious and sometimes even fatal if not promptly and appropriately treated. Moreover, the later consequences of VTE may result in reduced quality of life. The treatment of VTE depends on various factors, including the type, cause, and patient comorbidities. Furthermore, bleeding may occur as a side effect of VTE treatment. Thus, it is necessary to carefully weigh the benefits versus the risks of VTE treatment and to actively monitor patients undergoing treatment. Asian populations are known to have lower VTE incidences than Western populations, but recent studies have shown an increase in the incidence of VTE in Asia. A variety of treatment options are currently available owing to the introduction of direct oral anticoagulants.The current VTE treatment recommendation is based on evidence from previous studies, but it should be applied with careful consideration of the racial, genetic, and social characteristics in the Korean population.

The global crisis caused by the coronavirus disease 2019 (COVID-19) led to the most significant economic loss and human deaths after World War II. The pathogen causing this disease is a novel virus called the severe acute respiratory syndrome coronavirus 2 (SARSCoV-2). As of December 2020, there have been 80.2 million confirmed patients, and the mortality rate is known as 2.16% globally. A strategy to protect a host from SARS-CoV-2 is by suppressing intracellular viral replication or preventing viral entry. We focused on the spike glycoprotein that is responsible for the entry of SARS-CoV-2 into the host cell. Recently, the US Food and Drug Administration/EU Medicines Agency authorized a vaccine and antibody to treat COVID-19 patients by emergency use approval in the absence of long-term clinical trials. Both commercial and academic efforts to develop preventive and therapeutic agents continue all over the world. In this review, we present a perspective on current reports about the spike glycoprotein of SARS-CoV-2 as a therapeutic target.

Background/Aims: Combination therapy with immunomodulators (IMMs) was proposed as a strategy to prevent the development of loss of response (LOR) to anti-tumor necrosis factor (TNF) for patients with inflammatory bowel disease (IBD). However, the effect is unclear in patients already exposed to IMMs. The aim of this study was to evaluate whether combination therapy with IMMs is superior to monotherapy for prevention of LOR to anti-TNF. Methods: This was a retrospective study of patients in Seoul National University Bundang Hospital with IBD between January 2009 and October 2018. LOR was defined as clinical deterioration after maintenance of anti-TNF for at least 6 months. We investigated the difference in incidence of LOR to anti-TNF between the monotherapy and combination groups. We additionally assessed factors affecting LOR development to anti-TNF. Results: A total of 116 patients with IBD were included in this study (monotherapy 61 patients; combination 55 patients). Overall, LOR to anti-TNF occurred in 31 patients during the follow-up period. The combination of an anti-TNF agent and IMM showed no significant difference in the incidence of LOR compared to anti-TNF agent monotherapy (hazard ratio [HR], 1.64; 95% confidence interval [CI], 0.786 to 3.148; p = 0.182). Female sex was significantly associated with the development of LOR to anti-TNF (HR, 3.032; 95% CI, 1.467 to 6.268; p = 0.003). Conclusions Anti-TNF and IMM combination therapy did not prove efficacious in preventing the development of LOR in IBD patients. Female sex was associated with the development of LOR to anti-TNF; further studies are required to confirm these results.

Purpose: Pharmacological inhibition of mutant isocitrate dehydrogenase (IDH) reduces R-2-hydroxyglutarate (2-HG) levels and restores cellular differentiation in vivo and in vitro. The IDH2 inhibitor enasidenib (AG-221) has been approved by the FDA as a first-in-class inhibitor for the treatment of relapsed or refractory (R/R) IDH2-mutant acute myeloid leukemia (AML). In this study,the effects of a combination of all-trans retinoic acid (ATRA) and AG-221 on AML cell differentiation was explored, along with the mechanisms employed by IDH2-mutant cells in AML. Materials and Methods: We treated the human AML cell line, IDH2-mutant-TF-1, and primary human AML cells carrying IDH2 mutation with 30 μM AG-221 and 100 nM ATRA, alone or in combination. Results: Combined treatment with AG-221 and ATRA inhibited 2-HG production and resulted in synergistic effects on differentiation among IDH2-mutant AML cells and primary AML cells expressing IDH2 mutation. Combined treatment with AG-221 and ATRA altered autophagic activity. AG-221 and ATRA treatment-induced differentiation of IDH2-mutant AML cells was associated with autophagy induction, without suppressing autophagy flux at maturation and degradation stages. A RAF-1/MEK/ERK pathway was founded to be associated with AG-221 and ATRA-induced differentiation in IDH2-mutant AML cells. IDH-associated changes in histone methylation markers decreased after AG-221 and ATRA combination treatment. Conclusion Our preliminary evidence indicates that the addition of ATRA to treatments with IDH2 inhibitor may lead to further improvements or increases in response rates in IDH2-mutant AML patients who do not appear to benefit from treatments with IDH2 inhibitor alone.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is a positive-sense singlestranded RNA (+ssRNA) that causes coronavirus disease 2019 (COVID-19). The viral genome encodes twelve genes for viral replication and infection. The third open reading frame is the spike (S) gene that encodes for the spike glycoprotein interacting with specific cell surface receptor – angiotensin converting enzyme 2 (ACE2) – on the host cell membrane. Most recent studies identified a single point mutation in S gene. A single point mutation in S gene leading to an amino acid substitution at codon 614 from an aspartic acid 614 into glycine (D614G) resulted in greater infectivity compared to the wild type SARS-CoV2. We were interested in investigating the mutation region of S gene of SARS-CoV2 from Korean COVID-19 patients. New mutation sites were found in the critical receptor binding domain (RBD) of S gene, which is adjacent to the aforementioned D614G mutation residue. This specific sequence data demonstrated the active progression of SARS-CoV2 by mutations in the RBD of S gene.The sequence information of new mutations is critical to the development of recombinant SARS-CoV2 spike antigens, which may be required to improve and advance the strategy against a wide range of possible SARS-CoV2 mutations.

Neutrophilic granule protein (NGP) was previously reported as a granular protein of neutrophils in mouse, but the function has not been known clearly. We found the presence of the possible signal peptide in NGP and validated this protein is circulating in the bloodstream. In our findings, NGP is being modified post-translationally in Golgi apparatus and endoplasmic reticulum, which is a universal character of secretory molecules with a signal peptide. The secreted NGP protein could be detected both in vitro and in vivo. NGP has sequence similarity with an antimicrobial protein cathelicidin, and we observed the aspect of inflammation of NGP. Interestingly, NGP interacts with the complex of LPS and LPS binding protein (LBP). This interaction blocks the binding of the complex of LPS and LBP to TLR4 and the downstream inflammatory signals. Furthermore, the inhibitory function of NGP against the inflammatory effect of LPS could be observed in both in vitro and in vivo. With these findings, we report NGP is a novel secretory protein to mask LPS and inhibit its function.
Animals ; Carrier Proteins ; Cytokines ; Endoplasmic Reticulum ; Golgi Apparatus ; In Vitro Techniques ; Inflammation ; Lipopolysaccharides ; Masks ; Mice ; Neutrophils ; Protein Binding ; Protein Sorting Signals

PURPOSE: Transduodenal ampullectomy (TDA) has been reported in a limited number of cases and in a small number of case series. The aim of this study was to analyze perioperative and long-term oncological outcomes of patients with ampullary tumors who underwent TDA in a single large-volume center. METHODS: Through a retrospective review of data from 2004 to 2016, we identified 26 patients who underwent TDA at Asan Medical Center. RESULTS: Eleven of 26 patients underwent TDA for T1 and carcinoma in situ (high-grade dysplasia) cancer; these patients are still alive without recurrence. A major in-hospital complication (3.8%) occurred in 1 case, but there was no case of 90-day mortality. In addition, none of the patients was diagnosed as having newly developed diabetes mellitus after TDA. No significant differences were found between open and laparoscopic-TDA in terms of operation time, painkiller use, and hospital stay. CONCLUSION: TDA is a feasible and effective surgical procedure for the treatment of selected patients with ampullary tumors. It is an alternative treatment option in cases of ampullary tumors not amenable to endoscopic papillectomy or pancreaticoduodenectomy.
Ampulla of Vater ; Carcinoma in Situ ; Chungcheongnam-do ; Diabetes Mellitus ; Humans ; Length of Stay ; Mortality ; Pancreaticoduodenectomy ; Recurrence ; Retrospective Studies

PURPOSE: The preoperative diagnosis of acute appendicitis is often challenging. Sometimes, pathologic results of the appendix embarrass or confuse surgeons. Therefore, more and more imaging studies are being performed to increase the accuracy of appendicitis diagnoses preoperatively. However, data on the effect of this increase in preoperative imaging studies on diagnostic accuracy are limited. We performed this study to explore unexpected appendiceal pathologies and to delineate the role of preoperative imaging studies in the diagnosis of acute appendicitis. METHODS: The medical records of 4,673 patients who underwent an appendectomy for assumed appendicitis between 1997 and 2012 were reviewed retrospectively. Pathological results and preoperative imaging studies were surveyed, and the frequencies of pathological results and preoperative imaging studies were investigated. RESULTS: The overall rate of pathology compatible with acute appendicitis was 84.4%. Unexpected pathological findings, such as normal histology, specific inflammations other than acute appendicitis, neoplastic lesions, and other pathologies, comprised 9.6%, 3.3%, 1.2%, and 1.5%, respectively. The rate of unexpected pathological results was significantly reduced because of the increase in preoperative imaging studies. The decrease in normal appendices contributed the most to the reduction while other unexpected pathologies did not change significantly despite the increased use of imaging studies. This decrease in normal appendices was significant in both male and female patients under the age of 60 years, but the differences in females were more prominent. CONCLUSION: Unexpected appendiceal pathologies comprised 15.6% of the cases. Preoperative imaging studies reduced them by decreasing the negative appendectomy rate of patients with normal appendices.
Appendectomy ; Appendicitis ; Appendix ; Diagnosis ; Female ; Humans ; Inflammation ; Male ; Medical Records ; Pathology* ; Retrospective Studies ; Surgeons