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Yesong Shin,1 Chungam Choi,2 Eun Sil Oh,2,3 Choon Ok Kim,2 Kyungsoo Park,1 Min Soo Park2– 4 1Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea; 2Department of Clinical Pharmacology and Clinical Trials Center, Severance Hospital, Yonsei University Health System, Seoul, Korea; 3Department of Pharmaceutical Medicine and Regulatory Science, Graduate Inter Program, Yonsei University College of Medicine, Seoul, Korea; 4Department of Pediatrics, Yonsei University College of Medicine, Seoul, KoreaCorrespondence: Min Soo Park, Department of Clinical Pharmacology, Severance Hospital, Yonsei University Health System, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea, Tel +82-2-2228-0400, Fax +82-31-787-4045, Email minspark@yuhs.acPurpose: Evogliptin (DA-1229) is a novel, potent, and selective dipeptidyl peptidase 4 (DPP-4) inhibitor for treating type 2 diabetes mellitus. This study investigates the effect of rifampicin on evogliptin pharmacokinetics.Patients and Methods: An open-label, crossover, one-sequence study was conducted on 12 healthy subjects. Reference baseline pharmacokinetic samples were collected on day 1 after the subjects were administered a single dose of 5 mg evogliptin. After a washout period, the subjects were administered 600 mg rifampicin once daily for 10 days, from days 8 to 17, for full induction of hepatic enzyme activity. On day 17, single doses of evogliptin (5 mg) were administered along with rifampicin (600 mg). The test pharmacokinetic samples were collected with a sampling schedule identical to that used for the reference.Results: Maximum concentration (Cmax) and area under the plasma drug concentration-time curve (AUC0-96h) of evogliptin with and without co-administration of rifampicin were compared. Reference and test Cmax and AUC0-96h values of evogliptin were 4.70 ng/mL vs 4.86 ng/mL and 153.97 ng∙h/mL vs 58.83 ng∙h/mL, respectively. All adverse events were mild in intensity and considered unrelated to evogliptin administration.Conclusion: Rifampicin decreased the AUC0-96h of evogliptin by 61.8% without significantly affecting Cmax. The mechanism underlying the decrease in AUC0-96h is thought to be the induction of cytochrome P450 (CYP), especially 3A, by rifampicin. The adverse events, none of which were serious, were not significantly altered by the concomitant administration of evogliptin and rifampicin. Nevertheless, it would be prudent that evogliptin dosing should be carefully considered when co-administered with CYP3A inducers.Keywords: drug–drug interaction, DPP-4 inhibitor, CYP3A inducer, evogliptin, rifampicin

Jake A Rice,1,2 Jonathan Brewer,2 Tyler Speaks,1 Christopher Choi,1 Peiman Lahsaei,1 Bryan T Romito1 1Department of Anesthesiology and Pain Management, The University of Texas Southwestern Medical Center, Dallas, TX, USA; 2Department of Emergency Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USACorrespondence: Bryan T RomitoDepartment of Anesthesiology and Pain Management, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390-9068, USATel +1 214 648 7674Fax +1 214 648 5461Email Bryan.Romito@UTSouthwestern.eduAbstract: Point of care ultrasound (POCUS) allows for rapid, real-time evaluation of cardiovascular and respiratory pathology. The advent of portable, handheld devices and increased recognition by accrediting bodies of the importance of POCUS in guiding clinical decision making has expanded its use across the hospital setting and within medical training programs. POCUS allows clinicians to begin immediate investigation into their differential diagnoses without waiting for a formal imaging study, enhancing the speed of clinical interpretation. In addition to its diagnostic utility, POCUS can also inform clinicians of patients’ response to interventions when serial exams are obtained. This review examines the role of POCUS in the context of frequently encountered patients and highlights the key clinical questions that can be readily answered by POCUS.Keywords: hemodynamics, trauma, respiratory failure, hypotension

Chungam Choi,1 Byung Won Yoo,2 Choon Ok Kim,2 Taegon Hong,2 Byung Hak Jin,2 Kwang-Seok Seo,3 Ja Yun Jang,4 Min Soo Park2 1Department of Nuclear Medicine, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea; 2Department of Clinical Pharmacology, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea; 3Biopharmaceutical Research Laboratories, Dong-A Socio R&D Center, Yongin-si, Republic of Korea; 4Product Development Division, Dong-A ST Co., Ltd, Seoul, Republic of Korea Purpose: Filgrastim, a granulocyte-colony stimulating factor, is used to treat patients with neutropenia, including neutropenic fever. Leucostim® is a recombinant filgrastim product tested for biosimilarity with its reference product, Neupogen®. We conducted a comparative clinical trial of the 2 products. Patients and methods: A randomized, open-label, 2-way crossover, single-dose Phase I study was conducted for 56 healthy subjects. After a 5 and 10 μg/kg single subcutaneous administration of test and reference product, pharmacokinetic and pharmacodynamic parameters (absolute neutrophil count and CD34+ cell count) were compared. During the study, safety tests and adverse event monitoring were performed. Results: The test and the reference products had a comparable pharmacokinetic, pharmacodynamic, and safety profile. In both 5 and 10 μg/kg dosing, the 90% CIs of the test to reference ratio for primary parameters (peak plasma concentration and area under the plasma concentration vs time curve from time 0 extrapolated to the infinite time for plasma filgrastim concentration; maximal effect and area under the time-effect curve from time 0 to time of the last quantifiable effect for absolute neutrophil count) were within the 0.8–1.25 range. In addition, safety profiles between the 2 products were similar without any serious adverse events. Conclusion: This study has provided firm clinical evidence that the test filgrastim product is similar to its reference filgrastim product. Keywords: bioequivalence, biosimilar, G-CSF, biologics

Yuri An,1 Jong Wook Jeon,2 Kihwan Kwon,3 Chulhee Choi1 1Department of Bio and Brain Engineering, KAIST, Daejeon, South Korea; 2Acupuncture, Moxibustion and Meridian Research Centre, Korea Institute of Oriental Medicine, Daejeon, South Korea; 3Department of Cardiology, College of Medicine, Ewha Womans University, Seoul, Korea Background: Even though acupuncture has long been used for alleviating symptoms related to vascular insufficiency, the clinical effect of acupuncture on peripheral circulation has not been fully confirmed. In this study, we investigated whether a near-infrared optical imaging-based method can be used to evaluate the efficacy of the acupuncture procedure to induce changes in peripheral tissue perfusion. Methods: Two normal, healthy controls were treated with acupuncture on two acupoints (LI-4 and SI-3) three times within 1 week. At the first and third visits, participants were examined using indocyanine green (ICG) perfusion imaging before and 10 minutes after the acupuncture procedure. Blood perfusion of the hands was determined after intravenous bolus injection of ICG and dynamic analysis of the fluorescence signals by near-infrared imaging system. Results: The blood perfusion rates of the hands were markedly increased immediately after acupuncture at the first trial in both cases. The baseline perfusion rates of the hands measured at the third visit were higher compared to the original basal level in one case; there was no difference in baseline perfusion rates of both hands in another case. In both cases, there was no acute effect of acupuncture on hand perfusion at the third trial. Conclusions: These results collectively suggest a potential of the ICG perfusion imaging as an effective evaluation tool to validate the vasoactive effect of acupuncture. Keywords: vasodilation, blood perfusion, imaging, Raynaud syndrome

BackgroundCollaborative data sharing between research groups provides an opportunity to explore the basis for the heterogeneity in cognitive training outcomes reported in the schizophrenia literature. The current analyses focused on the contribution of site and participant characteristics to these heterogeneous outcomes.MethodsData from two independent studies, from New York (NY) and Los Angeles (LA), were combined to yield a sample of 132 outpatient adults with schizophrenia/schizoaffective disorder. While similar treatment doses, cognitive exercises and outcome measures were used, sites differed in use of coaching, group discussion and compensation. Between-site differences in participant demographic and baseline clinical characteristics were tested. Regression examined predictors of change in cognition (MCCB) and functional capacity (UPSA) which could explain site differences in treatment effects.ResultsMedium to large treatment effect size differences in MCCB and UPSA favored the NY site over LA. When the studies were combined, the effect of site was significant for both outcomes with a medium effect size difference. After controlling for background characteristics, the effect of site was reduced for both outcomes, but remained significant for cognition. Improvement in UPSA was associated with better baseline MCCB (p

This study investigates the impact of green trade exports (GTE) on green total factor productivity (GTFP) and environmental sustainability in OECD countries using panel data from 2003 to 2016. We employ linear regression models, polynomial models, and threshold regression techniques to analyze this relationship. Our findings reveal an inverted N-shaped curve between GTE and GTFP, with two turning points. The threshold regression results indicate that when clean energy is below 8.660%, a 1 unit increase in GTE decreases GTFP by 1.518 units. However, when clean energy exceeds this threshold, a 1 unit increase in GTE increases GTFP by 1.056 units. For R&D, the effect of GTE on GTFP changes from −3.165 to 1.193 as R&D exceeds the threshold of 0.664%. Additionally, we find that GTE has a lagged effect on increasing CO2 emissions, with coefficients of 0.0234 and 0.0278 for 1-year and 2-year lags, respectively. The interaction between clean energy and GTE reduces CO2 emissions by 0.00234 units and PM2.5 by 0.0145 units. These results provide important insights for policymakers in developing countries seeking to participate effectively in the global industrial chain while promoting sustainable development. [ABSTRACT FROM AUTHOR]

A long-standing paradigm in astrophysics is that collisions-or mergers-of two neutron stars form highly relativistic and collimated outflows (jets) that power γ-ray bursts of short (less than two seconds) duration. The observational support for this model, however, is only indirect. A hitherto outstanding prediction is that gravitational-wave events from such mergers should be associated with γ-ray bursts, and that a majority of these bursts should be seen off-axis, that is, they should point away from Earth. Here we report the discovery observations of the X-ray counterpart associated with the gravitational-wave event GW170817. Although the electromagnetic counterpart at optical and infrared frequencies is dominated by the radioactive glow (known as a kilonova') from freshly synthesized rapid neutron capture (r-process) material in the merger ejecta, observations at X-ray and, later, radio frequencies are consistent with a short γ-ray burst viewed off-axis. Our detection of X-ray emission at a location coincident with the kilonova transient provides the missing observational link between short γ-ray bursts and gravitational waves from neutron-star mergers, and gives independent confirmation of the collimated nature of the γ-ray-burst emission.

Objective: To determine if treatment of co-occurring adult ADHD and Cannabis Use Disorder (CUD) with extended-release mixed amphetamine salts (MAS-ER) would be effective at improving ADHD symptoms and promoting abstinence. Method: A 12-week randomized, double-blind, two-arm pilot feasibility trial of adults with comorbid ADHD and CUD (n = 28) comparing MAS-ER (80 mg) to placebo. Main outcomes: ADHD: ≥30% symptom reduction, measured by the Adult ADHD Investigator Symptom Rating Scale (AISRS). CUD: Abstinence during last 2 observed weeks of maintenance phase. Results: Overall, medication was well-tolerated. There was no significant difference in ADHD symptom reduction (MAS-ER: 83.3%; placebo: 71.4%; p =.65) or cannabis abstinence (MAS-ER: 15.4%; placebo: 0%; p =.27). MAS-ER group showed a significant decrease in weekly cannabis use days over time compared to placebo (p <.0001). Conclusions: MAS-ER was generally well-tolerated. The small sample size precluded a determination of MAS-ER's superiority reducing ADHD symptoms or promoting abstinence. Notably, MAS-ER significantly reduced weekly days of use over time. [ABSTRACT FROM AUTHOR]

Cannabis Use Disorder (CUD) has no FDA-approved treatment. Serotonin-2c (5HT2c) agonists have preclinical and human laboratory evidence for their potential efficacy for CUD. We assessed the tolerability and effects of lorcaserin (5HT2c agonist) on CUD. In a 10-week, open label, uncontrolled trial, the tolerability of lorcaserin was tested in outpatients with CUD. Adverse events (AE) were assessed weekly. Cannabis use was assessed twice weekly by the Timeline follow-back and quantitative urine metabolites. Seventeen participants enrolled, and 14 received medication. Participants' average age was 35 years; majority were male (N = 12). The medication was well tolerated in males. There were no serious adverse events (SAE). The most common AE's were headache/migraine (N = 4, all females), anorexia (N = 3), and irritability (N = 2). Participants decreased their frequency of cannabis use significantly (p < 0.001), adjusted for baseline use. By the end of the trial, participants decreased by 1.76 (SE = 0.47) cannabis using days/week. Average daily amount of cannabis and urine THC metabolite levels did not change significantly. Lorcaserin was well tolerated in males but not females, suggesting possible sex differences. Future trials of other 5HT2c agonists (lorcaserin was withdrawn at the request of the FDA) should consider longer dose titration phases. [ABSTRACT FROM AUTHOR]