• 한국임상약학회지
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• 제16권1호
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• pp.23-27
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• 2006

Doxorubicin (DXR) is a type of anti-cancer drug called an 'anthracycline glycoside', It works by impairing DNA synthesis, a crucial feature of cell division, and thus is able to target rapidly dividing cells. Doxorubicin is a very serious anti-cancer medication with definite potential to do great harm as well as great good. A liquid chromatography-tandem mass spectroscopy (LC-MS/MS) method was developed to identify and quantify DXR in small-volume biological samples. After the addition of internal standard (IS, $5{\mu}L\;of\;1{\mu}M/ml$ daunorubicin methanol solution) into the serum sample, the drug and IS were extracted by methanol. Following vortex for a 1min and centrifugation at 15,000g for 10 min the organic phase was transferred and evaporated under a vacuum. The residue was reconstituted with $350{\mu}L$ of mobile phase and $10{\mu}L$ was injected into C18 column with mobile phase composed of 0.05M ammonium acetate (0.1 M acetic acid adjusted to pH 3.5) and acetonitrile (40:60, v/v). The flow rate was kept constant at $350{\mu}L/min$. The ions were quantified in the multiple reaction mode (MRM), using positive ions, on a triple quadrupole mass spectrometer. The lower limits of quantification for Doxorubicin in plasma and small tissues were approximately 0.5 ng/mL and 0.5 ng/mL respectively. Intra- and inter-assay accuracy (% of nominal concentration) and precision (% CV) for all analytes were within 15%, respectively.

• Journal of Gastric Cancer
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• 제8권2호
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• pp.57-64
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• 2008

현재 국소 위암에서 유일한 완치적 치료법은 수술적 절제이나 적절한 수술적 치료에도 불구하고 상당 수의 환자들이 재발을 경험한다. 이에 다학제적 병용 치료 전략에 대해 많은 관심이 있어왔고 특히 최근에는 암의 병기 감소, 근치적 절제률의 증가, 미세 원격전이의 조기 치료 등의 가능성을 가지는 수술 전 선행항암화학요법에 대한 관심이 증대되고 있다. 최근의 3상 임상 연구인 MAGIC trial은 수술 전후 항암화학요법이, 수술 단독에 비해, 병리학적 병기를 감소시키며 국소 재발과 원격 전이를 감소시켜 생존율을 향상시킴을 보고하였고 또 다른 3상 연구인 FNLCC 94012/FFCD 9703 trial 역시, 수술 전후 항암화학요법이 근치적 절제율과 생존율을 향상시킴을 보고하였다. 두 연구는 수술 전후 항암화학요법에 대한 것이지만 수술 후 보조항암화학요법의 불량한 치료 순응도에 비추어 볼 때 치료성적의 향상은 주로 수술 전 선행항암화학요법에 기인하는 것으로 생각된다. 상기 연구들이 이루어진 서양과 달리 광범위(D2) 림프절 절제술을 표준적 치료로 시행하고 있는 한국의 현실에서 이들 연구결과를 그대로 적용하기에는 어려움이 있으나 한국에서 이루어진, 국소 진행성 위암 환자를 대상으로 한 몇 가지 임상 연구 역시 선행항암화학요법을 통한 근치적 절제률의 증가 및 병기 감소 효과를 시사하였다. 이러한 고무적인 치료 성적에 근거하여 향후 수술 전 또는 수술 전후 항암화학요법이 국소 위암에서 표준적인 치료 전략으로 자리잡을 수 있을 지 결론을 짓기 위해서는 대규모 임상 연구가 시행되어야 할 것이다.

• Journal of Ginseng Research
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• 제43권4호
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• pp.539-549
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• 2019

Background: 20(S)-Protopanaxadiol (PPD), the aglycone part of 20(S)-protopanaxadiol ginsenosides, possesses antidepressant activity among many other pharmacological activities. It is currently undergoing clinical trial in China as an antidepressant. Methods: In this study, an ultra-performance liquid chromatography coupled with triple quadrupole time-of-flight mass tandem mass spectrometry method was established to identify the metabolites of PPD in human plasma and urine following oral administration in phase IIa clinical trial. Results: A total of 40 metabolites in human plasma and urine were identified using this method. Four metabolites identified were isolated from rat feces, and two of them were analyzed by NMR to elucidate the exact structures. The structures of isolated compounds were confirmed as (20S,24S)-epoxydammarane-12,23,25-triol-3-one and (20S,24S)-epoxydammarane-3,12,23,25-tetrol. Both compounds were found as metabolites in human for the first time. Upon comparing our findings with the findings of the in vitro study of PPD metabolism in human liver microsomes and human hepatocytes, metabolites with m/z 475.3783 and phase II metabolites were not found in our study whereas metabolites with m/z 505.3530, 523.3641, and 525.3788 were exclusively detected in our experiments. Conclusion: The metabolites identified using ultra-performance liquid chromatography coupled with triple quadrupole time-of-flight mass spectrometry in our study were mostly hydroxylated metabolites. This indicated that PPD was metabolized in human body mainly through phase I hepatic metabolism. The main metabolites are in 20,24-oxide form with multiple hydroxylation sites. Finally, the metabolic pathways of PPD in vivo (human) were proposed based on structural analysis.

• Journal of Gastric Cancer
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• 제19권1호
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• pp.102-110
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• 2019

Purpose: Despite an increased acceptance of laparoscopic gastrectomy (LG) in early gastric cancer (EGC), there is insufficient evidence for its oncological safety in advanced gastric cancer (AGC). This is a prospective phase II clinical trial to evaluate the feasibility of LG with D2 lymph node dissection (LND) in AGC. Materials and Methods: The primary endpoint was set as 3-year disease-free survival (DFS). The eligibility criteria were as follows: 20-80 years of age, cT2N0-cT4aN3, American Society of Anesthesiologists score of 3 or less, and no other malignancy. Patients were enrolled in this single-arm study between November 2008 and May 2012. Exclusion criteria included cT4b or M1, or having final pathologic results as EGC. All patients underwent D2 lymphadenectomy. Three-year DFS rates were estimated by the Kaplan-Meier method. Results: A total of 157 patients were enrolled. The overall local complication rate was 10.2%. Conversion to open surgery occurred in 11 patients (7.0%). The mean follow-up period was $55.0{\pm}20.4months$ (1-81 months). The cumulative 3-year DFS rates were 76.3% for all stages, and 100%, 89.3%, 100%, 88.0%, 71.4%, and 35.3% for stage IB, IIA, IIB, IIIA, IIIB, and IIIC, respectively. Recurrence was observed in 37 patients (23.6%), including hematogenous (n=6), peritoneal (n=13), locoregional (n=1), distant node (n=8), and mixed recurrence (n=9). Conclusions: In addition to being technically feasible for treatment of AGC in terms of morbidity, LG with D2 LND for locally advanced gastric cancer showed acceptable 3-year DFS outcomes.

• Korean Journal of Radiology
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• 제21권1호
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• pp.68-76
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• 2020

Objective: To survey care providers' willingness to use 2-mSv computed tomography (CT) in their usual practice for adolescents and young adults with suspected appendicitis. Materials and Methods: An ethical committee approved this prospective study. We introduced 2-mSv CT in 20 hospitals through a pragmatic clinical trial. At the final phase of the trial, we invited 698 potentially-involved care providers in the survey regarding their willingness to use 2-mSv CT. Multivariable logistic regression analyses were performed to identify factors associated with willingness. Nine months after the completion of the trial patient recruitment, we surveyed whether the hospitals were using 2-mSv CT in usual practice. Results: The analyses included responses from 579 participants (203 attendings and 376 trainees; 221 radiologists, 196 emergency physicians, and 162 surgeons). Regarding the willingness to immediately change their standard practice to 2-mSv CT, 158 (27.3%), 375 (64.8%), and 46 (7.9%) participants responded as "yes" (consistently), "partly" (selectively), and "no", respectively. Willingness varied considerably across the hospitals, but only slightly across the participants' departments or job titles. Willingness was significantly associated with attendings (p = 0.004), intention to maintain the dedicated appendiceal CT protocol (p < 0.001), belief in compelling evidence on the carcinogenic risk of conventional-dose CT radiation (p = 0.028), and hospitals having more than 1000 beds (p = 0.031). Fourteen of the 20 hospitals kept using 2-mSv appendiceal CT in usual practice after the trial. Conclusion: Despite the extensive efforts over the years of this clinical trial, many care providers were willing to use 2-mSv CT selectively or not willing to use.

• Journal of Pharmaceutical Investigation
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• 제36권2호
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• pp.89-95
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• 2006

A selective and sensitive reversed-phase HPLC method for the determination of pentoxifylline in human serum was developed, validated, and applied to the pharmacokinetic study of pentoxifylline. Pentoxifylline and internal standard, chloramphenicol, were extracted from the serum by liquid-liquid extraction with dichloromethane and analyzed on a Luna CI8(2) column with the mobile phase of acetonitrile-0.034 M phosphoric acid (25:75, v/v, adjusted to pH 4.0 with 10 M NaOH). Detection wavelength of 273 nm and flow rate of 0.8 mL/min were used. This method showed linear response over the concentration range of 10-500 ng/mL with correlation coefficients greater than 0.999. The lower limit of quantification using 0.5 mL of the serum was 10 ng/mL, which was sensitive enough for pharmacokinetic studies of pentoxifylline. The overall accuracy of the quality control samples ranged from 89.3 to 92.7% for pentoxifylline with overall precision (% C.V.) being 4.1-9.2%. The relative mean recovery of pentoxifylline for human serum was 105.8%. Stability (stock solution, short and long-term) studies showed that pentoxifylline was not stable during storage. But three freeze-thaw cycles and extracted serum samples were stable. This method showed good ruggedness (within 15% C.V.) and was successfully applied for the analysis of pentoxifylline in human serum samples for the pharmacokinetic studies of orally administered $Trental^{\circledR}$ tablet (400 mg pentoxifylline), demonstrating the suitability of the method.

• Asian Pacific Journal of Cancer Prevention
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• 제16권17호
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• pp.7441-7447
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• 2015

Objective: This study evaluated the safety and objective response of combining $^{131}I$-labeled-metuximab (Licartin) with transarterial chemoembolization (TACE) in the treatment of unresectable hepatocellular carcinoma (HCC). Materials and Methods: In a multicenter open-label clinical trial, 341 enrolled patients with stage III/IV HCC according to TNM criteria were nonrandomly assigned to a trial group (n=167) and a control group (n=174), undergoing TACE following hepatic intra-arterial injection of licartin or TACE alone from July 2007 to July 2009. Radiopharmaceutical distribution was evaluated. The primary endpoint was overall survival; secondary endpoints included time-to-progression (TTP), toxicity and adverse events (AEs). Results: The radiobiological distribution demonstrated better localization of licartin in liver tumors than other tissues (P<0.01). The organ absorbed doses to liver and red marrow were $3.19{\pm}1.01Gy$ and $0.55{\pm}0.22Gy$, respectively. The 1-year survival rate was significantly higher [79.47% vs. 65.59%, hazard ratio (HR), 0.598, P=0.041] and TTP significantly improved ($6.82{\pm}1.28$ vs. $4.7{\pm}1.14months$, P=0.037) compared with the control group. Patients at stage III achieved more benefit of one year survival than stage IV in the trial group (86.9% vs. 53.8%, P<0.001). There were significant different toxicities in leukocytopenia, thrombocytopenia and increased total bilirubin level [P<0.001, P=0.013, P<0.01, relative risk (RR) 1.63, 1.33, 1.43], but no differences in severe AEs of upper GI hemorrhage and severe liver dysfunction between the groups (5.39% vs. 2.3%, P=0.136). Conclusions: Owing to excellent tumor-targeting, promised efficacy and favourable toxicity profile, the novel combination therapy of licartin and TACE could be applied in patients with unresectable HCC.

• Journal of Veterinary Science
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• 제22권6호
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• pp.78.1-78.10
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• 2021

Background: Recurrent subclinical mastitis (RScM) due to resistant bacteria has low clinical and bacteriological cure rates, often requiring the culling of cows. The sequential intramammary administration of enrofloxacin hydrochloride-dihydrate (enro-C) followed by ceftiofur HCl may be useful for treating these cases. Objectives: This study assessed the bacteriological and clinical cure-efficacies of the sequentially intramammary administration of enro-C, followed by ceftiofur HCl to treat RScM in Holstein/Friesian cows. Methods: This trial was conducted in a herd with a high prevalence of RScM, and 20 Holstein/Friesian cows were included: 45% suffering subclinical mastitis and 38.9% of the mammary quarters affected. Twenty-nine bacterial isolates in vitro resistant to enro-C were obtained (coagulase-negative Staphylococcus spp, 55.2%; Staphylococcus aureus, 27.6%; Escherichia coli, 6.9%; Streptococcus uberis, 6.9%; Corynebacterium bovis, 3.4%). Polymerase chain reaction-isolated the following genes linked to enro-C resistance: chromosomal (gyrA) and plasmid (aac(6')-lb-cr). The treatments were as follows: twice-daily intramammary infusions of enro-C (300 mg/10 mL) for 5 days. Cows clinically considered treatment failures were also treated with intramammary ceftiofur (125 mg/10 mL, twice daily for 5 days. The clinical and bacteriological cure rates were carried out when completing each treatment phase and at 14 and 21 days, aided by a California mastitis test, somatic cell count, and failure to identify the initially causative bacteria. Results: Enro-C achieved 65% clinical and bacteriological cure rates, and 100% cure rates were obtained after the rescue treatment with ceftiofur HCl. Conclusions: Outstanding clinical and bacteriological cure rates in cows affected by RScM were achieved with the consecutive intramammary infusions of enro-C, followed by ceftiofur HCl.

• The Korean Journal of Physiology and Pharmacology
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• 제20권1호
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• pp.63-67
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• 2016

Severe graft-versus-host disease (GVHD) is an often lethal complication of allogeneic hematopoietic stem cell transplantation (HSCT). The safety of clinical-grade mesenchymal stem cells (MSCs) has been validated, but mixed results have been obtained due to heterogeneity of the MSCs. In this phase I study, the safety of bone marrow-derived homogeneous clonal MSCs (cMSCs) isolated by a new subfractionation culturing method was evaluated. cMSCs were produced in a GMP facility and intravenously administered to patients who had refractory GVHD to standard treatment resulting after allogeneic HSCT for hematologic malignancies. After administration of a single dose ($1{\times}10^6cells/kg$), 11 patients were evaluated for cMSC treatment safety and efficacy. During the trial, nine patients had 85 total adverse events and the rate of serious adverse events was 27.3% (3/11 patients). The only one adverse drug reaction related to cMSC administration was grade 2 myalgia in one patient. Treatment response was observed in four patients: one with acute GVHD (partial response) and three with chronic GVHD. The other chronic patients maintained stable disease during the observation period. This study demonstrates single cMSC infusion to have an acceptable safety profile and promising efficacy, suggesting that we can proceed with the next stage of the clinical trial.

• 비만대사연구학술지
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• 제1권1호
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• pp.4-13
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• 2022

Currently, pharmacotherapy is becoming essential for obesity, owing to its expanding and increasing epidemiology. In this review, novel peptide-based drugs of four classes are covered: GLP-1 receptor agonist, GIP/GLP-1 receptor dual agonist, glucagon/GLP-1 receptor dual agonist, and a combination of amylin receptor agonist/GLP-1 receptor agonist. Semaglutide is a next-generation GLP-1 receptor agonist with a longer duration and stronger weight and glucose reduction effects than liraglutide and dulaglutide. In the STEP1 trial, semaglutide 2.4 mg reduced body weight by approximately 15% in people with obesity with similar or milder adverse events than liraglutide 3.0 mg. Tirzepatide, a GIP/GLP-1 receptor dual agonist, also has a long duration and strong weight- and glucose-lowering effect. According to SURPASS-2, 3, and 4, in patients with BMI≥25 kg/m² and type 2 diabetes mellitus (T2DM), tirzepatide 15 mg reduced the initial body weight by >13%. Cotadutide, a glucagon/GLP-1 receptor dual agonist, showed weaker weight-lowering effects than semaglutide and tirzepatide, while it was comparable to that of liraglutide in a phase 2 clinical trial for non-alcoholic fatty liver disease in patients with BMI≥25 kg/m² and T2DM. Additionally, its effect on the liver was noticeable. The long-acting amylin receptor agonist cargrilintide combined with semaglutide can be another effective option for obesity treatment. Even in a small phase 1 trial with a short study period of 20 weeks, cargrilintide 2.4 mg/semaglutide 2.4 mg reduced by 17% of initial body weight in people with BMI 27-39.9 kg/m². In coming several years, semaglutide, tirzepatide, and cargrilintide/semaglutide will become available for obesity treatment in Korea.