Simultaneous quantitative determination of 19 new psychoactive substances in human plasma and metabolic profiles of 25N-NBOMe and 25E-NBOMe in human liver microsomes

According to the World Drug Report 2018, hundreds of new psychoactive substances (NPS) have been synthesized and added to the established synthetic drug market for amphetamine-type substances. Health care provider and scientist on responding to NPS has posed a major challenge to drug policy. The purpose of this study is for simultaneous quantitative analytic method of 19 hallucinogenic NPS derivatives in human plasma using liquid chromatography tandem mass spectrometry. In addition, metabolic profile determination of 2-(2,5-Dimethoxy-4-nitrophenyl)-N-(2-methoxybenzyl)ethanamine(25N-NBOMe) and 2-(4-ethyl-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25E-NBOMe) in human liver microsomes by liquid chromatography-quadrupole time-of-flight mass spectrometry was performed. To determine simultaneous quantitative analysis of 19 NPS(25H-NBOMe, 25B-NBF, 25CNBOH, 25C-NBF, 25I-NBF, 25I-NBOH, 25B-NBOMe, 25N-NBOMe, 25E-NBOMe, 4-methyl-2, 5,beta-trimethoxyphen-ethylamine known as BOD, Methallylescaline, Allylescaline, Flubromazepam, piperidine-based Desoxypipradol also known as 2-DPMP, Mexedrone of Methcathinone class, Synthacaine of synthetic cocaine, 2-MeO-diphenidine of diarylalkylamine class, ORG27569 of synthetic cannabinoids and W-18), human plasma samples were pre-treated using solid-phase extraction. Separation was achieved on a C18 column under gradient elution using a mobile phase containing 0.1% formic acid in acetonitrile and 0.1% formic acid in water at a flow rate of 0.3mL/min. Mass detection was performed in the positive ion mode using multiple reaction monitoring. The calibration range was 1 to 100ng/mL for all quantitative analytes, with a correlation coefficient greater than 0.99. The intra- and inter-day precision and accuracy varied from 0.85 to 12.70% and from 92.65 to 110.97%, respectively. The recovery ranged from 14.63 to 117.40%, and the matrix effects ranged from 54.03 to 118.52%. The stability was acceptable in various conditions. The LC-MS/MS method was validated for linearity, accuracy, precision, matrix effects, recovery and stability in accordance with the FDA guidance. In addition, the in vitro metabolism of 25N-NBOMe and 25E-NBOMe were investigated with human liver microsomes, and the reaction mixture was analyzed using liquid chromatography-quadrupole time-of-flight mass spectrometry(LC-Q-TOF/MS). Formation of 14 metabolites(M1-M14) of 25N-NBOMe and 22 metabolites(M1-M22) of 25E-NBOMe were yielded with incubation of 25N-NBOMe and 25E-NBOMe in human liver microsomes in the presence of NADPH, respectively. The metabolic profiles of 25N-NBOMe and 25E-NBOMe were structurally determined on the basis of the MS/MS fragmentation patterns. The biotransformations included hydroxylation, O-demethylation, N-dealkylation, nitro reduction, dehydrogenation carbonylation, and combinations thereof. Hydroxyl metabolite was the most abundant compound after the phase I process. It is considered that these results of simultaneous quantitative determination of 19 NPS and metabolic profile of 25N-NBOMe and 25E-NBOMe will be globally helpful information to health care provider as well as scientists in drug enforcement agencies.;신종 마약류의 경우 중독성, 환각 증세, 공격성 있는 물질이 대부분으로 최근 페이스북, 소셜 네트워크 서비스 등 인터넷을 통한 개인적구매가 손쉬워지면서 오남용 사례들이 급증하고 있다. 이로 인한 심각한 범죄가 증가함에 따라 사회적 문제를 예방하고 확산방지를 위해 과학적 근거 제공이 절실히 요구되고 있다. 이에 본 연구에서는 19종 신종마약류, 25H-NBOMe, 25B-NBF, 25CNBOH, 25C-NBF, 25I-NBF, 25I-NBOH, 25B-NBOMe, 25N-NBOMe, 25E-NBOMe, BOD, Methallylescaline, Allylescaline, 2-DPMP, Mexedrone, Synthacaine, 2-MeO-diphenidine, ORG27569, W-18 및 Flubromazepam을 동시에 분석할 수 있는 분석법 및 25N-NBOMe와 25E-NBOMe의 대사체 규명하였다. 생체시료인 혈장에서 신종 마약류 19종에 대한 동시분석법을 확립하고자 직선성, 정확성, 정밀성, 안정성 조건을 확립하였다. 이 중 신종마약류 2종, 25N-NBOMe, 25E-NBOMe에 대해서는 사람 간 소포체를 이용해 대사시킨 후 각 대사반응물의 LC-HRMS 분석조건을 확립하고 accurate mass 측정한 후 대사경로 및 대사체를 확인한 결과, 조사된 대사체로는 25N-NBOMe의 경우는 N-dealkylation, O-demethyl-ation, hydroxylation, desaturation, carbonylation, nitro reduction 이며, 25E-NBOMe의 경우는 N-dealkylation, O-demethylation, desaturation, hydroxylation, di-hydroxylation 과정을 통해 대사됨을 알 수 있었다. 이러한 연구결과는 실제 신종 마약 검출을 위해 활용될 수 있을 뿐만 아니라 비슷한 구조의 신종 마약 검출법 개발에 활용 가능한바 마약류 단속을 실행하는 정부 행정기관 및 연구 전문가에게 유익한 새로운 정보로 제공 될 수 있을 것으로 사료된다.Ⅰ. Introduction 1 Ⅱ. Materials and Methods 4 A. Determination of simultaneous analytical method applied to matrix that contains 19 types of new psychotic substances(NPS) including amphetamines 4 B. Metabolic profile determination of 25N-NBOMe and 25E-NBOMe 16 Ⅲ. Results 21 A. Determination of simultaneous analytical method applied to matrix that contains 19 types of NPS including amphetamines 21 B. Metabolic profile determination of 25N-NBOMe and 25E-NBOMe 45 Ⅳ. Discussion 104 A. Determination of simultaneous analytical method applied to matrix that contains 19 types of NPS including amphetamines 104 B. Metabolic profile determination of 25N-NBOMe and 25E-NBOMe 107 Ⅴ. References 110 ABSTRACT(in Korean) 11

Irreducible characters of a group arising from a study of the fractional quantum hall effect

Thesis (master`s)--서울대학교 대학원 :수학과,1996.Maste

의학유전학 전문인력 교육프로그램의 개발과 인증에 관한 연구

Purpose : This Study was Undertaken to Provide Prerequisites for accreditation of medical genetics training program and certification plocess for medical genetics professionals as clinical specialist and set up guidelines on curriculum of medical genetics training Program in Korea. Methods : Six ad hoc committees for clinical geneticist, clinical cytogeneticist, clinical molecular geneticist, clinical biochemical geneticist, medical genetics technologists and genetic counselors were organized for reviewing current status in Korea as well as foreign countries. Each committee is composed of 6-8 mombers. They summarized their opinions according to the structured questionnaire inquiring the ways of accrediting training program, qualification of program director, trainee requirements, contents of curriculurn, duration of training Program, certification Process, estimation of numbers of each specialist needed in next 5 years in Korea. Results : Both prerequisites for the accreditation of medical geneticist training institutions and qualifica-tion of program director are suggested. Candidacy of trainees requires MD with board of medical specialty, or PhD degree with professional experiences in related field except clinical genetics program which only accepts MD with board of medical specialty, and Non-MD genetic counselor and medical technologists with degrees of BS or MS. General duration of fellowship will be 2-3 years depending on the cafegories they are enrolled into. Contents of curriculum for each specialty training are described. For the certification of each category, the candidacy should submit a log book detailing the cases they experienced during the fellowship, prove that they successfully completed course work and clinical experiences in the accredited program, and pass the written examination. Conclusion : As medical genetics becomes more important in daily routine clinical practice, the accreditation of medical genetics training program and certification of personnel are urgently needed. In thisregard, the study wil1 be providing guidelines and prerequisites for accreditation of medical genetics training program and certification process for medical genetics professionals as clinical specialist

Fabrication Process of a Nano-precision Polydimethylsiloxane Replica using Vacuum Pressure-Difference Technique

본 연구는 나노 복화공정을 이용하여 마이크로 혹은 나노공정에 응용이 가능한 형상모형 제작공정 개발과 폴리디메틸실록산 (polydimethylsiloxane)를 이용하여 만들어진 형상모형의 몰드로 나노급 정밀도의 폴리디메틸실록산 형상을 복제하는 공정에 관한 것이다. 본 연구에서 제안한 나노 복화공정은 복잡한 형상모형 (pattern)이나 2차원 형상을 CAD 파일 없이 비트맵 그림파일을 이용하여 직접적으로 200 nm 정밀도를 가지는 형상으로 만들 수 있다. 형상모형은 펨토초 레이저를 이용하여 이광자 흡수 중합법으로 제작하기 때문에 형상의 정밀도는 레이저 빔의 회절한계 이하로 얻을 수 있다. 이렇게 제작된 마스터 형상모형은 본 연구에서 제안한 진공압력차이법으로 폴리디메틸실록산 몰드를 제작하여 기존의 제작방법에 비하여 정밀한 제작이 가능함을 보였으며 또한 제작된 몰드를 이용하여 양각의 폴리디메틸실록산 스탬프를 제작하였다.A vacuum pressure-difference technique for making a nano-precision replica is investigated for various applications. Master patterns for replication were fabricated using a nano-replication printing (nRP) process. In the nRP process, any picture and pattern can be replicated from a bitmap figure file in the range of several micrometers with resolution of 200 nm. A liquid-state monomer is solidified by two-photon absorption (TPA) induced by a femto-second laser according to a voxel matrix scanning. After polymerization, the remaining monomers were removed simply by using ethanol droplets. And then, a gold metal layer of about 30 nm thickness was deposited on the fabricated master patterns prior to polydimethylsiloxane molding for preventing bonding between the master and the polydimethylsiloxane mold. A few gold particles attached on the polydimethylsiloxane stamp during detaching process were removed by a gold selecting etchant. After fabricating the polydimethylsiloxane mold, a nano-precision polydimethylsiloxane replica was reproduced. More precise replica was produced by the vacuum pressure-difference technique that is proposed in this paper. Through this study, direct patterning on a glass plate, replicating a polydimethylsiloxane mold, and reproducing polydimethylsiloxane replica are demonstrated with a vacuum pressure-difference technique for various micro/nano-applications

Development of Large-area Two-photon Stereolithography Process for the Fabrication of Large Three-dimensional Microstructures

Two-photon stereo lithography is recognized as a promising process for the fabrication of three-dimensional (3D) microstructures with 100 ㎚ resolution. Generally, beam-scanning system has been used in the conventional process of two-photon stereo lithography, which is limited to the fabrication of micro-prototypes in small area of several tens micrometers. For the applications to 3D high-functional micro-devices, the fabrication area of the process is required to be enlarged. In this paper, large-area two-photon stereo lithography (L-TPS) employing stage scanning system has been developed. Continuous scanning method is suggested to improve the fabrication speed and parameter study is conducted. An objective lens of high numerical aperture (N.A.) and high strength material were employed in this system. Through this work, 3D microstructures of 600*600* 100 ㎛ were fabricated

국내 소아에서의 과민성방광 유병률 및 위험인자: 정의에 따른 비교분석

Purpose: We wanted to estimate the prevalence and risk factors of overactive bladder(OAB) in Korean children who were 5-13 years of age, according to the definition of OAB. Materials and Methods: A randomly selected cross-sectional study was conducted on 26 kindergartens and 27 elementary schools nationwide in Korea. There were 19,240 children; a parent was asked to complete the questionnaires, which included items about OAB and the children’s voiding and defecating habits. OAB was defined as urgency with or without urge incontinence, and usually with an increased daytime frequency and nocturia(ICCS 2006, group A) or an increased daytime frequency(＞8 times/day) and/or urge urinary incontinence with or without urgency (group B); its prevalence and associated factors were investigated. Results: The response rate for the questionnaires was 85.84%. The overall prevalence of OAB was 16.59%(group A) and 18.79%(group B). For groups A and B, the prevalence of OAB decreased with age from 22.89% to 12.16% and from 40.44% to 9.60%, respectively(p=0.0001). The overall rate of wet and dry OAB was 26.97% and 73.03%, respectively. Compared to the normal group, the children with OAB had a higher prevalence of nocturnal enuresis(NE), constipation, fecal incontinence, a history of urinary tract infection and delayed bladder control in both groups A and B(p＜0.05). The rate of increased daytime frequency and urge incontinence were 3.69% and 2.31%(p=0.009), and 26.97% and 14.78%(p=0.0001) in group A and for the non-OAB children, respectively; their prevalence in group A decreased with age from 5.04% to 3.06% and from 45.74% to 18.50%, respectively(p=0.0001). Conclusions: The overall prevalence of OAB in group A for Korean children 5-13 years of age was similar to that in group B. However, the range of prevalence in group B was much more variable than that in group A. NE, constipation, fecal incontinence, a history of urinary tract infection and delayed bladder control may be risk factors for OAB in children

한국 주요정신장애의 유병률 및 관련요인：2006 전국정신질환역학조사

Objectives: The aims of this study are to estimate the prevalence of the DSM-IV psychiatric disorders in the Korean population using the Korean version of Composite International Diagnostic Interview (K-CIDI), and to compare those with previous studies. Methods: The Korean Epidemiologic Catchment Area study Replication (KECA-R) was conducted between August 2006 and April 2007. The sampling of the subjects was carried out across 12 catchment areas. A multistage, cluster sampling design was adopted. The target population included all eligible residents aged 18 to 64 years. Face-to-face interviews were conducted with the Korean version of Composite International Diagnostic Interview (K-CIDI) based on the DSM-IV (N=6,510, response rate=81.7%). Results: A total of 6,510 participants completed the interview. The lifetime and 12-month prevalence rates for all types of DSM-IV disorders were 30.0% and 17.3%, respectively. Those of specific disorders were as follows：1) alcohol use disorder, 16.2% and 5.6%；2) nictotine use disorder, 9.0% and 6.0%；3) specific phobia, 3.8% and 3.4%；4) major depressive disorder, 5.6% and 2.5%；and 5) generalized anxiety disorder, 1.6% and 0.8%. Data relating to nicotine and alcohol use disorder revealed a very high male/female ratio. Mood disorder and anxiety disorder were more prevalent among females than males. Conclusion: The prevalence of psychiatric disorders was high. In comparison with other studies, remarkable differences in the distribution of psychiatric disorders across the country and times were observed