홍합 접착을 모사한 지르코니아용 카테콜 프라이머 연구

학위논문 (박사)-- 서울대학교 대학원 : 치의학대학원 치의과학과, 2019. 2. 안진수.이 연구는 생물모사된 카테콜 프라이머의 지르코니아에 대한 전처리효과를 알아보기 위한 것이다. 실험을 위해 치과용 지르코니아 표면처리에 사용된 것으로 보고된 bifunctional catechol-methacrylate primer를 이용하였다. 이번 연구를 통하여, 카테콜 프라이머를 적용한 경우가 그렇지 않은 경우와 비교했을 때 전단결합강도가 상당히 우수함을 확인할 수 있었다. Triethylsilyl (TES)-protected (or silylated) catechol-methacrylate 은 유지놀로부터 합성하였고 일련의 조절 과정을 거쳤다. 지르코니아 시편은 소결되지 않은 지르코니아 (yttria-stabilized tetragonal zirconia polycrystal) 를 주수 하에 0.15 mm 두께의 다이아몬드 날을 가진 톱으로, 2 mm 두께와 5 mm x 5 mm의 길이와 너비를 갖도록 절삭하여 준비하였다. 그 다음, 시편을 프라이머에 따라 5개 군으로 나누었다 ( Zirconia Liner (ZL), Alloy Primer (AP), Universal Primer (UP), catechol primer (CP), 대조군). 전처리 전 후의 지르코니아 표면을 비교하기 위해 SEM 분석을 진행하였다.전단결합강도실험을 시행하였고 이 결과를 통계적으로 분석하였다.(α = 0.05) 지르코니아 표면에 카테콜 전처리를 한 쪽의 전단결합강도의 평균값과 표준편차가 phosphate와 carboxylate methacrylates를 함유하고 있는 다른 상용 지르코니아 프라이머 보다 높았고, 아무런 전처리를 하지 않은 대조군보다는 3배 높은 수치를 보여주었다. Tukeys test 결과 카테콜 프라이머와 여타 상용 프라이머 사이에 상당한 차이가 있었다 (p < 0.05). 카테콜 프라이머는 다른 프라이머 및 대조군 보다 월등히 높은 전단결합강도 수치를 보였지만, 사후 검정 결과 ZL, AP, UP 사이에는 큰 차이가 없었다. 이번 연구를 통해 생물모사된 카테콜 프라이머는 지르코니아 접착을 위해 현재 널리 사용중인 타 프라이머 대비 우수한 본딩력을 보여주었다. 카테콜 프라이머는 지르코니아에 대한 높은 본딩력을 갖고 있으면서도 그 적용이 어렵지 않기 때문에 지르코니아를 치과영역에서 사용하기 위해 필요한 전처리법을 개발하는 데 있어 좋은 방법이 될 수 있다.The aim of this study is to investigate bioinspired surface priming of catechol to zirconia. In this study, I used a bifunctional catechol-methacrylate primer, that has been reported previously to treat the surface of dental zirconia. Using the catecholic primer, in this study, we demonstrate a significant improvement in the knife shear bond strength compared to untreated surfaces. Triethylsilyl (TES)-protected (or silylated) catechol-methacrylate was synthesized from eugenol and modified. The zirconia specimens were obtained by cutting presintered zirconia frames: yttria-stabilized tetragonal zirconia polycrystal, using a water cooled diamond saw with a 0.15 mm thick diamond blade to 2 mm thickness and 5 mm length x 5 mm width. The specimens were then divided into five groups according to the types of used primers - Zirconia Liner (ZL), Alloy Primer (AP), Universal Primer (UP), fresh Catechol primer in methanol degassed and purged with argon, and control. SEM analysis was conducted for the primed and the non-primed zirconia surfaces. The knife-edge shear bond test was performed. The results were statistically analyzed (α = 0.05). The means, standard deviations of the knife-edge shear bond strengths of catechol primer on zirconia surface was higher than commercial zirconia primers containing phosphate and carboxylate methacrylates (ZL, AP, UP) and three times stronger than the control without any primer. The Tukeys test showed significant differences (p < 0.05) between CP and the each commercial primer. While CP showing significantly higher shear bond strength, the Tukeys post hoc analysis indicated that there was a similarity between ZL, AP, and UP. I have then validated the superior bonding performance of the bioinspired primer to zirconia, compared to several popular commercially available dental zirconia primer. Considering the catecholic primers higher strength and ease of application, this priming strategy is well poised for further development in dental applications requiring bonding to zirconia.Contents 1. Introduction 2. Material and Methods 2.1 Synthesis of Catechol Methacrylate Primer 2.2 Zirconia Specimen 2.3 Surface Treatment 2.4 Surface Morphology 2.5 Shear Bond Strength 2.6 Statistical Analysis 3. Results and Discussion 3.1 Improved Synthesis of Catechol Methacrylate Primer 3.2 Scanning Electron Microscope (SEM) Imaging of Primed Zirconia Surface 3.3 Shear Bond Strength of Dental Adhesives on Bioinspired Catechol Primed Zirconia Surface 4. Conclusions References Korean Abstract AcknowledgementDocto

Pharmacokinetics and safety profiles of tadalafil/tamsulosin HCl fixed-dose combination capsule under fasted and fed condition in healthy volunteers

Co-administration of tadalafil and tamsulosin HCl in patients with benign prostate hyperplasia and erectile dysfunction is increasing in clinical settings. Development of fixed-dose combination (FDC) of tadalafil and tamsulosin HCl could contribute to improving patients’ adherence and treatment efficacy. We evaluated the pharmacokinetics and safety profiles of a newly developed fixed-dose combination capsule of tadalafil 5 mg/tamsulosin HCl 0.4 mg in comparison with co-administration of each formulation in healthy volunteers under fasted and fed conditions. Two randomized, openlabel, single-dose, two-way, crossover studies were completed in 29 subjects under fasted condition, and 33 subjects under fed condition. Serial blood sample collection for PK analysis was conducted up to 72 hours after dosing, and PK parameters were calculated using non-compartmental analysis. Geometric mean ratios and 90% confidence intervals of the Cmax and AUClast were used to evaluate comparative bioavailability. In both fasted and fed condition studies, the bioequivalence was established. The most common adverse drug reactions were orthostatic hypotension and headache with no statistical difference between treatment groups. All subjects with orthostatic hypotension recovered at follow-up test. Although changes in vital signs from baseline were statistically significant, there were no subjects with systolic blood pressure < 90 mmHg and there were no clinically meaningful signs or symptoms associated. FDC of tadalafil and tamsulosin HCl can be an alternative to co-administration of individual drugs for providing better compliance. Changes in blood pressure should be kept in mind when tadalafil and tamsulosin HCl are co-administered in clinical settings.ope

Pharmacokinetic drug interaction between atorvastatin and ezetimibe in healthy Korean volunteers

Atorvastatin and ezetimibe are frequently co-administered to treat patients with dyslipidemia for the purpose of low-density lipoprotein cholesterol control. However, pharmacokinetic (PK) drug interaction between atorvastatin and ezetimibe has not been evaluated in Korean population. The aim of this study was to investigate PK drug interaction between two drugs in healthy Korean volunteers. An open-label, randomized, multiple-dose, three-treatment, three-period, Williams design crossover study was conducted in 36 healthy male subjects. During each period, the subjects received one of the following three treatments for seven days: atorvastatin 40 mg, ezetimibe 10 mg, or a combination of both. Blood samples were collected up to 96 h after dosing, and PK parameters of atorvastatin, 2-hydroxyatorvastatin, total ezetimibe (free ezetimibe + ezetimibe-glucuronide), and free ezetimibe were estimated by non-compartmental analysis in 32 subjects who completed the study. Geometric mean ratios (GMRs) with 90% confidence intervals (CIs) of the maximum plasma concentration (Cmax,ss) and the area under the curve within a dosing interval at steady state (AUCτ,ss) of atorvastatin when administered with and without ezetimibe were 1.1087 (0.9799-1.2544) and 1.1154 (1.0079-1.2344), respectively. The corresponding values for total ezetimibe were 1.0005 (0.9227-1.0849) and 1.0176 (0.9465-1.0941). There was no clinically significant change in safety assessment related to either atorvastatin or ezetimibe. Co-administration of atorvastatin and ezetimibe showed similar PK and safety profile compared with each drug alone. The PK interaction between two drugs was not clinically significant in healthy Korean volunteers.ope

Immune Response to SA14-14-2 Live Attenuated Japanese Encephalitis Vaccine

Purpose : SA14-14-2 live attenuated Japanese encephalitis(JE) vaccine has been administered safely and effectively to more than 100 million children in China since 1988, and recently licensure of the vaccine in Korea has been sought. Immune response to the vaccine was investigated. Methods : In the first clinical evaluation of the vaccine outside of China, we monitored side effects in 93 children and evaluated plaque reduction neutralizing test(PRNT) antibody and IgM antibody responses to a single dose given as primary JE vaccination in 74 children, 1-3 years old (mean age 27 months). Results : No significant adverse events were noted. PRNT antibodies(geometric mean titer [GMT] of 183) were produced in 96% of the 74 subjects. In 10 other children who previously had been immunized with two or three doses of inactivated JE vaccine, the booster administration of SA14-14-2 vaccine produced an anamnestic response in all, with a GMT of 3378. In a comparison group of 25 children previously immunized with two doses of inactivated vaccine, neutralizing antibody titers were detected in 16(64%). Viral specific IgM was detected in nine primary vaccinees(13%) but in others, IgM may have declined to undetectable levels in the four week postimmunization sample. Conclusion : Live attenuated SA14-14-2 JE vaccine is a promising alternative to the only commercially available live attenuated JE vaccine for national childhood immunization programs in Asia. (J Korean Pediatr Soc 1999;43:351-359)ope

Signal Detection of Adverse Events Following Pneumococcal Vaccines from the Korea Adverse Event Reporting System Database, 2005-2016

Purpose: We aimed to analyze the surveillance reports of adverse events (AEs) due to different types of pneumococcal vaccines, in addition to detecting and validating signals of pneumococcal vaccines by comparing AEs with labels. Materials and methods: We analyzed the percentages of AEs according to vaccine type [pneumococcal polysaccharide vaccines (PPSVs) and pneumococcal conjugate vaccines (PCVs)] in children and adults using data from the Korea Adverse Event Reporting System (KAERS) database from 2005 to 2016. A signal was defined as an AE that met all three indices of data mining: proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC). We validated the detected signals by calculating sensitivity, specificity, as well as positive and negative predictive values of the signals against label information. Results: Of the 39933 AE reports on vaccination, 5718 (7.0%) were related to pneumococcal vaccine. The most frequent AE after vaccination with PPSV was fever (23.9%) in children and injection-site reaction in adults. The most frequent AE after vaccination with PCV in children was pharyngitis (26.2%). In total, 13 AEs met all three indices for signal detection. Among these, hypotension, apathy, sepsis, and increased serum glutamic oxaloacetic transaminase level were not listed on vaccine labels. In validation analysis, PRR and ROR performed slightly better than IC for adults who were vaccinated with PPSVs. Conclusion: Overall, 13 new signals of PPSVs, including four signals not listed on the labels, were detected. Further research based on additional AE reports is required to confirm the validity of these signals for children.ope

Adequacy of safety data for regulatory approval of pediatric indication through extrapolation algorithm

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Lung development alterations in newborn mice after recovery from exposure to sublethal hyperoxia

Exposure of newborn mice to hyperoxia arrests lung development, with resultant pathological characteristics similar to bronchopulmonary dysplasia in infants born prematurely. We tested the hypothesis that aberrations in lung development caused by 14 days of sublethal hyperoxia would be reversed during 14 days of recovery to room air (RA) when the concentration of oxygen exposure was weaned gradually. Newborn FVB mice were exposed to 85% oxygen or RA for 14 days. Weaning from hyperoxia was by either transfer directly into RA or a decrease in the concentration of oxygen by 10% per days. At 28 days, pups were euthanized, and the lungs were inflation fixed and assessed. At postnatal day 28, lungs of mice weaned abruptly from hyperoxia had fewer (6 ± 0.6 versus 10 ± 0.7; P < 0.001) alveoli per high-powered field and larger alveoli (4050 ± 207 versus 2305 ± 182 μm(2)) than animals weaned gradually; both hyperoxia-exposed groups were different from lungs obtained from air-breathing controls (20 ± 0.5 alveoli per high-powered field; P < 0.001). The results are consistent with the absence of catch-up alveolarization in this model and indicate that the long-term consequences of early exposures to hyperoxia merit closer examination. The effects of abrupt weaning to RA observed further suggest that weaning should be considered in experimental models of newborn exposure to hyperoxia.ope

Evalution and Management of Macrosomic Neonates

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Comparison of acute kidney injury and clinical prognosis of vancomycin monotherapy and combination therapy with beta-lactams in the intensive care unit

Antibiotics induced acute kidney injury (AKI) risk in critically ill patients is not well known. This study aimed to evaluate the AKI development and clinical outcomes in critically ill adult patients treated with vancomycin (VAN) or combined with piperacillin-tazobactam (TZP) or meropenem (MEM). This was a retrospective study on critically ill adult patients who were given VAN, TZP or MEM and maintained for at least 48 h. The risk of AKI development and clinical outcomes were compared using the simple analysis and multivariate logistic regression. Three hundred forty patients were eligible. The incidence of any AKI was significantly higher in patients treated with VAN + TZP than those with VAN + MEM or VAN alone (52.7% vs. 27.7% vs. 25.7%; p < .0001). The adjusted odds of AKI increased 2.43-fold in VAN + TZP versus VAN, but not different in VAN + MEM versus VAN. However, AKI duration and recovery rate were not statistically different. In addition, all-cause death within 30 days after AKI onset was not significantly associated with antibiotic regimens. AKI incidence is higher in critically ill patients administered with VAN + TZP than those with VAN + MEM or VAN. However, no obvious evidence was found to prove that antibiotic-induced AKI leads to poor clinical outcomes.ope

Effect of Voriconazole or Itraconazole on the Plasma Concentrations of Tacrolimus in Lung Transplant Recipients

Objective: This study was performed to compare the changes in the blood concentrations of tacrolimus when either itraconazole or voriconazole is together with tacrolimus to prevent or treat invasive aspergillus pneumonia (IAP) in patients with lung transplants. Therefore we can compare the degree of drug-drug interactions between tacrolimus and itraconazole against tacrolimus and voriconazole. Methods: Patients who were admitted and had lung transplants in a territory referral hospital from September 2012 to May 2015 were analyzed retrospectively. The effects of itraconazole and voriconazole on the plasma concentrations of tacrolimus were analyzed. Results: Mean tacrolimus concentrations was $10.49{\pm}2.35ng/mL$ vs. $10.95{\pm}2.98ng/mL$ (p=0.722), and mean concentration of tacrolimus over the dose of tacrolimus per day was $8.510{\pm}5.890(ng/mL)/(mg/d)$ vs. $15.45{\pm}28.47(ng/mL)/(mg/d)$ (p=0.947) in itraconazole vs. voriconazole group each. The ratio of the number of the results out of target tacrolimus concentrations to the total number of tacrolimus concentration results was $18.0{\pm}13.3$ vs. $24.4{\pm}18.5$ (p=0.185). Conclusion: There were no significant differences between itraconzaole and voriconazole to have influences on mean concentrations of tacrolimus over tacrolimus dose per weight per day. However voriconazole tended to raise tacrolimus plasma concentrations more than itraconazole. Safer and more effective drug management to prevent and treat fungal infections should be done by therapeutic drug monitoring not only of tacrolimus but of itraconazole and voriconazole in lung transplant patients.ope