염증성 장질환 마우스 모델에서 칼륨 경쟁적 위산분비 차단제인 테고프라잔의 항염증 효과

Inflammatory bowel diseases (IBD), including both ulcerative colitis (UC) and Crohn’s disease (CD) are autoimmune diseases characterized by progressive inflammatory condition that affects the damage in the gastrointestinal tract. The etiology of IBD remains unclear, but it is thought that IBD results from abnormal intestinal immunity and altered gut microbiota caused by environmental factors such as diet and infection in genetically susceptible individuals. Specifically, gut microbiota can influence intestinal functional integrity, barrier strength, and permeability regulation, thereby affecting the immune response, which has been linked to the development of IBD. Proton pump inhibitors (PPIs) are widely used medication for gastric acid inhibition. However, long-term PPI administration can alter the composition of the intestinal microbiome, which worsens the severity of disease in IBD patients. The present study demonstrated that tegoprazan significantly ameliorates the symptoms of DSS-induced colitis such as body weight loss, diarrhea, bleeding, colon shortening, and histological damage and enhanced intestinal epithelial barrier function by upregulating tight junction protein expression. Tegoprazan significantly improved the symptoms of colitis, even in a DNBS-induced colitis model. Above all, tegoprazan alleviated gut microbiota dysbiosis and enhanced the growth of Bacteroides vulgatus (B.vulgatus). B. vulgatus alleviated intestinal inflammation by inhibiting the epithelial adhesion of pathogenic bacteria. Especially, unlike rabeprazole, Tegoprazan did not have adverse effects such as gut dysbiosis. These results suggest that Tegoprazan has potential as a therapeutic agent for IBD. 염증성 장질환은 장내 비정상적인 염증과 궤양을 반복하는 만성 질환이다. 염증성 장질환의 원인은 아직 불분명하지만, 유전적 요인과 환경적 요인 등 다양한 요인이 복합적으로 작용하는 것으로 알려져 있으며 특히 장내 미생물무리의 조성 변화가 중요한 요인으로 여겨진다. 특히 장내 미생물은 장상피세포의 분화를 도우며 Tight junction protein 발현 촉진 등을 통해 장벽 기능 강화에 영향을 미친다. 양성자 펌프 억제제(이하 PPI)는 위산 분비 억제제로 전세계적으로 널리 처방되는 약제이지만 PPI를 장기 복용 시 골절, 폐렴, 장내 미생물 불균형과 같은 부작용이 발생할 수 있다는 보고가 있다. 칼륨 경쟁적 위산 분비 차단제(이하 P-CAB)는 PPI와 다른 메커니즘을 사용하여 위산 분비를 억제하며 기존 PPI보다 위산 억제에 대해 더 강력하고 오래 지속되는 효과가 있다. 그러나 장 염증에 대한 테고프라잔의 효과는 아직 알려져 있지 않다. 본 연구에서는 대장염 동물모델을 이용하여, 테고프라잔의 항대장염 효과를 평가하였다. 테고프라잔은 DSS로 유도한 궤양성 대장염 동물 모델에서 체중 감소, 설사, 출혈, 및 조직 학적 손상과 같은 대장염의 증상을 개선하였고 Tight junction 단백질들의 발현을 상향 조절함으로써 장 상피 장벽 기능을 향상시켰다. 또한, 장내 미생물 유전체 분석을 통해 테고프라잔이 DSS에 의한 장내 미생물의 불균형을 완화시키고 박테로이데스 불가투스를 증가시킴을 확인하였다. 박테로이데스 불가투스는 병원성 세균의 상피 부착을 억제하였고, 대장염 증상 완화에 효과가 있음을 DSS 유도 궤양성 대장염 동물 모델을 통해서 증명하였다. 뿐만 아니라, 테고프라잔은 크론병 모델인 DNBS로 유도한 대장염 모델에서도 대장염의 증상을 개선하는 결과를 보였다. 이러한 결과들을 통해, 테고프라잔이 효과적으로 장 염증을 완화한다는 것을 알 수 있으며, 새로운 염증성 장질환 치료제로서 가능성을 제시할 수 있다.open석

한국인에서 갑상선 절제술이 칼슘 농도에 미치는 영향과 칼슘 보조제 효과의 예측 모형

Dept. of Medical science/박사갑상선절제술은 한국뿐 아니라 미국 등 세계적으로 매우 높은 빈도로 수행되는 수술의 하나이다. 저칼슘혈증은 갑상선절제술 후 가장 많이 나타나면서도 중요한 부작용 중에 하나로, 술 후 환자의 재원 기간의 증가와 삶의 질 저하를 가져올 수 있다. 현재까지 술 후 저칼슘혈증이 일어나는 환자를 예측하기 위하여 많은 연구가 이루어졌으나 주로 특정 시기에서의 칼슘농도를 영향 인자에 따라 서로 비교하는 것에 그치고 있으며 갑상선 절제술 후 시간에 따른 칼슘 농도의 변화를 예측하는 종적연구는 찾을 수 없었다. 이러한 배경을 바탕으로 본 연구는 한국인에서 갑상선 절제술 후 시간에 따른 칼슘 농도의 변화와 저칼슘혈증의 치료에 사용되는 칼슘 보조제의 효과를 예측하는 모형을 개발하여 효과적인 술 후 저칼슘혈증 관리에 도움이 될 것을 목적으로 한다. 본 연구는 한국인 표준모형을 개발하는 연구로써, 연세의료원 신촌 세브란스병원 외과에서 2013년 1월부터 2013년 6월 사이의 기간에 갑상선 절제술을 받은 20세 이상의 한국인 환자들을 대상으로 갑상선 절제술 후의 칼슘 보조제 투약 정보 및 칼슘과 부갑상선 호르몬 농도의 시계열 자료, 문헌조사를 통해 선정한 칼슘 농도에 영향을 미칠 것으로 기대되는 인자들에 대한 정보를 얻어 분석하였다. 이 중 갑상선 절제술의 과거력이 있는 대상자와 술전 칼슘 및 부갑상선호르몬 수치가 없는 대상자는 제외하였으며, 유사저칼슘혈증 (pseudohypocalcemia)를 나타낼 수 있는 저알부민혈증의 가능성이 있는 질환 (간경변, 신질환, 암 등)을 가진 경우도 제외하였다. 질병진행모형(disease progression model) 개념을 바탕으로, 일상적 임상자료(routine clinical data)의 분석에 유용한 비선형혼합효과모형을 사용하여 모형이 구축되었다. 기본적으로 turnover model을 사용하여 항상성을 가진 내인성 인자인 칼슘 및 부갑상선 호르몬의 기저모형을 구현하였고, 알려진 생리적 현상인 칼슘-부갑상선 호르몬 피드백 메카니즘을 추가함으로써 모형을 개선할 수 있었다. 여기에 술 후 급격하게 떨어졌다가 회복되는 칼슘 및 부갑상선 호르몬의 초기 추세와 일부 환자에서 후반부까지 지속되는 칼슘 및 부갑상선 호르몬의 감소를 각각 갑상선 절제술의 초기 및 후기 효과로 반영하였다. 칼슘 보조제를 투약 받은 경우, 하루에 투여하는 칼슘의 총량만큼 일정한 속도로 혈중 칼슘농도를 직접 증가시키는 모형으로 그 효과를 정량화 할 수 있었다. 공변량 분석 후 최종 모형에서 체중, 경부청소술 (neck dissection) 범위 와 술 전 칼슘 농도가 KoutCa 와, 갑상선 절제술의 종류가 KR,Ca 와 관련 있었으며, 술 전 부갑상선 호르몬 농도, 제거된 부갑상선의 개수, 갑상선 절제술의 종류, 나이가 Amp_p 와 관련 있었다. 최종모형은 Akaike information criterion (AIC), goodness of fit, visual predictive check, bootstrap 등을 통해 평가되었고 이에 따라 최종 모델이 자료를 잘 설명한다고 판단할 수 있었다. 향후 충분한 타당성의 검증이 이루어진다면, 본 연구를 통해 최종적으로 제안된 모형을 통해 갑상선 절제술 후 시간에 변화하는 칼슘 농도와 이에 영향을 미치는 인자들 및 칼슘 보조제의 효과를 예측함으로써 효과적인 술 후 칼슘 농도 관리에 도움이 될 수 있을 것으로 기대된다. Hypocalcemia is known as one of the most common complications after thyroidectomy, which can lead to prolonged hospitalization and low quality of life. Although a number of studies have been reported on hypocalcemia so far, no study is found that investigated the longitudinal change of calcium after thyroidectomy. With this background, the objectives of this work are to develop a quantitative model to predict calcium and parathyroid hormone level changes after thyroidectomy in Korean population and to identify associated influencing factors. The data were collected from clinical data retrieve system (CDRS) and electrical medical records (EMR) system of Severance Hospital. Included patients were Korean patients aged above 19 when they underwent a thyroidectomy under general anesthesia in Severance Hospital between January and June 2013. Patients who had a past history of thyroidectomy or who underwent thyroidectomy due to secondary hypocalcemia or whose baseline calcium level was missing or who had diseases that can cause hypoalbuminemia were excluded. The analysis variables were plasma calcium and PTH concentrations before and after thyroidectomy and, treatment effect of external calcium supplement, if any, was also analyzed. Using a non-linear mixed effect modeling approach which is widely used in the analysis of routine clinical data, the model was developed based on the disease progression modeling concept. Basically, turnover model was used to describe changes of endogenous calcium and PTH levels. Feedback effect of calcium on PTH level was included in the model according to the known mechanism of calcium-PTH homeostasis. Not only sudden drops in calcium and PTH levels observed at the early phase immediately after thyroidectomy, but late-phase effects, including the influence of incomplete recoveries from surgery and additional calcium supplements, were considered in developing the model to represent the typical pattern of hypocalcemia observed in patients receiving thyroidectomy. The model was evaluated by goodness of fit plots, Akaike information criterion (AIC) and a visual predictive check (VPC). The refined model, which is the final model, shows that KoutCa increases with body weight and radical neck dissection and it decreases with baseline calcium...ope

Pharmacokinetics of a telmisartan/rosuvastatin fixed-dose combination: a single-dose, randomized, open-label, 2-period crossover study in healthy Korean subjects

OBJECTIVE: As hypertension and dyslipidemia are frequent comorbidities, antihypertensive drugs and lipid-lowering agents are often prescribed together for their treatment. Telmisartan and rosuvastatin are widely used together to treat hypertension and dyslipidemia. A combination formulation of these two drugs would improve patient compliance due to ease of dosing. The purpose of this study was to assess bioequivalence of single-dose administration of a newly-developed fixed-dose combination (FDC) tablet containing telmisartan/rosuvastatin 80/20 mg (test treatment) and coadministration of a telmisartan 80-mg tablet and a rosuvastatin 20-mg tablet (reference treatment) in healthy Korean male volunteers. METHODS: This was a single-dose, randomized, open-label, 2-period crossover study enrolling healthy males aged 20 - 50 years with BMI between 18.5 and 25 kg/m2. Each subject received a single dose of the reference and test treatments with a 14-day washout period. Blood sampling was performed at prespecified intervals for up to 72 hours after dosing. Primary pharmacokinetic parameters were Cmax, AUClast, and AUC0-∞ of telmisartan, rosuvastatin, and N-desmethyl rosuvastatin. Bioequivalence was assessed by determining whether the 90% confidence intervals (CIs) of the geometric mean ratios (test treatment/reference treatment) of these parameters were within the standard range of 80% to 125%. Adverse events were monitored via regular interviews with the subjects and by physical examinations. RESULTS: 60 subjects were enrolled and 55 completed the study. The 90% CIs of the geometric mean ratios of Cmax, AUClast, and AUC00-∞ were 0.9262-1.1498, 0.9294-1.0313, and 0.9312-1.0320 for telmisartan, 0.9041-1.0428, 0.9262-1.0085, and 0.9307-1.0094 for rosuvastatin, and 0.8718-1.0022, 0.8901-0.9904, and 0.8872-0.9767 for N-desmethyl rosuvastatin, respectively. There was no statistical difference in the incidence of adverse events (AEs) (all of which were mild or moderate) between the reference and test treatments. CONCLUSIONS: Our findings suggest that the telmisartan/rosuvastatin FDC is bioequivalent to coadministration of separate tablets, and both treatments were safe and well tolerated. Administration of this FDC tablet is expected to improve patient compliance.ope

Pharmacokinetic Comparison of 2 Fixed-Dose Combination Tablets of Amlodipine and Valsartan in Healthy Male Korean Volunteers: A Randomized, Open-Label, 2-Period, Single-Dose, Crossover Study

BACKGROUND: Amlodipine and valsartan have different mechanisms of action, and it is known that the combination therapy with the 2 drugs increases treatment effects compared with the monotherapy with each drug. A fixed-dose combination (FDC) drug is a formulation including fixed amounts of active drug ingredients combined in a single dosage form that is expected to improve medication compliance. OBJECTIVE: The goal of this study was to compare the pharmacokinetic profiles of single administration of a newly developed FDC tablet containing amlodipine orotate 10 mg and valsartan 160 mg (test formulation) with the conventional FDC tablet of amlodipine besylate 10 mg and valsartan 160 mg (reference formulation) in healthy male Korean volunteers. METHODS: This was a randomized, open-label, single-dose, 2-way crossover study. Eligible subjects were between the ages of 20 and 50 years and within 20% of their ideal weight. Each subject received a single dose of the reference and the test formulations, with a 14-day washout period between formulations. Blood samples were collected up to 144 hours after the dose, and pharmacokinetic parameters were determined for amlodipine and valsartan. Adverse events were evaluated based on subject interviews and physical examinations. RESULTS: Forty-eight of the 50 enrolled subjects completed the study. For both amlodipine and valsartan, the primary pharmacokinetic parameters were included in the range for assumed bioequivalence, yielding 90% CI ratios of 0.9277 to 0.9903 for AUC(0-last) and 0.9357 to 1.0068 for C(max) in amlodipine, and 0.9784 to 1.1817 for AUC(0-last) and 0.9738 to 1.2145 for C(max) in valsartan. Dizziness was the most frequently noted adverse event, occurring in 4 subjects with the test formulation, followed by oropharyngeal pain occurring in 1 subject with the test formulation and 3 subjects with the reference formulation. All other adverse events occurred in <3 subjects. CONCLUSIONS: These findings suggest that the pharmacokinetics of the newly developed FDC tablet of amlodipine and valsartan did not differ significantly from the conventional FDC tablet in these healthy Korean male subjects. Both formulations were well tolerated, with no serious adverse events observed. ClinicalTrials.gov identifier: NCT01823913.ope