호흡곤란 증후군 미숙아에서 동맥관 개존증의 약물 치료 : 경구용 ibuprofen과 indomethacin의 비교

이수진,김지영,손세정,박은애 대한소아청소년과학회 2008 Clinical and Experimental Pediatrics (CEP) Vol.51 No.9

Purpose:Indomethacin is widely used for the prophylaxis and treatment of patent ductus arteriosus (PDA); however, it is associated with side effects such as renal failure, intraventricular hemorrhage, and gastrointestinal bleeding. Intravenous ibuprofen has been shown to be as effective as indomethacin in prompting PDA closure. If treatment with oral ibuprofen is as effective as indomethacin, it would have the advantages of greater availability, simpler administration, and lower cost. We conducted this study to compare the efficacy and side effects of indomethacin with those of oral ibuprofen, vis-à-vis on the pharmacological closure of PDA. Methods:As a randomized double-blind study, 34 preterm infants with respiratory distress syndrome and hemodynamically significant PDA were treated with either intravenous indomethacin or oral ibuprofen. Echocardiography was performed by one cardiologist who was blind to the treatment that any given infant received. The rate of ductal closure, the need for additional drug treatment or surgical ligation, clinical outcome, and the side effects of drug treatment were compared. Results:Ductal closure occurred in 16 of 18 patients (88.9%) from the indomethacin group and in 14 of 16 patients (87.5%) from the ibuprofen group (P>0.05). Three patients in the indomethacin group and four in the ibuprofen group required a second drug treatment (P>0.05). Three patients (i.e., one patient in the indomethacin group and two in the ibuprofen group) underwent surgical ligation (P>0.05). Between the two groups, there was no significant difference vis-à-vis in side effects or clinical outcome. Conclusion:Compared to indomethacin, oral ibuprofen has the advantages of simpler administration and lower cost, while being as effective; in addition, there are no differences between the two drug treatments with regards to side effects or clinical outcomes. Therefore, the widespread use of oral ibuprofen should be considered in treating PDA in preterm infants. (Korean J Pediatr 2008;51:956-963) Purpose:Indomethacin is widely used for the prophylaxis and treatment of patent ductus arteriosus (PDA); however, it is associated with side effects such as renal failure, intraventricular hemorrhage, and gastrointestinal bleeding. Intravenous ibuprofen has been shown to be as effective as indomethacin in prompting PDA closure. If treatment with oral ibuprofen is as effective as indomethacin, it would have the advantages of greater availability, simpler administration, and lower cost. We conducted this study to compare the efficacy and side effects of indomethacin with those of oral ibuprofen, vis-à-vis on the pharmacological closure of PDA. Methods:As a randomized double-blind study, 34 preterm infants with respiratory distress syndrome and hemodynamically significant PDA were treated with either intravenous indomethacin or oral ibuprofen. Echocardiography was performed by one cardiologist who was blind to the treatment that any given infant received. The rate of ductal closure, the need for additional drug treatment or surgical ligation, clinical outcome, and the side effects of drug treatment were compared. Results:Ductal closure occurred in 16 of 18 patients (88.9%) from the indomethacin group and in 14 of 16 patients (87.5%) from the ibuprofen group (P>0.05). Three patients in the indomethacin group and four in the ibuprofen group required a second drug treatment (P>0.05). Three patients (i.e., one patient in the indomethacin group and two in the ibuprofen group) underwent surgical ligation (P>0.05). Between the two groups, there was no significant difference vis-à-vis in side effects or clinical outcome. Conclusion:Compared to indomethacin, oral ibuprofen has the advantages of simpler administration and lower cost, while being as effective; in addition, there are no differences between the two drug treatments with regards to side effects or clinical outcomes. Therefore, the widespread use of oral ibuprofen should be considered in treating PDA in preterm infants. (Korean J Pediatr 2008;51:956-963)

미숙아 동맥관 개존증의 예방적 치료로서 Indomethacin과 Ibuprofen의 효과

전복선,권경아,박경희,변신연,김묘징 대한신생아학회 2011 Neonatal medicine Vol.18 No.2

Purpose: The aim of our study was to compare the efficacy and safety of ibuprofen and indomethacin in the prophylaxis of patent ductus arteriosus (PDA) in preterm infants and to determine whether ibuprofen could be an alternative agent in prophylactic use. Methods: A retrospective study including 37 preterm infants <1,500 g of birth weight, <34 weeks of gestation, whom were administrated indomethacin (n=17; January 2009-December 2009) or ibuprofen (n=20; January 2010-February 2011) within 24 hr after birth was conducted. The rate of ductal closure, need for surgical ligation, clinical outcomes such as necrotizing enterocolitis,intraventricular hemorrhage, bronchopulmonary dysplasia, retinopathy of prematurity (ROP) and death rate were compared. Results: There were no statistically significant differences between the two groups in mean gestational age, mean birth weight,Apgar score, sex, type of delivery, maternal dexamethasone treatment, frequency and duration of ventilator and surfactant treatment. The closure of PDA on day 7 of life was in 19 of 20 infants of the ibuprofen group and 13 of 17 infants of the indomethacin group (P=0.159). Between the two groups, there were no significant differences with respect to clinical outcomes. Conclusion: Ibuprofen has similar effects to indomethacin in the rate of PDA closure. Our study demonstrates that prophylactic ibuprofen is relatively effective without significant differences with respect to clinical outcomes compared with indomethacin. Therefore, ibuprofen may be used as an alternative agent in the prophylaxis of PDA in preterm infants. 목적: Indomethacin은 미숙아 동맥관 개존증의 예방적 용법및 치료적 용법에 사용되어 왔다. 하지만 최근에는 indomethacin의국내 보급이 중단됨에 ibuprofen이 사용되고 있다. Ibuprofen은 동맥관 폐쇄에 indomethacin만큼 효과적이며 부작용은 적은 것으로 알려져 있다. 그러나 ibuprofen의 예방적용법에 관한 연구는 많지 않다. 본 연구에서는 미숙아에서 동맥관 개존증의 예방적 치료에 대한 ibuprofen의 효과와 안정성을indomethacin과 비교하여 분석하고자 하였다. 방법: 2009년 1월부터 2009년 12월, 그리고 2010년 1월부터2011년 2월까지 두 기간동안 3개의 참여 대학병원 신생아 중환자실에 입원한 34주 미만, 1,500 g 미만의 신생아 중에서 생후24시간 이내에 indomethacin이나 ibuprofen이 예방적 목적으로 투여된 환자를 대상으로 하여 의무기록을 후향적으로 검토하였다. 두 군간의 동맥관 폐쇄에 대한 효과와 주산기 합병증의발생 정도를 조사하였다. 결과: 두 군간에 환아의 성별, 재태 연령, 출생체중, 분만 방법,1분 및 5분 Apgar 점수, 산모의 steroid 사용 여부, 폐 표면활성제 사용 여부 및 인공호흡기 사용여부 및 사용기간에 있어 유의한 차이는 없었다. 생후 7일에 시행한 심초음파 검사에서indomethacin군은 17명 중 13명, ibuprofen군은 20명 중 19명이 동맥관의 폐쇄를 보였다. 총 입원 기간 외에 주산기 합병증의빈도는 두 군간의 유의한 차이가 없었다. 결론: Ibuprofen의 예방적 사용은 동맥관 폐쇄에 효과적이며주산기 합병증 측면에서 유의한 부정적인 차이가 없었다. 따라서 indomethacin을 대체하여 ibuprofen의 사용을 고려해 볼수 있겠다.

Bisphosphonate와 Indomethacin이 백서 치조골의 골개조에 미치는 영향

조명숙,김종철 대한치과교정학회 1996 대한치과교정학회지 Vol.26 No.2

본 실험은 서로 다른 기전으로 골흡수를 억제한다고 추정되는 약제인 bisphosphonate와 indomethacin을 백서에 투여한 후 교정력을 이용한 치아이동시 약제가 골개조에 미치는 영향을 밝히고자 시행되었다. 동일한 조건에서 사육된 체중 260-300g의 웅성백서(Sprague-DawleyrP)를 대조군, bisphosphonate 투여군 및 indomethacin 투여군으로 분류하고 각 군은 다시 장치를 장착한 실험측과 장치를 장착하지 않은 대조측으로 분류하였다. Bisphosphonate(6.3mg/kg,2.52x10 mol/L)와 indomethacin(9mg/kg, 2.52x10 mol/L)은 교정장치 장착 6시간 전, 1시간 전 및 24시간 후에 복강내 주사하였으며, 교정력이 가해진 시점으로부터 72시간이 경과한 후 파골세포수를 측정하고 조직학적인 성상을 관찰하였다. 또한 혈액을 채취한 후 혈청 acid phosphatase ac lactate dehydrogenase 양을 측정하여 다음과 같은 성적을 얻었다. 실험측의 파골세포수는 장치장착 1시간 전에 투여한 bisphosphonaterns과 indomethacinrns에서 가장 적게 나타났으며, 다른 시간의 약물 투여군은 대조군과 차이가 없었다. 대조측의 파골세포수는 실험측보다 현저히 적게 나타났으며, 대조군 및 약물투여군간에 차이가 없었다. 대조군과 6시간 전 및 24시간 후에 투여한 indomethacin군은 심한 골흡수 양상을 보인 반면 1시간전 indomethacinrns 및 모든 bisphosphonate군에서는 골흡수의 정도가 적었다. 파골세포의 주름변연과 투명대는 대조군 및 indomethacin군에서 가장 뚜렷하게 나타났으며, bisphosphonate 투여군에서는 일부 파골세포들이 무딘 세포돌기만을 내거나 골표면에 부착하지 않고 있는 경우가 많았다. Bisphosphonate와 indomethacin 투여군 모두에서 acid phosphatase 및 lactate dehydrogenase 값이 대조군보다 낮았으며, acid phosphatase 값은 bisphosphonaterns이 indomethacinrns보다 낮았으나 lactate dehydrogenase 값은 차이가 없었다. 이상의 결과로 bisphosphonate는 파골세포의 수 및 대사활동을 감소시키며 indomethacin은 파골세포의 수를 감소시킴을 알 수 있었다. 또한 두 약물을 비교하면 bisphosphonate는 indomethacin에 비해 골흡수 억제효과가 더 크며 투여시간에 따른 제약도 더 적은 것으로 사료된다. The purpose of the study was to examine the effects of bisphosphonate and indomethacin, blockers of bone resorption with different mechanisms, on alveolar bone remodeling. Male rats were divided into control, bisphosphonate and indomethacin groups, and then each group was divided into an experimental side and a control side according to the force application. Bisphosphonate(6.3mg/kg,2.52x10 mol/L) and indomethacin (9mg/kg, 2.52x10 mol/L) were injected 6 hours and I hour before or 24 hours after the force application. The rats were killed 72 hours after the force application and histologic examination was perfomed. The values of serum acid phosphatase and lactate dehydrogenase were also measured in the control and experimental groups treated with bisphosphonate or indomethacin 1 hour before the force application. In the experimental side, the least number of osteoclasts was noted in the groups treated 1 hour before the force application with indomethacin or bisphosphonate, while there were no differences between the control and the groups treated with drugs 6 hours before or 24 hours after the force application. In the control side, the number of osteoclasts was not inecreased with no differences among the groups. Histologic examination revealed a severe alveolar bone resorption in the control group and the groups treated with indomethacin 6 hours before or 24 hours after the force application. Indomethacin treatment 1 hour before the force application and bisphosphonate treatment at any time significantly attenuated the bone resorption. Electron microscopically, ruffled border and clear zone of osteoclasts were observed in the control and indomethacin groups, while some osteoclasts were detached from the bone surface and exhibited dull cellular projections in the bisphosphonate groups. The bisphosphonate and indomethacin groups showed lower values of acid phosphatase and lactate dehydrogenase than the control group. The acid phosphatase value in the bisphosphonate group was lower than that in the indomethacin group, whereas there was no difference in the lactate dehydrogenase value between the groups. These results suggest that bisphosphonate reduces the activity of osteoclasts as well as the number of osteoclasts and that indomethacin reduces the number of osteoclasts without affecting the activity of osteoclasts. Bisphosphonate has a larger inhibitory effect on bone resorption and thus less limitation in the application time than indomethacin.

임상 ; 증상이 동반된 동맥관 개존증 만삭아에서Indomethacin의 치료효과

김한결 ( Han Kyul Kim ),최인수 ( In Su Choi ),조화진 ( Hwa Jin Cho ),송은송 ( Eun Song Song ),조영국 ( Young Kuk Cho ),최영륜 ( Young Youn Choi ),마재숙 ( Jae Sook Ma ) 대한주산의학회 2013 Perinatology Vol.24 No.4

목적: Indomethacin은 동맥관 개존을 가진 미숙아에서 예방요법 및 일차 치료로 보고되고 있다. 그러나, 혈 역학적으로 의미 있는 동맥관 개존을 가진 만삭아에 대한 indomethacin 치료에 관하여는 아직까지 논란이 있는 상태이다. 따라서, 본 연구는 만삭아에서 동맥관 개존에 대한 indomethacin 치료의 효과를 알아보고자 한다. 방법: 2007년 1월부터 2009년12월까지 전남대학교병원에서 증상이 동반된 동맥관 개존증으로 치료를 받은 2,500 g이상, 재태 주령 37주 이상인 만삭아를 대상으로 indomethacin 치료의 효과를 후향적으로 조사하였다. Indomethacin치료의 반응에 따라 1) indomethacin 치료 후에 완전 폐쇄된 완전 반응군, 2) 완전히 폐쇄되지는 않았으나 추가적인 치료 없이 임상 소견이 호전된 부분 반응군, 3) 반응을 보이지 않아서 추후 수술적 결찰을 시행한 비 반응군으로 구분하였다. 결과: 동맥관 개존을 가진 만삭아 29명에서 indomethacin으로 치료한 후에 21명(72.4%)에서 indomethacin 치료에 완전 폐쇄와 부분폐쇄를 보이며, 13명(44.8%)이 완전 반응군, 8명(27.6%)이 부분 반응군, 나머지 8명(27.6%)은 비 반응군 이었다. 출생 체중, 동맥관 최소 직경, indomethacin 투여 횟수는 세 군간에 유의한 차이를 보이지 않았다. 그러나, indoemthacin을 처음 투여한 시기에 있어서 완전 반응군(4.8±4.5일, P=0.03)과 부분 반응군(6.3±2.0 일, P=0.04)이 비반응군(13.8±8.1일)에 비해 더 빨랐다. 결론: 만삭아의 동맥관 개존증 치료에 있어서 수술적 치료 이전에 우선적으로indomethacin 정주 치료를 시행함으로써 동맥관의 완전 폐쇄 및 부분 폐쇄를 통한 임상 증상 호전을 기대할 수 있을 것이다. Purpose: Indomethacin has been reported as the prophylaxis and initial treatment of preterm infants with patentductus arteriosus (PDA). However, there was controversy over indomethacin treatment in full-term infants with symptomatic PDA. Therefore, we evaluate the effect of indomethacin as a treatment of full-term infants withsymptomatic PDA. Methods: A retrospective study was performed to evaluate the effectiveness of indomethacin in full-terminfants who had birth weight ≥2,500 g and a gestational age ≥37 weeks with symptomatic PDA at ChonnamNational University Hospital between January 2007 and December 2009. According to responsiveness ofindomethacin, we classified them into three groups: 1) complete responder which were completely closed after indomethacin treatment, 2) partial responder which were incompletely closed but symptoms were improved, 3)non responder which were conducted surgical ligation because did not respond. Results: Among the total 29 full-term infants treated with indomethacin, 13 (44.8%) were complete responder,8 (27.6%) were partial responder, and 8 (27.6%) were non responder. There were no significant differences inbirth weight, narrow diameter of PDA, and dose of indomethacin between three groups. However, the age atinitiation of treatment using indomethacin of complete (4.8±4.5 days, P =0.03) and partial responder (6.3±2.0days, P =0.04) were earlier than those of non responder (13.8±8.1 days). Conclusion: Indomethacin can expect an effective treatment of PDA in full-term infants prior to surgical ligation.

Helicobacter pylori 감염에 대한 indomethacin 투여의 영향

이진욱(Jin-Uk Lee),김옥진(Okjin Kim) 한국실험동물학회 2004 Laboratory Animal Research Vol.20 No.3

본 연구자은 NSAIDs가 H pylori 병증 발현에 영향을 미치는 것으로 추론하고 H. pylori 감염 양태가 사람과 가장 유사한 실험동물 모델인 Mongolian gerbil을 사용하여 확인실험을 실시한 결과, NSAIDs의 일종인 indomethacin익 투여가 H. pylori 감염에 의한 위장관 손상을 심화시키는 것을 확인하였다. 이러한 결과는 H. pylori 감염 환자들에서 NSAIDs의 복용은 제한되어져야함을 시사한다. This study was designed to find out the effects of indomethacin on Helicobacter pylori (H. pylori)induced gastrointestinal injuries. We used Mongolian gerbils which have been reported as a most optimal laboratory animal to study H. pylori ill vivo. To determine an optimal indomethacin concentration for oral administration, 5-week-old Mongolian gerbils were divided into different indomethacin concentrations. After graded concentrations of indomethacin, the gross and histological lesion scores were measured with the stomach and duodenum of sacrificed animals. The gross lesion scores in the stomachs of sacrificed animals increased in a concentration-dependent fashion. We determined an optimal indomethacin concentration in gerbil as 40 ㎎/㎏ body weight. We evaluated the effects of indomethacin on H. pylori-induced gastrointestinal injuries. Mongolian gerbils were divided into H. pylori-infected and PBS-treated groups. Thereafter, after 1 week later, they were divided again into following subgroups-20 ㎎/㎏ indomethacin-administrated and 40 ㎎/㎏ indomethacintreated and PBS-treated animals. After per oral treatment, the severity of pathological changes was evaluated in a same manner with previous indomethacin concentration-determining experiment. When the animals were exposed to indomethacin, the gross and histological lesion scores were higher in the infected groups than in the uninfected groups. These results suggested that indomethacin could induce the enhancement of H. pylori-induced gastrointestinal injuries.

두경부 편평상피암 세포주기에서 indomethacin에 유도된 세포주기의 정지

이동욱 충북대학교 의과대학 충북대학교 의학연구소 2004 忠北醫大學術誌 Vol.14 No.1

연구 목적: 최근. cyclooxygenase를 억제하는 비스테로이드성 항염제들이 대장암 세포들의 세포주기를 정지시키는 기전을 통하여 대장암 세포의 성장을 억제한다는 연구 결과들이 보고 되고 있다. 이에 저자는 비스테로이드성 항염제 중의 하나인 indomethacin이 두겨부 편평상피암 세포들의 세포주기에 어떠한 영향을 주는지 알아보고자 본 연구를 시행하였다. 대상 및 방법: 배양된 두경부 편평상피암 세포주에 다양한 농도의 indomethacin을 투여하였고, indomethacin이 두경부 편평상피암 세포들의 세포주기에 미치는 영향을 FACS 분석을 통하여 조사하였다. 결과: Indomethacin의 농도에 비례하는 양상으로 G0/G1 기 세포들의 분획이 증가하였으며, 동시에 S 기 세포들의 분획이 감소하였다. 이를 통해 indomethacin이 두경부 편평상피암 세포주에 있어서 세포주기를 정지시키는 효과가 있음을 알 수 있었다. 결론: 향후 indomethacin 등의 비스테로이드성 항염제가 두경부 편평상피암 세포들의 세포주기를 정지시키는 기전을 통하여 두경부 편평상피암의 예방이나 치료에 기여할 수 있으리라고 생각된다. Purpose: Recent studies have revealed that growth inhibition of colorectal cancer cells with nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclooxygenases (COX), involves cell cycle arrest. The aim of this study was to investigate the effects of indomethacin, an well-known NSAID, on cell cycle arrest of cultured head and neck squamous cell carcinoma (HNSCC) cell lines. Materials and Methods: HNSCC cells were cultured, and after addition of various concentrations of indomethacin, the effects of it on cell cycle of HNSCC cells were exam-ined using FACS analysis. Results: The percentage of cells in G0/G1 phases was increased in all the cell lines tested in a dose-dependent manner. And this increasing proportion of cells in G0/G1 phases was accompanied by a concomitant reduction in the number of cells at the S phase of the cell cycle demonstrating the indomethacin induced arrest of the cell cycle at the G0/G1 phases. Conclusion: It seems that inhibiting COX with NSAIDs, such as indomethacin, at an early stage may block the development of HNSCC from pre-malignant lesions and it may be able to improve the treatment outcome even if cancer is established through cell cycle arrest followed by inhibition of proliferation of cancer cells in HNSCC.

극소 저출생 체중아의 동맥관 개존증의 치료에 사용되는 경구용 Ibuprofen과 정주용 Indomethacin의 효과 비교

이지형,최민환,심규홍,송영환,최명재 대한신생아학회 2013 Neonatal medicine Vol.20 No.1

Purpose: Ibuprofen and indomethacin has been used in treatment of patent ductus arteriosus (PDA) in Korea. But, there were few reports about oral ibuprofen for the treatment of PDA. We aimed to evaluate the efficacy and safety of oral ibuprofen versus intravenous indomethacin for the treatment of PDA in very low birth weight (VLBW) infants. Methods: A retrospective study of VLBW infants treated with oral ibuprofen or intravenous indomethacin for symptomatic PDA at Inje University Sanggye Paik Hospital between February 2002 and April 2012 was performed. Results: We identified 43 infants that received oral ibuprofen and 9 infants that received intravenous indomethacin. There were no significant differences in the efficacy and safety between oral ibuprofen group and intravenous indomethacin group. There was no significant difference between the use of oral ibuprofen before 48 hours after birth and after 48 hours the efficacy and safety. Conclusion: In our study, oral ibuprofen appears to be as effective as intravenous indomethacin for the treatment of PDA in VLBW infants with similar complication rates. 목적: 극소 저체중 출생아 동맥관 개존증의 약물 치료로 경구용 ibuprofen과 정주용 indomethacin의 효과 및 부작용을 비교분석해 보고 경구용 ibuprofen군 내에서도 48시간 이전에 사용한 경우와 이후에 사용한 경우를 나누어 각 군에서의 효과와 부작용의 차이를 조사하여 경구용 ibuprofen 제제의 효용성과 치료 시기 결정에 대한 실마리를 얻고자 하였다. 방법: 2002년 2월부터 2012년 4월까지 인제대학교 상계백병원 소아청소년과에서 출생한 재태연령 32주 미만이면서 출생체중 1,500 g 미만인 신생아 중 혈역학적으로 의미 있는 동맥관 개존증으로 치료받은 52명 중 정주용 indomethacin 투여군 9명과 경구용 ibuprofen 투여군 43명을 대상으로 약물의 효능과 부작용을 후향적인 방법으로 조사하여 비교 분석하였다. 결과: 각 군에서 첫 번째 주기 약물 치료 후 반응을 보인 환아는 정주용 indomethacin 투여군 전체 9명 중 7명, 경구용ibuprofen 투여군 43명 중 35명으로 유의한 차이가 없었다(77.8% vs 81.3%, P=0.802). 부작용 측면에서도 유의한 차이는 없었다. 경구용 ibuprofen 투여군 내에서 48시간 이전에 사용한 경우와 48시간 이후에 사용한 경우 효능과 부작용측면에서의 유의한 차이는 없었다. 결론: 극소저체중 출생아에 있어 동맥관 개존증의 치료에 경구용 ibuprofen이 정주용 indomethacin에 비해 효능과 부작용 면에서도 유의한 차이가 없는 것으로 보임에 따라 저렴하면서도 간단하게 사용할 수 있는 경구용 ibuprofen의 사용이 권장될 수 있겠다.

구연 : 백서 암컷에서 에스트로겐에 의한 간 손상시 Indomethacin의 영향

이소연,이진선,장우임,정우철,이강문,조현미,양진모,이영석,정인식,정규원,선희식 대한간학회 2003 Clinical and Molecular Hepatology(대한간학회지) Vol.9 No.3(S)

배경/목적: 에스트로겐 투여시 간 내에서 Kupffer세포를 활성화시켜 저산소증을 유발시키고 대사물질 및 여러 mediator를 유리시켜 간 독성을 일으킨다. 이에 연자등은 Prostaglandin생성 억제제인 indomethacin투여시 에스트로겐에 의한 간 손상에 미치는 영향을 알아보고자 하였다. 대상과 방법: 암컷 백서에서 정상군(saline투여), 에스트로겐투여군(실험 24시간전에 estriol 20mg/bw Kg을 복강내 투여), Indomethacin과 에스트로겐 병합투여군(실험 7일전부터 indomethacin 50uM을 복강내 투여후 실험 1일전 estriol투여)으로 나누어 간문맥으로부터 상대정맥으로 관류액을 순환시켜 상대정맥에서 관류액을 체취하여 oxygen uptake를 측정하였고 혈청내 AST치를 측정하였으며 Kuffer세포를 분리 배양하여 lipopolysaccharide를 투여후 Kupffer세포내 calcium농도를 측정하여 비교하였다. 결과: 1) Oxygen uptake는 정상군, 에스트로겐투여군, indomethacin병합투여군에서 각각 114±4, 146±6, 118±8 umole/g/hr로 에스트로겐투여군에서는 의의있게 증가되었지만 indomethacin투여군에서는 정상군과 차이가 없었다. 2) AST치는 정상군에서는 50±8U/L, 에스트로겐 투여군에서는 458±126U/L, indomethacin병합 투여군에서는 124±57U/L로 에스트로겐 투여군에 비해 의의있게 낮았다. 3) Lipopolysaccharide 1 ug/mL를 투여한 후 측정한 Kupffer세포내 calcium농도는 정상군에서는 195 nM, 에스트로겐투여군에서는 372 nM, indomethacin병합 투여군에서는 213 nM로 에스트로겐투여군에 비해 의의있게 낮았다. 결론: 이상의 결과로 indomethacin은 에스트로겐에 의한 간 손상으로부터 보호작용이 있으며 기전은 Kupffer세포내에서 indomethacin이 arachidonic acid로부터 prostaglandin의 생성을 저해시키는 등 Kupffer세포를 불활성화시킴으로써 oxygen uptake를 감소시키고 prostaglandin의 생성을 억제시켜 prostglandin(E2)에 의한 간 실질세포에서의 oxygen uptake증가를 억제시킴으로써 간 독성으로부터 보호된다.

Indomethacin으로 유발된 생쥐의 위점막 손상에 대한 쑥을 함유한 천연물 복합제의 효과

정성연 ( Seong-yeon ),주인환 ( Jeong In-hwan Joo ),박종민 ( Jong-min Park ) 대전대학교 한의학연구소 2022 혜화의학회지 Vol.32 No.1

Objectives : This study was aimed to investigate whether gastritis care mixture (GCM) with artemisi a can prevent indomethacin-induced gastric damages. GCM consisted of artemisiae argyi folium, diosc oreae rhizoma, crataegi fructus, zizyphi fructus, and glycyrrhizae radix. Methods : Antioxidant activities were evaluated using 2,2-dipheny-1-picrylhydrazyl (DPPH), 2,2'-a zinobis-(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), and ferric reducing antioxidant power (FRA P) method. GCM were pretreated 6 h before indomethacin treatment on rat gastricmucosal epithelial BGM1 cells. Cytoprotection effects eavluated by MTT. [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide]. Reverse-transcription PCR (RT-PCR) and Western blot was performed to check anti-inflammatory actions. Different doses of GCM were administrated intragastrically before the indomethacin administration in mouse models. After killing, addition to gross and pathological evaluation of ulcer, the expressions of inflammatory mediators were analyzed by enzyme-linked immunosorbent assay (ELISA). Results : GCM was very effective in preventing indomethacin-induced gastric damages in a low dose. indomethacin increased the expression of cyclooxygenase-2 (COX-2) and decreased the expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and Heme oxygenase-1 (HO-1), but GCM significantly attenuated indomethacin-induced COX-2 expression. Interestingly, GCM induced expression of 15-PGDH and HO-1. These in vitro findings were exactly validated in indomethacin-induced gastritis mouse models. GCM groups showed significantly ameliorated patheologic lesion compared to the control group. The serum levels of proinflammatory cytokines including interleukin-6 and tumor necrosis factor were significantly attenuated in the GCM group. However, these preventive effects of G CM were dependent on dosage of GCM; higher dose above 200mg/kg paradoxically aggravated indomethacin-induced inflammation. Conclusions : GCM is a candidate substance which can attenuate NSAIDs-induced gastritis on potent anti-inflammatory action.

Activation of SAPK and Increase in Bak Levels during Ceramide and Indomethacin-Induced Apoptosis in HT29 Cells

Ju Ho Kim,Sae Ock Oh,Sung Sook Jun,Jin Sup Jung,Jae Suk Woo,Yong Keun Kim,Sang Ho Lee 대한생리학회-대한약리학회 1999 The Korean Journal of Physiology & Pharmacology Vol.3 No.1

<P> It has been reported that activation of sphingomyelin pathway and nonsteroidal anti-inflammatory drugs (NSAIDS) inhibit the promotion of colon carcinoma. Ceramide, a metabolite of sphingomyelin, and indomethacin were shown to induce apoptosis in colon carcinoma cells. However, the mechanisms of ceramide- and indomethacin-induced apoptosis in the colon carcinoma cells are not clearly elucidated. Recent studys showed that indomethacin-induced apoptosis in colon cancer cells through the cyclooxygenase-independent pathways, and that may be mediated by generation of ceramide. In this study, we compared effects of ceramide and indomethacin on important modulators of apoptotic processes in HT29 cells, a human colon cancer cell line. Ceramide and indomethacin induced apoptosis dose- and time- dependently. Ceramide and indomethacin increased stress-activated protein kinase (SAPK) activity, and decreased mitogen-activated protein kinase (MAPK) activity. The expression of Bak was increased by the treatment of ceramide and indomethacin. The expression of other Bcl-2 related proteins (Mcl-1, Bcl-X<SUB>L</SUB>, Bax) which were known to be expressed in colon epithelial cells was not changed during the ceramide- and indomethacin-induced apoptosis. Our results suggest that ceramide and indomethacin share common mechanisms for induction of apoptosis in HT29 cells.