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1 J Korean Med Obes Res 2017;17(2): pissn , eissn JKOMOR Original Article 소청룡탕추출물의당뇨병질환에서위장관운동기능개선에관한연구 배진수ㆍ김익성ㆍ서병도 1 ㆍ김병주 부산대학교한의학전문대학원양생기능의학부, 1 경운대학교물리치료학과 Effects of Socheongryong-Tang, a Traditional Chinese Medicine, on Gastrointestinal Motility Disorders (Diabetic Models) in Mice Jinsoo Bae, Iksung Kim, Byoung-Do Seo 1, Byung Joo Kim Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, 1 Department of Physical Therapy, Kyungwoon University Received: October 27, 2017 Revised: December 1, 2017 Accepted: December 1, 2017 Correspondence to: Byung Joo Kim Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, 49 Busandaehak-ro, Mulgeum-eup, Yangsan 50612, Korea Tel: Fax: vision@pusan.ac.kr Copyright 2017 by The Society of Korean Medicine for Obesity Research Objectives: The purpose of this study was to investigate the effects of Socheongryong-tang, a traditional herbal medicine, on gastrointestinal (GI) motility disorders (inflammatory and diabetic models) in mice. Methods: The in vivo effects of Socheongryong-tang on GI motility were investigated by calculating percent intestinal transit rates (ITR) and gastric emptying (GE) values using Evans Blue and phenol red, respectively, in normal mice and in mice with experimentally induced GI motility dysfunction (GMD). GMD models were induced by acetic acid and streptozotocin. Results: In normal ICR mice, ITR and GE values were significantly and dose-dependently increased by the intragastric administration of Socheongryong-tang ( g/kg). The ITR values (%) of GMD mice were significantly lower than those of normal mice, and these reductions were significantly and dose-dependently inhibited by Socheongryong-tang. Conclusions: These results suggest that Socheongryong-tang is a good candidate for the development of a prokinetic agent that may prevent or alleviate GMD. Key Words: Traditional medicine, Gastrointestinal motility, Gastric emptying, Streptozotocin, Diabetes mellitus 서론 과거부터현재까지전통의학은건강관리에큰역할을하고있다. 현대의학의큰발달에도불구하고전통의학은여전히많은나라에서질병치료에이용되고있으며또한현대의학의많은약들이전통의학에기반을두고만들어지고있다 1,2). 소청룡탕 ( 小靑龍湯 ) 은한국, 일본, 중국에서잘알려진호흡기질환치료제로, 마황 (Herba Ephedrae), 작약 (Radix Paeoniae), 세신 (Herba Asari), 건강 (Rhizoma Zingiberis), 감초 (Radix Glycyrrhizae), 계지 (Ramulus Cinnamomi), 반하 (Rhizoma Pinelliae), 오미자 (Fructus Schisandrae) 의 8가지한약재로이루어져있다. 소청룡탕은주로알레르기비염, 알레르기천식, 감기등에주로사용되어왔으며그외에도결막염, 습진, 수포, 신염등에도사용한다고알려져있다 3-5). 최근들어소청룡탕이항히스타민작용을한다고밝혀진바있으며또한기관지평활근의확장작용을한다는것이밝혀졌다 6-8). 또한천식환자에게서 interleukin-4 와 immunoglobulin E의레벨을감소시키고기도내로의염증세포침윤을막아 CD4 + T세포면역반응에영향을미처천식치료에도움을준다는사실도알려져있다 9-12). 또한위장관 (gastrointestinal tract) 에서향도잡이 (pacemaker activity) 의역할을하는카할간질세포 (interstitial cells of Cajal) 에서소청룡탕이향도잡이기능을증진시키고이반응이 61

2 mitogen-activated protein kinases (MAPKs) 와 phospholipase C (PLC) 에의해조절되고있음이알려져있다 1). 그러나소청룡탕에관한위장관에서의효능에관한생체내 (in vivo) 연구는많이이루어져있지않다. 위장관운동성질환을일으키는많은질환중에서최근에당뇨병에의한위장관질환환자들이많이증가하고있다 13). 당뇨병성위장관운동성장애는망막병증 (retinopathy), 신경병증 (neuropathy), 신증 (nephropathy) 등의미세혈관합병증이동반된당뇨환자에서흔히발생하는위장관증상으로 14), 삶의질이낮고잦은입원과높은이환율등을나타내며 15) 지속적인치료가필요한질환이라는측면에서적절한진단및치료가필요한질환이다. 이러한장기간지속적인치료가필요한질환에서는한의학적이치료가많은도움이되는것으로알려지고있다 16). 따라서본연구에서는소청룡탕의위장관운동성증진과위장관염증및당뇨병에서생기는위장관운동성질환의개선에관한유의한효과를얻었기에이를보고하는바이다. 재료및방법 1. 약재소청룡탕은마황, 작약, 세신, 건강, 감초, 계지, 반하, 오미자로이루어져있다 (Table 1). 소청룡탕은한국신약제약회사 (HANKOOKSHINYAK Pharmaceutical CO. LTD., Nonsan, Korea; 에서기증받아사용하였다. 증류수에 0.5 g/ml의농도로녹인후에냉장고에보관사용하였다. Table 1. Amount and Composition of Socheongryong-tang Herb Scientific name Amount (g) Ban Ha Rhizoma Pinelliae 2 Ma Hwang Herba Ephedrae 1 Jak Yak Radix Paeoniae 1 Omija Fructus Schisandrae 1 Sae Shin Herba Asari 1 Gun Kang Rhizoma Zingiberis 1 Kae Ji Ramulus Cinnamomi 1 Kam Cho Radix Glycyrrhizae 1 Total amount 9 2. 동물 8주령의 ICR 수컷마우스 (25 30 g) 를 ( 주 ) 샘타코바이오코리아 (Samtako Bio Korea Co., Ltd., Osan, Korea) 에서구입하여, 1주간실험실환경에적응하도록한후사용하였다. 실험기간동안온도는 22 o C±2 o C, 습도 53%±2%, 환기횟수 13 15회 /h, 그리고조명에 12시간의명암 ( 점등 : 06:00, 소등 : 18:00) 주기가있는실험실환경에서고형사료 (Samtako Bio Korea Co., Ltd.) 와물을자유롭게공급받았다. 본실험은부산대학교동물실험윤리위원회의승인 ( 승인번호 : PNU ) 을받아동물윤리준칙에의거하여실험을진행하였다. 3. 위배출능 (gastric emptying, GE) 측정소청룡탕을위내투여한 30분후에 0.05% 패놀레드용액을 0.5 ml 투여한다. 20분이지난후에위를제거하고 0.01 N NaOH 5 ml에서조각으로나눈후에균질화한다. 균질화된조직을 20% trichloroacetic acid 0.2 ml에넣은후 1,050 g의속도로 10분동안원심분리기로돌린다. 상층액에 0.5 N NaOH 0.2 ml를넣은후분광기 560 nm의파장으로흡입력을측정한다. 위배출능은 100 (A/B) 100 의공식으로계산하는데여기서 A는소청룡탕을넣은후측정한위흡입력, B는패놀레드용액을투여한후바로측정한위흡입력을말한다. 4. Evans blue에의한장이동능 (intestinal transit rate, ITR) 측정소청룡탕에의한장이동능력은 Evans blue solution (5%) 에의한장이동거리 (distance) 로측정하였다. 정상 ICR 생쥐에소청룡탕을위내투여 (intragastric administration) 후 30분이지나 Evans blue를구위관 (orogastric tube) 을이용하여위내투여하였다. 다시 30분이지난후생쥐장에서 Evans blue가유문 (pylorus) 에서장까지이동한거리를측정하였다. 전체장거리에서 Evans blue가이동한거리의비율로 ITR을결정하였다. 같은날정상생쥐와위장관운동질환생쥐를모두실험하였고, 다른한약재와의위장관운동능비교를위해서지실 (Poncirus trifoliata Raf., PF) 을사용하였다 17). PF는대한민국에서가장널리이용되는한약재로강력한위장관운동촉진제로알려지고 62

배진수외 : 소청룡탕과위장관운동기능 있으며다양한위장관운동질환치료에이용되고있다 18,19). 결과 5. Acetic acid에의한복막자극 (peritoneal irritation) 생쥐모델복막자극은 acetic acid (0.6%) 의투여로유발하였다 20,21). Acetic acid의투여후 30분 cage에서회복후실험을진행하였다. 6.

정상 (normal) 생쥐에는같은양의 0.1 mol/l citrate 용액을복막안으로주사하였다. 생쥐들은자유롭게먹이와물을먹을수있게하였으며, 일반적인정상환경에서지내도록하였다. 7. 통계처리대조군과실험군사이의통계학적유의성검정은 Student s t-test를사용하였으며유의수준 P<0.05를사용하였다. 실험결과는빈도 (%) 로기재하였다. 1.

3 배진수외 : 소청룡탕과위장관운동기능 있으며다양한위장관운동질환치료에이용되고있다 18,19). 결과 5. Acetic acid에의한복막자극 (peritoneal irritation) 생쥐모델복막자극은 acetic acid (0.6%) 의투여로유발하였다 20,21). Acetic acid의투여후 30분 cage에서회복후실험을진행하였다. 6. 스트렙토조토신 (streptozotocin; STZ) 에의한당뇨 (diabetic) 생쥐모델 ICR 생쥐 (5주령) 를이용하여당뇨병을유발하기위해서 STZ (Sigma-Aldrich, St. Louis, MO, USA) 를 0.1 mol/l ice-cold citrate 용액 (ph=4.0) 에녹인후 200 mg/kg의농도로복막안으로주사하였다. 정상 (normal) 생쥐에는같은양의 0.1 mol/l citrate 용액을복막안으로주사하였다. 생쥐들은자유롭게먹이와물을먹을수있게하였으며, 일반적인정상환경에서지내도록하였다. 7. 통계처리대조군과실험군사이의통계학적유의성검정은 Student s t-test를사용하였으며유의수준 P<0.05를사용하였다. 실험결과는빈도 (%) 로기재하였다. 1. 정상생쥐의위배출능 (GE) 에서소청룡탕의효과정상생쥐에서소청룡탕에의한 GE를 Fig. 1에정리하였다. 정상 (normal) 생쥐에서는 58.5%±1.2% 의평균 GE를나타냈으며, 소청룡탕 g/kg 투여시에는 57.5%± 1.1%, g/kg에서는 61.1%±0.7% (P<0.05), 0.25 g/kg에서는 77.0%±1.3% (P<0.01) 를나타냈다 (Fig. 1). 소청룡탕농도가증가할수록 GE가증가하는현상을보였다. 다른위에작용하는약들과의효능비교를위해 GE 연구에많이사용되는 mosapride (5 mg/kg) 와 domperidone (5 mg/kg) 을투여해보니평균 GE가각각 71.9%±0.9% (P< 0.01) 와 69.0%±1.5% (P<0.01) 로과거의연구와비슷하게나타났다 22,23). 2. 정상생쥐의장이동능 (ITR) 에서소청룡탕의효과정상생쥐에서 Evans blue를위내투여후 30분후에나타난평균 ITR을 Fig. 2에정리하였다. 정상 (normal) 생쥐에서는 54.5%±3.1% 의평균 ITR을나타냈으며, 소청룡탕 g/kg 투여시에는 56.0%±0.9%, g/kg에서는 59.6%±2.2% (P<0.01), 0.25 g/kg에서는 66.0%± 1.6% (P<0.01) 를나타냈다 (Fig. 2). 소청룡탕농도가증가 Fig. 1. Increasing effect of extract of Socheongryong-tang on normal gastric emptying (GE). 5-HT 4 receptor agonist (mosapride [Mosa], 5 mg/kg) or a dopamine receptor antagonist (domperidone [Dom], 5 mg/kg) was administered in distilled water. After a 24 hours fast, mice were orally dosed with Socheongryong-tang at the indicated dosages. GE percentages were calculated as described in Materials and Methods. Bars represent mean±standard error. i.g.: intragastric infusion. *P<0.05. **P<0.01. Fig. 2. Effect of Socheongryong-tang on intestinal transit rate (ITR) in normal mice. Mice were treated with Socheongryong-tang and then intragastrically administered Evans blue 30 minutes later. ITR (%) values were determined 30 minutes after Evans blue administration. Bars represent mean±standard error. PF: Poncirus trifoliata Raf., i.g.: intragastric infusion. **P<

Bars represent mean±standard error. PF: Poncirus trifoliata Raf., i.g.: intragastric infusion. **P<0.01. 할수록 ITR이증가하는현상을보였다. 다른한약재와의효능비교를위해위장관운동성연구에많이사용되는 PF (1 g/kg) 를투여해보니평균 ITR은 68.1%±2.8% (P< 0.

4 Fig. 3. Effect of Socheongryong-tang on intestinal transit rate (ITR) in acetic acid treated mice. Mice were treated with Socheongryong-tang and then intragastrically administered Evans blue 30 minutes later. ITR (%) values were determined 30 minutes after Evans blue administration. Bars represent mean±standard error. PF: Poncirus trifoliata Raf., i.g.: intragastric infusion. **P<0.01. 할수록 ITR이증가하는현상을보였다. 다른한약재와의효능비교를위해위장관운동성연구에많이사용되는 PF (1 g/kg) 를투여해보니평균 ITR은 68.1%±2.8% (P< 0.01) 로과거의연구와비슷하게나타났다 19,24). 3. 위장관기능장애생쥐의장이동능 (ITR) 에서소청룡탕의효과위장관기능장애생쥐를만들기위해서위에서언급한대로 acetic acid에의한복막자극유발생쥐및 STZ에의한당뇨생쥐모델에서소청룡탕의위장관운동성기능회복효능을알아보았다. Acetic acid에의한복막자극은 ITR 측정시주사부위의염증소견으로확인하였고, 당뇨유도는 STZ 투여 2개월후, 공복후 8시간후에꼬리정맥을통해서채혈하여 one-touch blood glucose monitoring system (Johnson and Johnson, New Brunswick, NJ, USA) 을이용하여혈당을측정하였다. 혈당수치가 16 mmol/l 이상인경우만실험에이용하였다. Acetic acid에의한복막자극유발생쥐에서 ITR의감소를나타냈고 (26.3%±2.1%), 이생쥐에소청룡탕을위내투여시 ITR 이회복하는현상을보였다. 소청룡탕 g/kg에서는 28.9%±1.7%, g/kg에서는 35.0%±0.9% (P<0.01), 0.25 g/kg에서는 44.0%±1.9% (P<0.01) 의 ITR을보였다 (Fig. 3). 또한 STZ에의한당뇨생쥐모델에서 ITR의감소 Fig. 4. Effect of Socheongryong-tang on intestinal transit rate (ITR) in streptozotocin (STZ) induced diabetic mice. Two months after administering STZ, mice were treated with Socheongryong-tang and then intragastrically administered Evans blue 30 minutes later. ITR (%) values were determined 30 minutes after Evans blue administration. Bars represent mean±standard error. SPF: Poncirus trifoliata Raf., i.g.: intragastric infusion. **P<0.01. 를나타냈고 (38.7%±1.3%), 이생쥐에소청룡탕을위내투여시 ITR이회복하는현상을보였다. 생맥산 g/kg 에서는 54.8%±1.4% (P<0.01), g/kg에서는 60.9%± 2.0% (P<0.01), 0.25 g/kg에서는 75.0%±2.3% (P<0.01) 의 ITR을보였다 (Fig. 4). Acetic acid에의한복막자극유발생쥐와 STZ에의한당뇨생쥐모델두경우모두 PF (1 g/kg) 에의해서도소청룡탕과비슷하게 ITR을보였다 (acetic acid인경우는 47.5%±2.1%, STZ인경우는 68.1%± 2.8%, P<0.01; Fig. 3, 4). 또한소청룡탕에의한어떤다른복부임상증상은보이지않았다. 고찰 본연구는소청룡탕이정상생쥐및위장관운동성질환생쥐에서위장관운동성을증가시키는기능이있음을확인한연구로소청룡탕이위장관운동촉진제 (prokinetic activity) 로서사용가능함을보여주고있다. 전통한방제제가다양한소화기질환치료제및보조제로서많이사용되고있지만, 위장관운동성개선에관한효능은많이알려져있지않다. 소청룡탕에의한위장관운동조절가능성은 2013년본 64

5 배진수외 : 소청룡탕과위장관운동기능 연구팀에서위장관카할간질세포에서조절가능성을확인한연구가있다 1). 카할간질세포는위장관향도잡이세포로서위장관평활근의자발적인서파 (slow wave) 를조절하는것으로알려지고있다 25). 이카할간질세포에소청룡탕을투여해보니카할세포의향도잡이전압을탈분극시키고이러한탈분극은세포내 MAPKs와 PLC를통해서이루어짐을밝혔다 1). 따라서소청룡탕은카할간질세포를통해서평활근을수축시키고따라서위장관운동성이증가할것으로예상되었는데이번연구를통해서소청룡탕에의한위장관운동성증가를확인할수있었다. 본연구에서소청룡탕은정상생쥐의 GE를증가시켰다. 일반적으로위장관운동성조절약으로많이사용되는 mosapride와 domperidon과의비교를해보면소청룡탕 0.25 g/kg에서의효능과거의비슷하게나왔다 (Fig. 1). 하지만이결과는소청룡탕의용량이 mosapride와 domperidon 용량보다 50배나많아단순히효능을비교하기는힘들것같고, 앞으로 mosapride 와 domperidon 같은약이외의다른적당한천연물이나한약제제를찾아서비교하는연구가필요할것으로생각된다. 또한소청룡탕의 ITR을보면소청룡탕의농도가증가할수록 ITR도증가함을확인할수있었다. 일반적으로한의학에서 ITR을증가시키는한약으로많이사용되는 PF와의효능을비교해보았고소청룡탕 0.25 g/kg에서의효능과거의비슷하게나왔다 (Fig. 2). 위장관의운동성이감소되는동물모델에서의소청룡탕의효능을보면 acetic acid에의한복막자극유발생쥐에서소청룡탕의농도가증가할수록 ITR이증가하였고 (Fig. 3), 또한 STZ에의한당뇨생쥐모델에서도소청룡탕의농도가증가할수록 ITR이증가하였다 (Fig. 4). 따라서소청룡탕은카할간질세포를조절해서결국에 GE와 ITR을증가시키는것으로생각된다. 한약제제성분을이용한위장관운동성관련연구는많이이루어지고있다. 인삼은카할간질세포에서비선택성양이온통로 (nonselective cation channel) 를통해내향전류 (inward current) 를촉진시키고세포안팎칼슘농도에따라활성이증가하는것으로알려지고있다 26). 또한오미자는평활근및카할간질세포를통해세포안팎칼슘농도를조절하여위장관운동성을증가시키며 27) 다양한병태적인질환에서위장관운동성을증가시키는것으로알려지고있다 28). 생맥산과평위산은카할간질세포의세포안칼슘농도및 PLC 기전에따라활성을조절해위장관운동성을증가시키는것으로알려지고있다 29,30). 또한삼황사심탕과 22) 황련해독탕도 30) 카할세포를조절해위장관운동성증진효과가두드러지게나타남을확인하였다. 위장관운동성은위장관신경계에서분비되는다양한신경전달물질과호르몬및약물들이상호작용하여조절되고있으므로 31) 한약재도이와비슷한기능을하는것으로생각된다. 위장관운동성조절은카할간질세포의세포막에있는비선택성양이온통로인일과성수용체잠재이온채널멜라스타틴 7 아류형 (transient receptor potential ion channel subtype7) 과세포내칼슘에의해조절되는염소이온채널 (Cl channel) 에의한것임이밝혀졌다 32,33). 따라서앞으로소청룡탕에의한이러한이온통로의조절및기전에관한추가연구가필요할것으로생각된다. 당뇨병에의한위장관운동장애는보통자율신경계의손상으로인한것으로생각되어왔으나신경손상의조직병리학적소견은잘보이지않고 34), 또한평활근의작용을직접적으로억제하는것으로도보이지않는다 35,36). 최근에위에서언급한카할간질세포의기능을억제하여당뇨병에의한위장관운동장애를일으킨다는보고가많아지고있다 37,38). 따라서앞으로당뇨병에의한위장관운동장애연구는카할간질세포를중심으로하면좋은결과가있을것으로생각되고, 소청룡탕에의한위장관운동성개선은카할간질세포를조절해서나타나는것으로생각된다. 당뇨환자는위장관모든부위에서운동장애가있다는사실은잘알려져있다. 이러한운동장애는영양부족, 불충분한혈당조절, 경구투여약제의흡수장애등을초래할수있다 36,39). 따라서당뇨병에의한위장관운동장애가나타나면적극적으로지속적으로치료를하는것이앞으로의삶의질을높일수있으리라생각된다. 또이러한적극적이고지속적인치료는부작용이적으면부담이덜한한의학적인치료가가장적합하다고생각된다. 위장관운동촉진제는위장의운동능력을촉진시켜음식물의이동및배출을원활히함으로써음식물의배출장애로생기는증상을개선하기위해사용된다. 위장관운동촉진제는크게 5HT 4 작용제, 도파민수용체길항제, 모틸린수용체작용제등이있다 40). 위장관운동촉진제의대표적인약제로 cisapride 가있지만심장관련부작용으로현재 65

6 사용이불가능해졌다. 이로인해과거부터사용되어왔던도파민수용체길항제가재조명되어많이사용되고있으며이외에도여러약제들이 cisapride 를대체하여사용되고있다. 하지만이런약제들도여러가지부작용들을가지고있는것으로알려지고있다 40). 결론 현재위장증상을개선시킬수있는위장관운동조절약제들이많이소개되어있다. 각각의약제들은제각기다양한약리학적특성을갖고있다. 또한환자들은개개인이각기다른특성을갖고있고다양한증상을호소한다. 따라서환자의증상, 특성등을고려하여적절한약제를사용하는것이중요한데, 소청룡탕과같은한약제제는다양한부작용이적으면서도적절한효능을볼수있어앞으로더깊이있는연구가필요할것으로생각된다. 이번연구로소청룡탕이위장관운동성개선효과가있음을알수있었고다양한위장관질환및당뇨병으로고생하는많은환자들에게도움이되어삶의질향상에도움이되기를바란다. 감사의글 이논문은부산대학교기본연구지원사업 (2년) 에의하여연구되었다. References 1. Hwang MW, Lee HJ, Song HJ, Kim BJ. Involvement of MAPKs and PLC pathways in modulation of pacemaking activity by So-Cheong-Ryong-Tang in interstitial cells of Cajal from murine small intestine. Sci World J ; 2013 : Bai D. Traditional Chinese medicines and new drug development. Pure Appl Chem ; 65(6) : Jung S, Cho SJ, Moon KI, Kim HW, Kim BY, Cho SI. Effects of Socheongryong-Tang on immunoglobulin production in asthmatic mice. Kor J Herbol ; 23(1) : Zuo Y, Zhu Z, Huang Y, Tao J, Li Z. Science of prescriptions. Nanjing : Library of Traditional Chinese Medicine : Ko E, Rho S, Cho C, Choi H, Ko S, Lee Y, et al. So-Cheong- Ryong-Tang, tradititional Korean medicine, suppresses Th2 lineage development. Biol Pharm Bull ; 27(5) : Sakaguchi M, Iizuka A, Yuzurihara M, Ishige A, Komatsu Y, Matsumiya T, et al. Pharmacological characteristics of Shoseiryu-to, an antiallergic Kampo medicine without effects on histamine H1 receptors and muscarinic cholinergic system in the brain. Methods Find Exp Clin Pharmacol ; 18(1) : Kao ST, Lin CS, Hsieh CC, Hsieh WT, Lin JG. Effects of xiao-qing-long-tang (XQLT) on bronchoconstriction and airway eosinophil infiltration in ovalbumin-sensitized guinea pigs: in vivo and in vitro studies. Allergy ; 56(12) : Kao ST, Wang SD, Wang JY, Yu CK, Lei HY. The effect of Chinese herbal medicine, xiao-qing-long tang (XQLT), on allergen-induced bronchial inflammation in mite-sensitized mice. Allergy ; 55(12) : Ikeda Y, Kaneko A, Yamamoto M, Ishige A, Sasaki H. Possible involvement of suppression of Th2 differentiation in the antiallergic effect of Sho-seiryu-to in mice. Jpn J Pharmacol ; 90(4) : Makino T, Sasaki SY, Ito Y, Kano Y. Pharmacological properties of traditional medicine: effects of Gyokuheifusan on murine antigen-specific antibody production. Biol Pharm Bull ; 28(1) : Ko E, Rho S, Lee EJ, Seo YH, Cho C, Lee Y, et al. Traditional Korean medicine (SCRT) modulate Th1/Th2 specific cytokine production in mice CD4+ T cell. J Ethnopharmacol ; 92(1) : Lee JS, Oh SY, Seo SH, Kim TS, Ma JY. Protective effect of Socheongryong-Tang on hydrogen peroxide-induced hepatotoxicity. Kor J Herbol ; 26(4) : Maisey A. A practical approach to gastrointestinal complications of diabetes. Diabetes Ther ; 7(3) : Camilleri M. Clinical practice: diabetic gastroparesis. N Engl J Med ; 356 : Bell RA, Jones-Vessey K, Summerson JH. Hospitalizations and outcomes for diabetic gastroparesis in North Carolina. South Med J ; 95(11) : Maggie BC. Traditional Chinese medicine in the treatment of diabetes. Diabet Spectrum ; 14(3) : Hasler WL, Soudah HC, Dulai G, Owyang C. Mediation of hyperglycemia-evoked gastric slow-wave dysrhythmias by endogenous prostaglandins. Gastroenterology ; 108(3) : Kim BJ, Kim HW, Lee GS, Choi S, Jun JY, So I, et al. Poncirus trifoliate fruit modulates pacemaker activity in interstitial cells of Cajal from the murine small intestine. J Ethnopharmacol ; 149(3) : Lee HT, Seo EK, Chung SJ, Shim CK. Prokinetic activity of an 66

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386-390.hwp 386 HANYANG MEDICAL REVIEWS Vol. 29 No. 4, 2009 우리나라 미숙아의 통계와 의료비용 Statistics and Medical Cost of Preterm in Korea 윤혜선 을지대학교 노원을지병원 소아청소년과학교실 Hye Sun Yoon, M.D., Ph.D., Department of Pediatrics, Nowon