背景：消化性潰瘍出血是臨床上常見且有潛在致命危險的疾病。潰瘍再出血是病人死亡的危險因子。氫離子幫浦抑制劑，樂酸克（Omeprazole），是一種很強的胃酸分泌抑制藥物，可以改善消化性潰瘍出血的患者，經內視鏡治療止血後發生再出血的比率。血清反應因子（serum response factor，SRF）在潰瘍癒合過程為上皮細胞再生和肌肉組織重建之必要因子。
目的：本研究在評估消化性潰瘍出血的患者，使用低劑量3日的靜脈輸注Omeprazole，患者是否合併有多重器官疾病為發生再出血的危險因子。同時亦研究合併多重器官疾病的患者發生消化性潰瘍出血，使用低劑量7日靜脈輸注Omeprazole的再出血控制效益。此外，評估使用高劑量和低劑量靜脈輸注Omeprazole患者胃內的pH值。進一步瞭解合併多重器官疾病的患者在使用靜脈輸注Omeprazole後發生再出血的相關因子。另外亦研究SRF在胃潰瘍組織是否有表現增強的情形，以及影響SRF增強表現的因素。同時也評估是否因為缺乏SRF增強表現與最近出血表徵的持續存在有關，而容易發生再出血。
方法：收集臨床上合併多重器官疾病發生消化性潰瘍出血的患者，經內視鏡治療成功止血後，每位給予Omeprazole靜脈輸注80 mg後收入研究。在第一個研究中，另外收集沒有合併多重器官疾病的消化性潰瘍出血患者做對照組。而在第二個和第三個研究中，這些合併多重器官疾病的潰瘍出血患者被隨機分配至使用8 mg/h的高劑量組或3.3 mg/h的低劑量組。在第二個研究中，我們比較使用高劑量3日和低劑量3日患者之間的再出血率。在第三個研究中，我們比較使用低劑量7日和高劑量3日患者之間的再出血率。隨機選取幾位患者來紀錄連續24小時的胃內pH值，以及進行免疫組織化學染色來測定胃潰瘍部和非潰瘍部組織上SRF的表現強弱。
結果：消化性潰瘍出血的患者，使用低劑量3日Omeprazole靜脈輸注，合併多重器官疾病的患者比起沒有合併多重器官疾病的患者有比較高的再出血率（7日內：32.5% vs. 2.5%，P<0.05；28日內：37.5% vs. 5%，P<0.05）。合併多重器官疾病患者的累計再出血率在3日內是15%，7日內是20%，14日內是30%，28日內是35%。而使用低劑量7日Omeprazole靜脈輸注的患者，比起使用高劑量3日，在第8日至第28日的延遲再出血率會較低（0% vs. 10.7%，P=0.03；relative risk 0.52 [95% CI 0.43~0.63]）。在使用高劑量或是低劑量的患者，胃內pH值>5.4的時間相似（89.5%±11.1% vs. 86.3%±15.2%，P=0.60）。血清白蛋白濃度<3.0 g/dL是影響患者在7日內和28日內發生再出血的獨立因子（Odds ratio 9.9 and 5.9，P<0.001）。SRF會表現在胃潰瘍組織的強度會高於非潰瘍組織，包括了在上皮細胞（54.2% vs. 30.3%，P<0.01）、固有層的單核球細胞（69.0% vs. 58.5%，P=0.02）和黏膜層的平滑肌細胞（80.0% vs. 68.1%， P=0.02）的表現。SRF在胃潰瘍組織的增強表現程度與患者是否出現最近出血表徵呈負相關（22.2% vs. 58.5%，P=0.01）。而胃潰瘍組織SRF沒有增強表現的患者相較於SRF有增強表現者，會有較高的再出血率（9.8% vs. 0%，P=0.036）。
結論：在沒有合併多重器官疾病的消化性潰瘍出血患者，使用靜脈輸注低劑量Omeprazole 3日，可以有效地控制潰瘍再出血。合併多重器官疾病的消化性潰瘍出血患者，使用較長時間的低劑量Omeprazole 7日可以降低8日後的延遲再出血率。SRF在胃潰瘍組織的增強表現可能扮演調控胃潰瘍癒合的重要角色。SRF在胃潰瘍組織的增強表現與患者出現最近出血表徵呈負相關，而胃潰瘍組織的SRF沒有增強表現之患者較容易發生胃潰瘍再出血。

關鍵詞：消化性潰瘍再出血，合併多重器官疾病，樂酸克，血清反應因子

Backgrounds: Peptic ulcer bleeding is a common but lethal disease. Rebleeding is a risk factor of mortality. Omeprazole, a proton pump inhibitor is a powerful gastric acid suppression agent to improve rebleeding control of peptic ulcer bleeding after receiving endoscopic local therapy. Serum response factor (SRF) is crucial for re-epithelialization and muscle restoration in ulcer healing.
Aims: This study aimed to evaluate whether comorbidity was a risk factor of peptic ulcer rebleeding when the patients received 3-day low-dose omeprazole infusion. Then, this study determined the efficacy of 7-day low-dose omeprazole infusion in preventing peptic ulcer rebleeding for comorbid patients. Moreover, we assessed the intragastric pH between the patients receving high-dose and low-dose omeprazole infusion. Further, we determined the factors related to rebleeding after omeprazole infusion in the comorbid patients. In addition, we assessed whether SRF was up regulated in the gastric ulcer tissue, and the factors related to such up-regulation. We determined whether lacking of such up-regulated SRF correlated with persistence of stigmata of recent hemorrhage (SRH) to predispose rebleeding.
Methods: The patients with co-morbidities and peptic ulcer bleeding were consecutively enrolled after successful hemostasis by endoscopy, and then each patient received 80 mg bolus of intravenous omeprazole. In the first study, the non-comorbid patients with peptic ulcer bleeding were also enrolled as the control group. In the second and third study, the patients were randomized into either the high-dose group as 8 mg/h or the low-dose group as 3.3 mg/h. In the second study, we compared the rebleeding rates between the 3-day high-dose and 3-day low-dose groups. In the third study, we compared the rebleeding rates between the 7-day low-dose and 3-day high-dose groups. The intragastric pH was recorded for 24 h continuously. The gastric ulcer and the non-ulcer tissues are sampled for checking the intensity of SRF by immunohistochemistry staining.
Results: Among the patients with peptic ulcer bleeding who received 3-day low-dose omeprazole infusion, the presence of the comorbidity was a risk to have higher rebleeding rates than no comorbidity (within 7-day: 32.5% vs. 2.5%, P<0.05; within 28-day: 37.5% vs. 5%, P<0.05). The cumulative rebleeding rates in the comorbid patients were about 15% within 3 days, 20% within 7 days, 30% within 14 days, and 35% within 28 days. The 7-day low-dose group had a lower risk of rebleeding between the 8th and 28th day compared with the 3-day high-dose group (0% vs. 10.7%, P=0.03; relative risk, 0.52 [95% CI 0.43~0.63]). The intragastric pH>5.4 was similar between the patients receiving the high-dose and the low-dose omeprazole infusion (89.5±11.1 vs. 86.3±15.2, P=0.60). The serum albumin<3.0 g/dL was an independent risk factor related to rebleeding within 7 days and 28 days respectively (Odds ratio 9.9 and 5.9, P<0.001, respectively). The intensity of SRF was significantly higher in the ulcer tissue than in the non-ulcer tissues, including over superficial epithelium (54.2% vs. 30.3%, P<0.01), mononuclear cells of lamina propria (69.0% vs. 58.5%, P=0.02), and smooth muscle cells of mucosa (80.0% vs. 68.1%, P=0.02). The degree of SRF up-regulation in the ulcer tissue was negatively correlated with the presence of SRH (22.2% vs. 58.5%, P=0.01). The patients without up-regulation of SRF had a higher rate of ulcer rebleeding than those with up-regulation (9.8% vs. 0%, P=0.036).
Conclusions: The 3-day low-dose omeprazole infusion achieved favorable control of rebleeding in the non-comorbid patients with peptic ulcer bleeding. A prolonged course of 7-day low-dose omeprazole infusion reduced delay ulcer rebleeding for the patients with cormobidities. Up-regulation of SRF in the ulcer tissue may mediate a vital role for gastric ulcer healing. SRF up-regulation negatively correlated to the presence of SRH, and lack of such up-regulation in gastric ulcer tissue correlated to gastric ulcer rebleeding.
Key words: peptic ulcer rebleeding, comorbidity, omeprazole, serum response factor

Aabakken, L.: Non variceal upper gastrointestinal bleeding. Endoscopy 37: 195-200, 2005.
Andersson, T., Regardh, C.G., Lou, Y.C., Zhang, Y., Dahl, M.L. and Bertilsson, L.: Polymorphic hydroxylation of S-mephenytoin and omeprazole metabolism in Caucasian and Chinese subjects. Pharmacogenetics 2: 25-31, 1992.
Bennett, N.T. and Schultz, G.S.: Growth factors and wound healing: biochemical properties of growth factors and their receptors. Am. J. Surgery 165: 728-737, 1993.
Bertilsson, L.: Geographic/interracial differences in polymorphic drug oxidation. Current state of knowledge of cytochromes P450 (CYP) 2D6 and 2C19. Clin. Pharmacokinet. 29: 192-209, 1995.
Branicki, F.J., Boey, J., Fok, P.J., Pritchett, C.J., Fan, S.T., Lai, E.C., Mok, F.P., Wong, W.S., Lam, S.K., Hui, W.M., Ng, M.M., Lok, A.S., Lam, D.K., Tang, A.P. and Wong, J.: Bleeding duodenal ulcer. A prospective evaluation of risk factors for rebleeding and death. Ann. Surg. 211: 411-418, 1990.
Brown, L.F., Dubin, D., Lavigne, L., Logan, B., Dvorak, H.F. and Van de Water, L.: Macrophages and fibroblasts express “embryonic” fibronectins during cutaneous wound healing. Am. J. Pathol. 142: 793-801, 1993.
Brzozowski, T., Konturek, P.C., Pajdo, R., Kwiecien, S., Ptak, A., Sliwowski, Z., Drozdowicz, D., Pawlik, M., Konturek, S.J., Hahn, E.G.: Brain-gut axis in gastroprotection by leptin and cholecystokinin against ischemia-reperfusion induced gastric lesions. J. Physiol. Pharmacol. 52: 583-602, 2001.
Cappell, M.S. and Nadler, S.C.: Increased mortality of acute upper gastrointestinal bleeding in patients with chronic obstructive pulmonary disease. A case controlled, multiyear study of 53 consecutive patients. Dig. Dis. Sci. 40: 256-261, 1995.
Chai, J.Y. and Tarnawski, A.: Serum response factor: discovery, biochemistry, biological roles and implications for tissue injury healing. J. Physiol. Pharmacol. 53: 147-157, 2002a.
Chai, J.Y., Baatar, D., Moon, W. and Tarnawski, A.: Expression of serum response factor in normal rat gastric mucosa. J. Physiol. Pharmacol. 53: 289-294, 2002b.
Chai, J.Y., Baatar, D. and Tarnawski, A.: Serum response factor promotes re-epithelialization and muscular structure restoration during gastric ulcer healing. Gastroenterology 126: 1809-1818, 2004.
Chait, M.M., Turnbull, A.D. and Winawer, S.D.: Risk factors and mortality in patients with cancer and hemorrhage from stress ulcer. Am. J. Gastroenterol. 72: 227-233, 1979.
Chao, J.C.J., Hung, H.C., Chen, S.H. and Fang, C.L.: Effects of Ginkgo biloba extract on cytoprotective factors in rats with duodenal ulcer. World J. Gastroenterol. 10: 560-566, 2004.
Chen, L.S., Lin, H.C., Hwang, S.J., Lee, F.Y., Hou, M.C. and Lee, S.D.: Prevalence of gastric ulcer in cirrhotic patients and its relation to portal hypertension. J. Gastroenterol. Hepatol. 11: 59-64, 1996.
Cheng, H.C., Chuang, S.A., Kao, A.W., Chuang, C.H. and Sheu, B.S.: Increased risk of rebleeding of peptic ulcer bleeding in patients with comorbid illness receiving omeprazole infusion. Hepatogastroenterology 50: 2270-2273, 2003.
Cheng, H.C., Kao, A.W., Chuang, C.H. and Sheu, B.S.: The efficacy of high and low dose intravenous omeprazole in preventing rebleeding for patients with bleeding peptic ulcers and co-morbid illnesses. Dig. Dis. Sci. 50: 1194-1201, 2005.
Cheng, H.C., Chang, W.L., Yeh, Y.C., Chen, W.Y., Tsai, Y.C. and Sheu, B.S.: Seven-day intravenous low-dose omeprazole infusion reduces peptic ulcer rebleeding for patients with comorbidities. Gastrointest. Endosc. In press, 2009.
Christensen, S., Thomsen, R.W., Torring, M.L., Riis, A., Norgaard, M. and Sorensen, H.T.: Impact of COPD on Outcome Among Patients With Complicated Peptic Ulcer. Chest 133: 1360-1366, 2008.
Clark, R.A.F.: Potential roles of fibronectin in cutaneous wound repair. Arch. Dermatol. 124: 201-206, 1988.
Clark, R.A.F.: Wound repair. In: Clark, R.A.F. ed. The molecular and cellular biology of wound repair. 2nd ed. Plenum, New York. 3-50, 1996.
Colin, J.F., Elliot, P. and Ellis, H.: The effect of uraemia upon wound healing: an experimental study. Br. J. Surg. 66: 793-797, 1979.
Dallal, H.J. and Palmer, K.R.: ABC of the upper gastrointestinal tract: Upper gastrointestinal haemorrhage. B.M.J. 323: 1115-1117, 2001.
Darby, I., Skalli, O. and Gabbiani, G.: α-Smooth muscle actin is transiently expressed by myofibroblasts during experimental wound healing. Lab. Invest. 63: 21-29, 1990.
de Morais, S.M.F., Wilkinson, G.R., Blaisdell, J., Nakamura, K., Meyer, U.A. and Goldstein, J.A.: The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J. Biol. Chem. 269: 15419-15422, 1994a.
de Morais, S.M.F., Wilkinson, G.R., Blaisdell, J., Meyer, U.A., Nakamura, K. and Goldstein, J.A.: Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese. Mol. Pharmacol. 46: 594-598, 1994b.
de Morais, S.M.F., Goldstein, J.A., Xie, H.G., Huang, S.L., Lu, Y.Q., Xia, H., Xiao, Z.S., Ile, N. and Zhou, H.H.: Genetic analysis of the S-mephenytoin polymorphism in a Chinese population. Clin. Pharmacol. Ther. 58: 404-411, 1995.
Devlin, J.W. and Welage, L.S.: The cost-effectiveness of proton pump inhibitors for bleeding peptic ulcers: The unanswered questions. Crit. Care Med. 32: 1415-1416, 2004.
Diaz, D., Fabre, I., Daujat, M., Saint Aubert, B., Bories, P., Michel, H. and Maurel, P.: Omeprazole is an aryl hydrocarbon-like inducer of human hepatic cytochrome P450. Gastroenterology 99: 737-747, 1990.
D’Souza, R.S. and Dhume, V.G.: Gastric cytoprotection. Indian J. Physiol. Pharmacol. 35: 88-98, 1991.
Feil, W., Wentzl, E., Vattay, P., Starlinger, M., Sogukogli, R. and Schiessel, R.: Repair of rabbit duodenal mucosa after acid injury in vivo and in vitro. Gastroenterology 92: 1973-1986, 1987.
Fleischer D.: Etiology and prevalence of severe persistent upper gastrointestinal bleeding. Gastroenterology 84: 538-543, 1983.
Foley, E.F., Borlase, B.C., Dzik, W.H., Bistrian, B.R. and Benotti, P.N.: Albumin supplementation in the critically ill. A prospective, randomized trial. Arch. Surg. 125: 739-742, 1990.
Forrest, J.A.N., Finlayson, N.D.C. and Sherman, D.J.C.: Endoscopy in gastrointestinal bleeding. Lancet 2: 394-397, 1974.
Freston, J.W.: Overview of medical therapy of peptic ulcer disease. Gastroenterol. Clin. North. Am. 9: 121-140, 1990.
Furuta, T., Ohashi, K., Kamata, T., Takashima, M., Kosuge, K., Kawasaki, T., Hanai, H., Kubota, T., Ishizaki, T. and Kaneko, E.: Effect of genetic differences in omeprazole metabolism on cure rate for Helicobacter pylori infection and peptic ulcer. Ann. Intern. Med. 129: 1027-1030, 1998.
Gabbiani, G., Ryan, G.B. and Majno, G.: Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction. Experientia 27: 549-550, 1971.
Gan, K.H., Geus, W.P., Lamers, C.B.H.W. and Heijerman, H.G.M.: Effect of omeprazole 40 mg once daily on intraduodenal and intragastric pH in H. pylori-negative healthy subjects. Dig. Dis. Sci. 42: 2304-2309, 1997.
Glick, D.L. and Kern, F. Jr.: Peptic ulcer and chronic obstructive bronchopulmonary disease. Gastroenterology 47: 153-160, 1964.
Green, F.W., Kaplan, M.M., Curtis, L.E. and Levine, P.H.: Effect of acid and pepsin on blood coagulation and platelet aggregation. Gastroenterology 74: 38-43, 1978.
Greenberg, M.E. and Ziff, E.B.: Stimulation of 3T3 cells induces transcription of the c-fos proto-oncogene. Nature 311: 433-438, 1984.
Holt, M.E., Ryall, M.E. and Campbell, A.K.: Albumin inhibits human polymorphonuclear leucocyte luminal-dependent chemiluminescence: Evidence for oxygen radical scavenging. Br. J. Exp. Pathol. 65: 231-241, 1984.
Hunt, T.K.: Wound healing and wound infection: Theory and surgical practice. Appleton-Century-Crofts, New York. 1980.
Ieiri, I., Kubota, T., Urae, A., Kimura, M., Wada, Y., Mamiya, K., Yoshioka, S., Irie, S., Amamoto, T., Nakamura, K., Nakano, S. and Higuchi, S.: Pharmacokinetics of omeprazole (a substrate of CYP2C19) and comparison with two mutant alleles, CYP2C19m1 in exon 5 and CYP2C19m2 in exon 4, in Japanese subjects. Clin. Pharmacol. Ther. 59: 647-653, 1996.
Jensen, J.C. and Gugler, R.: Inhibition of human liver cytochrome P-450 by omeprazole. Br. J. Clin. Pharmacol. 21: 328-330, 1986.
Johnston, J.H.: Endoscopic risk factors for bleeding peptic ulcer. Gastrointest. Endosc. 36: S16-S20, 1990.
Kang JY.: Peptic ulcer in hepatic cirrhosis and renal failure. J. Gastroenterol. Hepatol. 9: S20-S23, 1994.
Kashiwagi, H.: Ulcers and gastritis. Endoscopy 37: 110-115, 2005.
Kellow, J.E., Tao, Z. and Piper, D.W.: Ventilatory function in chronic peptic ulcer. Gastroenterology 91: 590-595, 1986.
Kinney, J.M. and Weissmann, C.: Forms of malnutrition in stressed and unstressed patients. Clin. Chest Med. 7: 19-28, 1986.
Krawczyk, W.S.: A pattern of epidermal cell migration during wound healing. J. Cell Biol. 49: 247-263, 1971.
Kung, S.P., Tang, G.J., Wu, C.W. and Lui, W.Y.: Serum albumin concentration as a prognostic indicator for acute surgical patients. Chin. Med. J. (Taipei) 62: 61-67, 1999.
Kupfer, A. and Preisig, R.: Pharmacogenetics of mephenytoin: a new drug hydroxylation polymorphism in man. Eur. J. Clin. Pharmacol. 26: 753-759, 1984.
Lacy, E.R.: Epithelial restitution in the gastrointestinal tract. J. Clin. Gastroenterol. 10 (Suppl 1): 72-77, 1988.
Laine, L., Shah, A. and Bemanian, S.: Intragastric pH with oral vs. intravenous bolus plus infusion proton-pump inhibitor therapy in patients with bleeding ulcers. Gastroenterology 134: 1836-1841, 2008.
Lam, S.K., Hasan, M., Sircus, W., Wong, J., Ong, G.B. and Prescott, R.J.: Comparison of maximal acid output and gastrin response to meals in Chinese and Scottish normal and duodenal ulcer subjects. Gut 21: 324-328, 1980.
Larson, G., Schmidt, T., Gott, J., Bond, S., O’Connor, C.A. and Richardson, J.D.: Upper gastrointestinal bleeding: predictors of outcome. Surgery 100: 765-773, 1986.
Laterre, P.F. and Horsmans, Y.: Intravenous omeprazole in critically ill patients: a randomized, crossover study comparing 40 with 80 mg plus 8 mg/hour on intragastric pH. Crit. Care Med. 29: 1931-1935, 2001.
Lau, J.Y., Sung, J.J., Lee, K.K., Yung, M.Y., Wong, S.K., Wu, J.C., Chan, F.K., Ng, E.K., You, J.H., Lee, C.W., Chan, A.C. and Chung, S.C.: Effect of intravenous omeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcer. N. Engl. J. Med. 343: 310-316, 2000.
Lin, H.J., Lo, W.C., Lee, F.Y., Perng, C.L. and Tseng, G.Y.: A prospective randomized comparative trial showing that omeprazole prevents rebleeding in patients with bleeding peptic ulcer after successful endoscopic therapy. Arch. Intern. Med. 158: 54-58, 1998.
Longstreth, G.F.: Epidemiology of hospitalization for acute upper gastrointestinal hemorrhage: a population-based study. Am. J. Gastroenterol. 90: 206-210, 1995.
Martin, P.: Wound healing-aiming for perfect skin regeneration. Science 276: 75-81, 1997.
Maton, P.N.: Omeprazole. N. Engl. J. Med. 324: 965-975, 1991.
Monson, R.R.: Duodenal ulcer as a second disease. Gastroenterology 59: 712-716, 1970.
Nakamura, K., Goto, F., Ray, W.A., McAllister, C.B., Jacqz, E., Wilkinson, G.R. and Branch, R.A.: Interethnic differences in genetic polymorphism of debrisoquin and mephenytoin hydroxylation between Japanese and Caucasian populations. Clin. Pharmacol. Ther. 38: 402-408, 1985.
Netzer, P., Gaia, C., Sandoz, M., Huluk, T., Gut, A., Halter, F., Husler, J. and Inauen, W.: Effect of repeated injection and continuous infusion of omeprazole and ranitidine on intragastric pH over 72 hours. Am. J. Gastroenterol. 94: 351-357, 1999.
Ng, K.M., Cho, C.H., Chang, F.Y., Luo, J.C., Lin, H.C., Lin, H.Y., Chi, C.W. and Lee, S.D.: Omeprazole promotes gastric epithelial cell migration. J. Pharm. Pharmacol. 60: 655-660, 2008.
Orr, L.: Scientists align billion-year-old protein with embryonic heart defects. Medical News Today 2004.
Rabinovitz, M., Schade, R.R., Dindzans, V., Van Thiel, D.H. and Gavaler, J.S.: Prevalence of duodenal ulcer in cirrhotic males referred for liver transplantation- Does the etiology of cirrhosis make a difference? Dig. Dis. Sci. 35: 321-326, 1990.
Rady, M.Y., Ryan, T. and Starr, N.J.: Clinical characteristics of preoperative hypoalbuminemia predict outcome of cardiovascular surgery. J. Parenter. Enteral. Nutr. 21: 81-90, 1997.
Ravanti, L. and Kahari, V.M.: Matrix metalloproteinases in wound repair. Int. J. Mol. Med. 6: 391-407, 2000.
Rivkin, K. and Lyakhovetskiy, A.: Proton-pump inhibitors for upper-gastrointestinal bleeding. Am. J. Health. Syst. Pharm. 63: 216-217, 2006.
Rockall, T.A., Logan, R.F.A., Devlin, H.B. and Northfield, T.C.: Risk assessment after acute upper gastrointestinal haemorrhage. Gut 38: 316-321, 1996a.
Rockall, T.A., Logan, R.F.A., Devlin, H.B. and Northfield, T.C.: Selection of patients for early discharge or outpatient care after acute upper gastrointestinal haemorrhage. National Audit of Acute Upper Gastrointestinal Haemorrhage. Lancet 347: 1138-1140, 1996b.
Schaffalitzky de Muckadell, O.B., Havelund, T., Harling, H., Boesby, S., Snel, P., Vreeburg, E.M., Eriksson, S., Fernstrom, P. and Hasselgren, G.: Effect of omeprazole on the outcome of endoscopically treated bleeding peptic ulcers: Randomized double-blind placebo-controlled multicentre study. Scand. J. Gastroenterol. 32: 320-327, 1997.
Schmassmann, A., Tarnawski, A., Peskar, B.M., Varga, L., Flogerzi, B. and Halter, F.: Influence of acid and angiogenesis on kinetics of gastric ulcer healing in rats: interaction with indomethacin. Am. J. Physiol. 268: G276-285, 1995.
Shepherd, A.M.M., Stewart, W. K. and Wormsley, K.G.: Peptic ulceration in chronic renal failure. Lancet 1: 1357-1359, 1973.
Sheu, B.S., Chi, C.H., Yang, H.B., Jen, C.M. and Lin, X.Z.: A three-day course of intravenous omeprazole plus antibiotics for H. pylori-positive bleeding duodenal ulcer. Hepatogastroenterology 46: 2363-2371, 1999.
Sheu, B.S., Yang, H.B., Sheu, S.M., Huang, A.H. and Wu, J.J.: Higher gastric cycloxygenase-2 expression and precancerous change in Helicobacter pylori-infected relatives of gastric cancer patients. Clin. Cancer Res. 9: 5245-5251, 2003.
Sheu, B.S., Kao, A.W., Cheng, H.C., Huang, S.F., Chen, T.W. and Lu, C.C.: Esomeprazole 40 mg twice daily in triple therapy and the efficacy of Helicobacter pylori eradication related to CYP2C19 metabolism. Aliment. Pharmacol. Ther. 21: 283-288, 2005.
Shimatani, T., Inoue, M., Kuroiwa, T., Horikawa, Y., Mieno, H. and Nakamura, M.: Effect of omeprazole 10 mg on intragastric pH in three different CYP2C19 genotypes, compared with omeprazole 20 mg and lafutidine 20 mg, a new H2-receptor antagonist. Aliment. Pharmacol. Ther. 18: 1149-1157, 2003.
Silen, W.: Gastric mucosal defense and repair. In: Johnson, L.R. ed. Physiology of the gastrointestinal tract. 2nd ed. Raven, New York. 1044-1069, 1987.
Silvertstein, F.E., Gilbert, D.A., Tedesco, F.J., Buenger, N.K. and Persing, J.: The National ASGE Survey on upper gastrointestinal bleeding. I. Study design and baseline data. Gastrointest. Endosc. 27: 73-79, 1981a.
Silvertstein, F.E., Gilbert, D.A., Tedesco, F.J., Buenger, N.K. and Persing, J.: The National ASGE Survey on upper gastrointestinal bleeding. II. Clinical prognostic factors. Gastrointest. Endosc. 27: 80-93, 1981b.
Siringo, S., Burroughs, A.K., Bolondi, L., Muia, A., Febo, G.D., Miglioli, M., Cavalli, G. and Barbara, L.: Peptic ulcer and its course in cirrhosis: an endoscopic and clinical prospective study. J. Hepatol. 22: 633-641, 1995.
Sung, J.J., Leung, W.K., Go, M.Y., To, K.F., Cheng, A.S., Ng, E.K. and Chan, F.K.: Cyclooxygenase-2 expression in Helicobacter pylori-associated premalignant and malignant gastric lesions. Am. J. Pathol. 157: 729-735, 2000.
Sung, J.J.: Current management of peptic ulcer bleeding. Nat. Clin. Pract. Gastroenterol. Hepatol. 3: 24-32, 2006.
Suzuki, H., Masaoka, T., Minegishi, Y., Motosugi, Y., Miura, S. and Ishii, H.: Lansoprazole promotes gastric mucosal cell proliferation and migration by activating p44/p42 mitogen-activated protein kinase. Wound Rep. Reg. 12: 93-99, 2004.
Swain, C.P., Storey, D.W., Bown, S.G., Heath, J., Mills, T.N., Salmon, P.R., Northfield, T.C., Kirkham, J.S. and O'Sullivan, J.P. Nature of the bleeding vessel in recurrently bleeding gastric ulcers. Gastroenterology 90: 595-608, 1986.
Tarnawski, A., Stachura, J., Krause, W.J., Douglass, T.G. and Gergely, H.: Quality of gastric ulcer healing: a new, emerging concept. J. Clin. Gastroenterol. 13: S42-47, 1991.
Tarnawski, A.: Cellular mechanisms of gastric ulcer healing. In: Domschke, W. and Konturek, S.J. eds. The Stomach. Springer-Verlag, Berlin. 177-192, 1993.
Tarnawski, A.: Cellular and molecular mechanisms of ulcer healing. Drugs of Today 33: 697-706, 1997.
Tarnawski, A.: Molecular mechanisms of ulcer healing. Drug News Perspect. 13: 158-168, 2000.
Tarnawski, A.: Cellular and molecular mechanisms of gastrointestinal ulcer healing. Dig. Dis. Sci. 50: suppl 1: S24-33, 2005.
Terdiman, J.P. and Ostroff, J.W.: Gastrointestinal bleeding in the hospitalized patient: a case-control study to assess risk factors, causes, and outcome. Am. J. Med. 104: 349-354, 1998.
Thorne, F.L. and Nyhus, L.M.: Treatment of massive upper gastrointestinal hemorrhage: A ten year review. Am. Surg. 31: 413-419, 1965.
Travis, A.C., Wasan, S.K. and Saltzman, J.R.: Model to predict rebleeding following endoscopic therapy for non-variceal upper gastrointestinal hemorrhage. J. Gastroenterol. Hepatol. 23: 1505-1510, 2008.
Travis, J. and Salvesen, G.S.: Human plasma proteinase inhibitors. Annu. Rev. Biochem. 52: 655-709, 1983.
Treisman, R.: Identification of a protein-binding site that mediates transcriptional response of the c-fos gene to serum factors. Cell 46: 567-574, 1986.
Udd, M., Miettinen, P., Palmu, A., Heikkinen, M., Janatuinen, E., Pasanen, P., Tarvainen, R., Kairaluoma, M.V., Lohman, M., Mustonen, H. and Julkunen, R.: Regular-dose versus high-dose omeprazole in peptic ulcer bleeding: a prospective randomized double-blind study. Scand. J. Gastroenterol. 36: 1332-1338, 2001.
Vincent, J.L., Dubois, M.J., Navickis, R.J. and Wilkes, M.M.: Hypoalbuminemia in acute illness: is there a rationale for intervention? A meta-analysis of cohort studies and controlled trials. Ann. Surg. 237: 319-334, 2003.
Wallace, J.L. and McKnight, G.W.: The mucoid cap over superficial gastric damage in the rat. A high-pH microenvironment dissipated by nonsteroidal antiinflammatory drugs and endothelin. Gastroenterology 99: 295-304, 1990.
Wasil, M., Halliwell, B., Hutchison, D.C. and Baum, H.: The antioxidant action of human extracellular fluids. Biochem. J. 243: 219-223, 1987.
Wedlund, P.J., Aslanian, W.S., McAllister, C.B., Wilkinson, G.R. and Branch, R.A.: Mephenytoin hydroxylation deficiency in Caucasians: frequency of a new oxidative drug metabolism polymorphism. Clin. Pharmacol. Ther. 36: 773-780, 1984.
Wei, K.L., Tung, S.Y., Sheen, C.H., Chang, T.S., Lee, I.L. and Wu, C.S.: Effect of oral esomeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcers. J. Gastroenterol. Hepatol. 22: 43-46, 2007.
Welch, M.P., Odland, G.F. and Clark, R.A.F.: Temporal relationships of F-actin bundle formation, collagen and fibronectin matrix assembly, and fibronectin receptor expression to wound contraction. J. Cell. Biol. 110: 133-145, 1990.
Winter, M.E.: Basic principles: desired plasma concentration. In: Winter, M.E. ed. Basic clinical pharmacokinetics. 4th ed. Lippincott Williams & Wilkins, Philadelphia, 10-18, 2004a.
Winter, M.E.: Drug monographs: phenytoin. In: Winter, M.E. ed. Basic clinical pharmacokinetics. 4th ed. Lippincott Williams & Wilkins, Philadelphia, 321-363, 2004b.
Xiao, Z.S., Goldstein, J.A., Xie, H.G., Blaisdell, J., Wang, W., Jiang, C.H., Yang, F.X., He, N., Huang, S.L., Xu, Z.H. and Zhou, H.H.: Differences in the incidence of the CYP2C19 polymorphism affecting the S-mephenytoin phenotype in Chinese Han and Bai populations and identification of a new rare CYP2C19 mutant allele. J. Pharmacol. Exp. Ther. 281: 604-609, 1997.
Xie, H.G., Kim, R.B., Stein, C.M., Wilkinson, G.R. and Wood, A.J.: Genetic polymorphism of (S)-mephenytoin 4'-hydroxylation in populations of African descent. Br. J. Clin. Pharmacol. 48: 402-408, 1999a.
Xie, H.G., Stein, C.M., Kim, R.B., Wilkinson, G.R., Flockhart, D.A. and Wood, A.J.: Allelic, genotypic and phenotypic distributions of S-mephenytoin 4'-hydroxylase (CYP2C19) in healthy Caucasian populations of European descent throughout the world. Pharmacogenetics 9: 539-549, 1999b.
Yang, C.C., Shin, J.S., Lin, X.Z., Hsu, P.I., Chen, K.W. and Lin, C.Y.: The natural history (fading time) of stigmata of recent hemorrhage in peptic ulcer disease. Gastrointest. Endosc. 40: 562-566, 1994.
Yavorski, R.T., Wong, R.K., Maydonovitch, C., Battin, L.S., Furnia, A. and Amundson, D.E.: Analysis of 3,294 cases of upper gastrointestinal bleeding in military medical facilities. Am. J. Gastroenterol. 90: 568-573, 1995.
Zaragoza, A.M., Tenias, J.M., Llorente, M.J. and Alborch, A. Prognostic factors in gastrointestinal bleeding due to peptic ulcer: construction of a predictive model. J. Clin. Gastroenterol. 42: 786-790, 2008.
Zasly, L., Baum, G.L. and Rumball, J.M.: The incidence of peptic ulceration in chronic obstructive pulmonary disease. Dis. Chest 37: 400-405, 1960.
Zhang, Q., Dawodu, J.B., Etolhi, G., Husain, A., Gemmell, C.G. and Russell, R.I.: Relationship between the mucosal production of reactive oxygen radicals and density of Helicobacter pylori in patients with duodenal ulcer. Eur. J. Gastroenterol. Hepatol. 9: 261-265, 1997.