AIM: To investigate whether, or how, DA-9601, which is a new gastroprotective agent, inhibits TNF-α-induced inflammatory signals in gastric epithelial AGS cells. METHODS: Cell viability was determined by MTT assay. I...AIM: To investigate whether, or how, DA-9601, which is a new gastroprotective agent, inhibits TNF-α-induced inflammatory signals in gastric epithelial AGS cells. METHODS: Cell viability was determined by MTT assay. IL-8 and CCL20 promoter activities were determined by a luciferease reporter gene assay. NF-κB-dependent transcriptional activity was determined by I-κBαdegradation, NF-κB p65 nuclear translocation and a luciferase activity assay. IL-8 and CCL20 gene expression and protein secretion were determined by RT-PCR and an enzymelinked immunosorbent assay (ELISA). Total and phos-phorylated forms of mitogen-activated protein kinases (MAPKs) were determined by Western blot. RESULTS: Treatment of AGS cells with DA-9601 reduced TNF-α-induced IL-8 and CCL20 promoter activities, as well as their gene expression and protein release. TNF-αalso induced NF-κB-dependent transcriptional activity in AGS cells. In contrast, in cells treated with DA-9601, TNF-α-induced NF-κB activity was significantly blocked. Although all three MAP kinase family members were phosphorylated in response to TNF-α, a selective inhibitor of p38 kinase SB203580 only could inhibit both NF-κB-dependent transcriptional activity and IL-8 and CCL20 production, suggesting a potential link between p38 kinase and NF-κB-dependent pathways in AGS cells. Interestingly, DA-9601 also selectively inhibited p38 kinase phosphorylation induced by TNF-α. CONCLUSION: DA-9601 blocked TNF-α-mediated inflammatory signals by potentially modulating the p38 kinase pathway and/or a signal leading to NF-κBdependent pathways in gastric epithelial cells.展开更多
AIM: To investigate the therapeutic effects of DA-9601 on sodium taurocholate (TCA)-induced chronic reflux gastritis in SD rats.METHODS: In this study, we have investigated the therapeutic effects of DA-9601 on chroni...AIM: To investigate the therapeutic effects of DA-9601 on sodium taurocholate (TCA)-induced chronic reflux gastritis in SD rats.METHODS: In this study, we have investigated the therapeutic effects of DA-9601 on chronic erosive and atrophic gastritis induced by 6 mo of TCA administration (5 mmol/L in drinking water) in SD rats. RESULTS: Four weeks of DA-9601 administration (0.065%, 0.216% in rat chow), following the withdrawal of TCA treatment, resulted in a significant decrease in total length of erosions in rats in a dose-dependent manner. Furthermore, the indicators of atrophic gastritis, such as reduced mucosal thickness and reduction in the number of parietal cells, were improved by the administration of DA-9601 in a dose-related manner. DA-9601 also attenuated inflammatory cell infiltration and the proliferation of collagenous fiber in the gastric mucosa. The improvement in the reduction of the gastric mucus was observed in the rats receiving a high dose of DA-9601 (0.216%). The therapeutic effect of DA-9601 on experimental chronic erosive gastritis was superior to that of rebamipide (1.08% in rat chow). Biochemical analyses showed increased mucosal prostaglandin E2 and reduced glutathione levels by DA-9601 treatment. CONCLUSION: We suggest that DA-9601 is apromising agent for the treatment of chronic erosive and atrophic gastritis with an etiological factor of bile reflux. Increasedmucosal prostaglandin E2 and reduced glutathione by DA-9601 treatment may be therapeutic mechanisms for chronic erosive and atrophic gastritis.展开更多
AIM： To examine the effect of DA-9601, a new gastroprotective agent, on the vulnerability of ethanoltreated rat＇s stomach to naproxen （NAP）. METHODS： Male Sprague-Dawley rats were pretreated with 1 mL of 50% etha...AIM： To examine the effect of DA-9601, a new gastroprotective agent, on the vulnerability of ethanoltreated rat＇s stomach to naproxen （NAP）. METHODS： Male Sprague-Dawley rats were pretreated with 1 mL of 50% ethanol twice a day for 5 d and then NAP （50 mg/kg） was administered. DA-9601 was admin- istered 1 h before NAP. Four hours after NAP, the rats were killed to examine gross injury index （mm2）, histologic change and to determine mucosal levels of malondialdehyde （MDA）, prostaglandin E2 （PGE2）, glutathione （GSH） and myeloperoxidase （MPO）. RESULTS： Pretreatment of ethanol significantly increased NAP-induced gastric lesions, as well as an increase in NDA and MPO. On the contrary, mucosal PGE2 and GSH contents were decreased dramatically by ethanol pretreatment, which were aggravated by NAR DA-9601 significantly reduced NAP-induced gastric injury grossly and microscopically, regardless of pretreatment with ethanol. DA-9601 preserved, or rather, increased mucosal PGE2 and GSH in NAP-treated rats （P〈0.05）, with reduction in mucosal MDA and MPO levels. CONCLUSION： These results suggest that repeated alcohol consumption renders gastric mucosa more susceptible to NSAIDs though, at least in part, reduction of endogenous cytoprotectants including PGE2 and GSH, and increase in MPO activation, and that DA-9601, a new gastroprotectant, can reduce the increased vulnerability of ethanol consumers to NSAIDs-induced gastric damage via the mechanism in which PGE2 and GSH are involved.展开更多
AIM: To determine the efficacy and safety of DA-9601 on erosive gastritis versus cetraxate as a standard drug by gastrointestinal endoscopy.METHODS: Five hundred and twelve patients with erosive gastritis were divided...AIM: To determine the efficacy and safety of DA-9601 on erosive gastritis versus cetraxate as a standard drug by gastrointestinal endoscopy.METHODS: Five hundred and twelve patients with erosive gastritis were divided into three groups. The groups received 180 mg or 360 mg of DA-9601, or 600 mg of cetraxate (Neuer^TM) t.i.d, for 2 wk, respectively. Endoscopic observations were performed before and 2 wk after the treatment, and the cure and improvement rates were investigated.RESULTS: Of the 512 intention-to-treat (ITT) population,457 patients comprised the per protocol (PP) analysis.Endoscopic cure rate was significantly higher in the DA-9601 group than in the cetraxate group in both the PP (56%, 58% vs 36% DA-9601 180 mg, 360 mg and cetraxate,respectively) and ITT (52%, 51% vs 35%) populations.Two DA-9602 groups (280 and 360 mg) had significantly higher endoscopic improvement rates than the cetraxate group in both the PP (67%, 65% vs 46%) and In (63%,58% vs 45%) populations. The percentage of symptom relief over the 2 wk was found not significantly different between groups. During the study, both DA-9602 and cetraxate produced no treatment-associated adverse events.CONCLUSION: From these results, it appears that DA-9601 has excellent efficacy on erosive gastritis. This study also confirms the safety profile of DA-9601.展开更多
基金Supported by grants from the Korea Health 21 R&D Project, Ministry of Health and Welfare, No.01-PJ3-PG6-01GN09-003, and the Korea Food and Drug Administration, No. 05142-620
文摘AIM: To investigate whether, or how, DA-9601, which is a new gastroprotective agent, inhibits TNF-α-induced inflammatory signals in gastric epithelial AGS cells. METHODS: Cell viability was determined by MTT assay. IL-8 and CCL20 promoter activities were determined by a luciferease reporter gene assay. NF-κB-dependent transcriptional activity was determined by I-κBαdegradation, NF-κB p65 nuclear translocation and a luciferase activity assay. IL-8 and CCL20 gene expression and protein secretion were determined by RT-PCR and an enzymelinked immunosorbent assay (ELISA). Total and phos-phorylated forms of mitogen-activated protein kinases (MAPKs) were determined by Western blot. RESULTS: Treatment of AGS cells with DA-9601 reduced TNF-α-induced IL-8 and CCL20 promoter activities, as well as their gene expression and protein release. TNF-αalso induced NF-κB-dependent transcriptional activity in AGS cells. In contrast, in cells treated with DA-9601, TNF-α-induced NF-κB activity was significantly blocked. Although all three MAP kinase family members were phosphorylated in response to TNF-α, a selective inhibitor of p38 kinase SB203580 only could inhibit both NF-κB-dependent transcriptional activity and IL-8 and CCL20 production, suggesting a potential link between p38 kinase and NF-κB-dependent pathways in AGS cells. Interestingly, DA-9601 also selectively inhibited p38 kinase phosphorylation induced by TNF-α. CONCLUSION: DA-9601 blocked TNF-α-mediated inflammatory signals by potentially modulating the p38 kinase pathway and/or a signal leading to NF-κBdependent pathways in gastric epithelial cells.
基金Supported by the grant from Korean Ministry of Health and Welfare, HMP-98-D-1-0007
文摘AIM: To investigate the therapeutic effects of DA-9601 on sodium taurocholate (TCA)-induced chronic reflux gastritis in SD rats.METHODS: In this study, we have investigated the therapeutic effects of DA-9601 on chronic erosive and atrophic gastritis induced by 6 mo of TCA administration (5 mmol/L in drinking water) in SD rats. RESULTS: Four weeks of DA-9601 administration (0.065%, 0.216% in rat chow), following the withdrawal of TCA treatment, resulted in a significant decrease in total length of erosions in rats in a dose-dependent manner. Furthermore, the indicators of atrophic gastritis, such as reduced mucosal thickness and reduction in the number of parietal cells, were improved by the administration of DA-9601 in a dose-related manner. DA-9601 also attenuated inflammatory cell infiltration and the proliferation of collagenous fiber in the gastric mucosa. The improvement in the reduction of the gastric mucus was observed in the rats receiving a high dose of DA-9601 (0.216%). The therapeutic effect of DA-9601 on experimental chronic erosive gastritis was superior to that of rebamipide (1.08% in rat chow). Biochemical analyses showed increased mucosal prostaglandin E2 and reduced glutathione levels by DA-9601 treatment. CONCLUSION: We suggest that DA-9601 is apromising agent for the treatment of chronic erosive and atrophic gastritis with an etiological factor of bile reflux. Increasedmucosal prostaglandin E2 and reduced glutathione by DA-9601 treatment may be therapeutic mechanisms for chronic erosive and atrophic gastritis.
基金Supported by the National Ministry of Health and Welfare
文摘AIM： To examine the effect of DA-9601, a new gastroprotective agent, on the vulnerability of ethanoltreated rat＇s stomach to naproxen （NAP）. METHODS： Male Sprague-Dawley rats were pretreated with 1 mL of 50% ethanol twice a day for 5 d and then NAP （50 mg/kg） was administered. DA-9601 was admin- istered 1 h before NAP. Four hours after NAP, the rats were killed to examine gross injury index （mm2）, histologic change and to determine mucosal levels of malondialdehyde （MDA）, prostaglandin E2 （PGE2）, glutathione （GSH） and myeloperoxidase （MPO）. RESULTS： Pretreatment of ethanol significantly increased NAP-induced gastric lesions, as well as an increase in NDA and MPO. On the contrary, mucosal PGE2 and GSH contents were decreased dramatically by ethanol pretreatment, which were aggravated by NAR DA-9601 significantly reduced NAP-induced gastric injury grossly and microscopically, regardless of pretreatment with ethanol. DA-9601 preserved, or rather, increased mucosal PGE2 and GSH in NAP-treated rats （P〈0.05）, with reduction in mucosal MDA and MPO levels. CONCLUSION： These results suggest that repeated alcohol consumption renders gastric mucosa more susceptible to NSAIDs though, at least in part, reduction of endogenous cytoprotectants including PGE2 and GSH, and increase in MPO activation, and that DA-9601, a new gastroprotectant, can reduce the increased vulnerability of ethanol consumers to NSAIDs-induced gastric damage via the mechanism in which PGE2 and GSH are involved.
文摘AIM: To determine the efficacy and safety of DA-9601 on erosive gastritis versus cetraxate as a standard drug by gastrointestinal endoscopy.METHODS: Five hundred and twelve patients with erosive gastritis were divided into three groups. The groups received 180 mg or 360 mg of DA-9601, or 600 mg of cetraxate (Neuer^TM) t.i.d, for 2 wk, respectively. Endoscopic observations were performed before and 2 wk after the treatment, and the cure and improvement rates were investigated.RESULTS: Of the 512 intention-to-treat (ITT) population,457 patients comprised the per protocol (PP) analysis.Endoscopic cure rate was significantly higher in the DA-9601 group than in the cetraxate group in both the PP (56%, 58% vs 36% DA-9601 180 mg, 360 mg and cetraxate,respectively) and ITT (52%, 51% vs 35%) populations.Two DA-9602 groups (280 and 360 mg) had significantly higher endoscopic improvement rates than the cetraxate group in both the PP (67%, 65% vs 46%) and In (63%,58% vs 45%) populations. The percentage of symptom relief over the 2 wk was found not significantly different between groups. During the study, both DA-9602 and cetraxate produced no treatment-associated adverse events.CONCLUSION: From these results, it appears that DA-9601 has excellent efficacy on erosive gastritis. This study also confirms the safety profile of DA-9601.
