Mo1067 Guggulsterone, a Plant Sterol Inhibitor of NF-κB, Suppresses CDx2 and COX-2 Overexpression...
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AGA Abstracts the first demonstration that hydrotalcite enhances esophageal epithelial defense and protects keratinocyte progenitor cells. 3) These findings provide novel molecular mechanisms for hydrotalcite protective action on esophageal mucosa and a rationale for its therapeutic use. Mo1066 A Multi-Center, Randomized, Double Blinded, Phase 4 Clinical Trial to Assess the Efficacy and Cost Effectiveness of Omeprazole Compare to Rabeprazole in the Maintenance Therapy of Patients With Gastroesophageal Reflux Disease Jung Ho Park, Hyojin Park, Dong Ho Lee, In Kyung Sung Background and Aims: Due to recurring nature of GERD, Most patients require long term maintenance therapy and continuous medication of proton pump inhibitor (PPI) is an adequate option for patients with erosive esophagitis. The aim of this study was to evaluate the efficacy and cost minimization analysis of omeprazole 10 mg once daily and rabeprazole 10 mg once daily for 24 weeks in the maintenance of remission Methods:This is randomized, open-label study enrolled 279 patients with erosive esophagitis A or B (LA classification) and typical GERD symptoms. Patients who showed complete endoscopic and symptomatic healing after 8 weeks PPI treatment were randomly allocated to maintenance treatment with omeprazole 10mg once daily or rabeprazole 10mg once daily for 42 weeks. The primary efficacy endpoint was the proportion of patients with symptomatic remission at 42 weeks. Secondary assessments included healing of reflux esophagitis, severity and frequency of reflux symptoms and cost-minimization analysis in the maintenance phase Results:At the end of 42 weeks of maintenance therapy, 96.4% of omeprazole treated and 95.1% of rabeprazole treated patients remained symptom free (P>0.05). Omeprazole and rabeprazole were also similarly efficacious in terms of endoscopic non-relapse rate for RE with 93.3% of patients on omeprazole and 97.5% of patients of rabeprazle. (P>0.05) Two drugs were also comparable with regard to severity and frequency of reflux symptoms during maintenance phase. (P>0.05) In the cost-minimization analysis, The mean total costs per patient for remaining symptom free within 6 months was 241,775 won in omeprazole and 287,115 won in rabeprazole, respectively.(as if 24 November 2011, 1 USD= 1,176.33 won) Conclu- sions:Omeprazole 10mg appeared to have a similar efficacy in maintaining symptomatic remission as rabeprazole 10 mg, but had a lower total cost per patient than rabeprazole 10mg. Mo1067 Guggulsterone, a Plant Sterol Inhibitor of NF-κB, Suppresses CDx2 and COX- 2 Overexpression and Reduces Proliferation of Esophageal Adenocarcinoma Cells Takanori Yamada, Satoshi Osawa, Yasuhiro Takayanagi, Jiong Zhang, Yasushi Hamaya, Mitsushige Sugimoto, Shigeru Kanaoka, Takahisa Furuta, Ken Sugimoto BACKGROUND & AIMS: Induction of caudal type homeobox 2 (CDX2) and cyclooxygenase- 2 (COX-2) expression by acid and bile acid in the distal esophagus is a critical molecular event in the development of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Although proton pump inhibitors (PPIs) can reduce acid exposure in the distal esophagus, few remedies targeting bile acid reflux and concomitant exposure of esophageal tissue. Bile acids induce CDX2 and COX-2 expression by activating nuclear factor κB (NF-κB). Guggulsterone (GS) is a plant sterol known to inhibit NF-κB. Thus, we hypothesized that GS may suppress bile acid-induced CDX2 and COX-2 expression by NF-κB inactivation and inhibit BE and EAC development. METHODS: Two EAC cells lines, OE19 and OE33, were treated with biliary deoxycholic acid (DCA) in the presence of GS or vehicle. Phosphoryl- ation of the NF-κB regulatory peptide IκB was detected by immunoblot analysis. CDX2 and COX-2 expression was analyzed by qRT-PCR and immunoblot analysis. Prostaglandin E2 (PGE2) production by EAC cell lines was measured by ELISA. Cell viability was assessed by the MTT assay, and cell cycle distribution was measured by genomic DNA labeling and flow cytometry. RESULTS: GS inhibited DCA-induced IκB phosphorylation, possibly leading to reduce NF-κB-mediated gene expression. A known NF-κB inhibitor BAY11-7085 sup- pressed DCA-induced CDX2 and COX-2 expression in EAC cell lines, confirming that expression of these two genes depended on NF-κB activation. GS suppressed DCA-induced CDX2 and COX-2 expression in EAC cell lines. GS also suppressed basal CDX2 and COX- 2 expression and reduced constitutive synthesis of the COX-2 product and proliferation enhancer PGE2. Furthermore, GS reduced the viability of EAC cells and increased their fraction in sub-G1, the apoptosis-associated cell cycle phase. Finally, GS treatment activated the apoptosis effector caspase-3 and RARP. CONCLUSIONS: GS suppresses DCA-induced and NF-κB-dependent activation of CDX2 and COX-2 expression. Furthermore, GS reduces EAC proliferation by promoting apoptosis. Thus, GS is a possible candidate chemopreventive/ therapeutic agent for EAC as well as BE. Mo1068 Efficacy of Frequent PPI Dosing for Potent Acid Inhibition Over 24 Hours Mitsushige Sugimoto, Takahiro Uotani, Masafumi Nishino, Mihoko Yamade, Shu Sahara, Takanori Yamada, Satoshi Osawa, Ken Sugimoto, Takahisa Furuta Background: While proton pump inhibitors (PPIs) potently inhibit gastric acid secretion, their use is hamstrung by issues such as variation in efficacy due to CYP2C19 genotype, reduced efficacy for nocturnal gastric acid inhibition, and a slower onset efficacy of gastric acid inhibition. As such, advanced therapeutic regimens are required to sustain potent acid inhibition for a full 24-h, especially in nocturnal time, in all patients with acid-related diseases, regardless of genetic factors. However, optimum treatment regimen using PPIs is unclear at present, as most previous reports have involved type 2 error. Here, to help clarify this ideal regimen, we assessed acid inhibitory effects of a number of PPIs across several CYP2C19 genotypes using different dosing methods in a study involving more than 180 rounds of pH monitoring. Methods: Using pH monitoring, we compared acid inhibition of a number of PPIs (omeprazole at 20 mg, 30 times; lansoprazole at 30 mg, 33 times; rabeprazole at 10 mg, 55 times) in related with different CYP2C19 genotypes. We then evaluated efficacy of divided treatment with a specific PPI, rabeprazole, using pH monitoring S-586 AGA Abstracts (rabeprazole at 40 mg sid, 15 times; at 20 mg bid, 20 times; and at 10 mg qid, 35 times). Results: Median (range) 24-h intragastric pH values with omeprazole (20 mg), lansoprazole (30 mg), and rabeprazole (10 mg) were 4.3 (2.1-7.3), 4.8 (3.6-6.4), 5.5 (3.3-7.5), respectively. Although rabeprazole inhibited gastric acid to a significantly greater degree than omeprazole and lansoprazole (both p < 0.05, respectively), inhibition over 24-h attained by rabeprazole was insufficient (median percent time of intragastric pH < 4: 35.6% [3.5%-73.8%]). In our examination of the efficacy of divided PPI treatment, median (range) 24-h intragastric pH values for rabeprazole 40 mg sid, 20 mg bid, and 10 mg qid were 4.8 (3.6-6.4), 5.7 (4.1- 7.4), 6.6 (4.9-8.4), respectively. Although dosing dose a day was same, rabeprazole 40mg, increases in dosing times effectively increased intragastric pH, not only during the day but also at night (rabeprazole 10 mg qid: percent time of intragastric pH < 4: 3.4% [3.5-9.8%]). In CYP2C19 poor metabolizers, the acid inhibition attained by a PPI was enhanced in comparison with that in CYP2C19 intermediate metabolizers or rapid metabolizers (RMs) for all PPIs. Further, rabeprazole administered at 10 mg qid maintained pH > 4 for 24 h in RMs. Discussion: Although we cannot entirely ignore the influence of CYP2C19 genotype on acid inhibition, rabeprazole's effect is less influenced by CYP2C19 genotype than omepra- zole and lansoprazole. In addition, PPI sid treatment is difficult to maintain acid secretion for a full 24-h. However, PPI qid treatment achieved potent acid inhibition, including during the night, suggesting its potential usefulness in patients refractory to PPI therapeutic regimens. Mo1069 Effect of Oral Administration of a New Proton Pump Inhibitor E3710 on 24-h Intra-Gastric pH in Japanese Subjects Hideo Tonomura, Junichi Nagakawa, Carl Trygstad, Fumito Tsuji, Stanford Jhee, Sherry Unabia, Mark Yen Background: Proton pump inhibitors (PPIs) such as omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole are substituted benzimidazoles and the first line of choice for gastro-esophageal reflux disease (GERD) treatment. Twenty to thirty % of GERD patients are refractory with these PPIs mostly due to insufficient inhibition of gastric acid secretion. We developed a substituted benzimidazole PPI, E3710, which has a new type of long-lasting mechanism with strong acid-induced split. Aims: To investigate acid secretion inhibitory activity of multiple oral doses of E3710 and compare with those of rabeprazole (RPZ) or esomeprazole (EPZ). Methods: This open-label, randomized, 3-way crossover study was conducted in PAREXEL Early Phase unit in Los Angeles employing 30 healthy, male adults Japanese (20-50 years of age). Subjects were born in Japan of Japanese parents and Japanese grandparents and have lived no more than 5 years outside of Japan and have not changed their life style or habits, including diet, while living outside of Japan. Subjects were CYP2C19 homozygous or heterozygous extensive metabolizers and H. pylori-negative. Intra-gastric 24- h pH monitoring was performed on day 1 and day 5 of consecutive administration of PPI in addition to baseline. RPZ 10 mg, E3710 20 mg, 40 mg and 80 mg, and EPZ 40 mg were tested. Each patient randomly received 3 tests which were separated with 7 days washout. PPIs were administered before breakfast. Results: The mean % of time with pH≥4/24 h (the % / 24-h) at baseline was in the range of 9.9 - 10.3 in 5 tested groups. RPZ 10 mg increased the % / 24-h to 37.3 on day 1 and 48.0 on day 5. E3710 20 mg increased the % / 24-h to 46.0 on day 1 and 58.9 on day 5. E3710 40 mg increased the % / 24-h to 47.8 on day 1 and 63.8 on day 5. E3710 80 mg increased the % / 24-h to 52.6 on day 1 and 64.2 on day 5. EPZ 40 mg increased the % / 24-h to 48.8 on day 1 and 63.5 on day 5. Thus, the % / 24-h on day 1 and day 5 of E3710 40 mg were significantly greater than those of RPZ 10 mg, respectively. Next, we obtained the % of time with pH≥4/8 h from 11 PM to 7 AM (the % / 8-h). The % / 8-h at baseline was in the range of 2.2 - 3.5 in 5 tested groups. RPZ 10 mg increased the % / 8-h to 23.7 on day 1 and 26.1 on day 5. E3710 20 mg increased the % / 8-h to 38.0 on day 1 and 28.3 on day 5. E3710 40 mg increased the % / 8-h to 31.8 on day 1 and 39.5 on day 5. E3710 80 mg increased the % / 8-h to 34.9 on day 1 and 38.2 on day 5. EPZ 40 mg increased the % / 8-h to 23.0 on day 1 and 39.2 on day 5. Thus, the %/ 8-h on day 1 nighttime of E3710 20 mg and 40 mg were significantly greater than that of RPZ 10mg, and that of E3710 80 mg was significantly greater than that of EPZ 40 mg. Conclusion: The present results of E3710 on 24-h intra- gastric pH warrant future clinical evaluation of E3710 for GERD treatment. Mo1070 A Novel PPI Inhibitor E3710 With Acid-Induced Split Mechanism Hideo Tonomura, Kotaro Kodama, Misako Watanabe, Hideaki Fujisaki, Junichi Nagakawa, Noriaki Takeguchi Background: Proton pump inhibitors (PPIs) are the first choice for treatment of gastroeso- phageal reflux disease (GERD). But, 20-30% patients are refractory to presently available PPIs and remain unhealed or insufficient from symptom relief. We synthesized a new proton pump inhibitor E3710. The 24-h intragastric pH > 4 holding times after the first doses of E3710 0.4 mg/kg and esomeprazole (EPZ) 1.6 mg/kg were 82% and 61% of a day, respect- ively, in a cross-over study of gastric fistula dogs (Kodama K et al. J Pharmacol Exp Ther 2010). Aim: To study the possible mechanism of long-lasting effect of E3710 in comparison with EPZ. Method: In a very low pH environment such as gastric canaliculi, PPIs are transformed into acid-activated compounds which bind with gastric proton pump. We examined the acid-activated chemical transformation process of E3710 and calculated accom- panying change in the physicochemical property of lipophilicity using the PhysChem ver 12.01 (Advanced Chemistry Development, Canada). Results: The original and acid-activated structures of E3710 and values (D) for the distribution ratio (oil/water) are shown in the attached figure. PPIs including E3710 are absorbed from intestine into blood and reach in the canalicular space of gastric parietal cells finally crossing the basolateral and apical membranes of the parietal cell owing to the highly lipophilic characteristics of PPIs. The D value of E3710 was calculated to be 3.3-fold greater than that of EPZ at neutral pH, indicating that E3710 more quickly reach in the canalicular space than EPZ. E3710 has 2, 2-dimethyl- 1, 3-dioxane moiety. This dimethyl group is unstable in the strong acidic space and the isopropyl group including the dimethyl group is splitted leaving two OH groups in the remaining main body, which gives a higher hydrophilicity. The D value for the acid activated E3710 is (1/25)-fold the original compound, while that of EPZ is (1/1.2)-fold. D value of
Transcript of Mo1067 Guggulsterone, a Plant Sterol Inhibitor of NF-κB, Suppresses CDx2 and COX-2 Overexpression...
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sthe first demonstration that hydrotalcite enhances esophageal epithelial defense and protectskeratinocyte progenitor cells. 3) These findings provide novel molecular mechanisms forhydrotalcite protective action on esophageal mucosa and a rationale for its therapeutic use.
Mo1066
A Multi-Center, Randomized, Double Blinded, Phase 4 Clinical Trial to Assessthe Efficacy and Cost Effectiveness of Omeprazole Compare to Rabeprazole inthe Maintenance Therapy of Patients With Gastroesophageal Reflux DiseaseJung Ho Park, Hyojin Park, Dong Ho Lee, In Kyung Sung
Background and Aims: Due to recurring nature of GERD, Most patients require long termmaintenance therapy and continuous medication of proton pump inhibitor (PPI) is anadequate option for patients with erosive esophagitis. The aim of this study was to evaluatethe efficacy and cost minimization analysis of omeprazole 10 mg once daily and rabeprazole10 mg once daily for 24 weeks in the maintenance of remission Methods:This is randomized,open-label study enrolled 279 patients with erosive esophagitis A or B (LA classification)and typical GERD symptoms. Patients who showed complete endoscopic and symptomatichealing after 8 weeks PPI treatment were randomly allocated to maintenance treatment withomeprazole 10mg once daily or rabeprazole 10mg once daily for 42 weeks. The primaryefficacy endpoint was the proportion of patients with symptomatic remission at 42 weeks.Secondary assessments included healing of reflux esophagitis, severity and frequency ofreflux symptoms and cost-minimization analysis in the maintenance phase Results:At theend of 42 weeks of maintenance therapy, 96.4% of omeprazole treated and 95.1% ofrabeprazole treated patients remained symptom free (P>0.05). Omeprazole and rabeprazolewere also similarly efficacious in terms of endoscopic non-relapse rate for RE with 93.3%of patients on omeprazole and 97.5% of patients of rabeprazle. (P>0.05) Two drugs werealso comparable with regard to severity and frequency of reflux symptoms duringmaintenancephase. (P>0.05) In the cost-minimization analysis, The mean total costs per patient forremaining symptom free within 6 months was 241,775 won in omeprazole and 287,115won in rabeprazole, respectively.(as if 24 November 2011, 1 USD= 1,176.33 won) Conclu-sions:Omeprazole 10mg appeared to have a similar efficacy in maintaining symptomaticremission as rabeprazole 10 mg, but had a lower total cost per patient than rabeprazole 10mg.
Mo1067
Guggulsterone, a Plant Sterol Inhibitor of NF-κB, Suppresses CDx2 and COX-2 Overexpression and Reduces Proliferation of Esophageal AdenocarcinomaCellsTakanori Yamada, Satoshi Osawa, Yasuhiro Takayanagi, Jiong Zhang, Yasushi Hamaya,Mitsushige Sugimoto, Shigeru Kanaoka, Takahisa Furuta, Ken Sugimoto
BACKGROUND&AIMS: Induction of caudal type homeobox 2 (CDX2) and cyclooxygenase-2 (COX-2) expression by acid and bile acid in the distal esophagus is a critical molecularevent in the development of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC).Although proton pump inhibitors (PPIs) can reduce acid exposure in the distal esophagus,few remedies targeting bile acid reflux and concomitant exposure of esophageal tissue.Bile acids induce CDX2 and COX-2 expression by activating nuclear factor κB (NF-κB).Guggulsterone (GS) is a plant sterol known to inhibit NF-κB. Thus, we hypothesized thatGS may suppress bile acid-induced CDX2 and COX-2 expression by NF-κB inactivationand inhibit BE and EAC development. METHODS: Two EAC cells lines, OE19 and OE33,were treated with biliary deoxycholic acid (DCA) in the presence of GS or vehicle. Phosphoryl-ation of the NF-κB regulatory peptide IκB was detected by immunoblot analysis. CDX2 andCOX-2 expression was analyzed by qRT-PCR and immunoblot analysis. Prostaglandin E2(PGE2) production by EAC cell lines was measured by ELISA. Cell viability was assessedby the MTT assay, and cell cycle distribution was measured by genomic DNA labeling andflow cytometry. RESULTS: GS inhibited DCA-induced IκB phosphorylation, possibly leadingto reduce NF-κB-mediated gene expression. A known NF-κB inhibitor BAY11-7085 sup-pressed DCA-induced CDX2 and COX-2 expression in EAC cell lines, confirming thatexpression of these two genes depended on NF-κB activation. GS suppressed DCA-inducedCDX2 and COX-2 expression in EAC cell lines. GS also suppressed basal CDX2 and COX-2 expression and reduced constitutive synthesis of the COX-2 product and proliferationenhancer PGE2. Furthermore, GS reduced the viability of EAC cells and increased theirfraction in sub-G1, the apoptosis-associated cell cycle phase. Finally, GS treatment activatedthe apoptosis effector caspase-3 and RARP. CONCLUSIONS: GS suppresses DCA-inducedand NF-κB-dependent activation of CDX2 and COX-2 expression. Furthermore, GS reducesEAC proliferation by promoting apoptosis. Thus, GS is a possible candidate chemopreventive/therapeutic agent for EAC as well as BE.
Mo1068
Efficacy of Frequent PPI Dosing for Potent Acid Inhibition Over 24 HoursMitsushige Sugimoto, Takahiro Uotani, Masafumi Nishino, Mihoko Yamade, Shu Sahara,Takanori Yamada, Satoshi Osawa, Ken Sugimoto, Takahisa Furuta
Background: While proton pump inhibitors (PPIs) potently inhibit gastric acid secretion,their use is hamstrung by issues such as variation in efficacy due to CYP2C19 genotype,reduced efficacy for nocturnal gastric acid inhibition, and a slower onset efficacy of gastricacid inhibition. As such, advanced therapeutic regimens are required to sustain potent acidinhibition for a full 24-h, especially in nocturnal time, in all patients with acid-relateddiseases, regardless of genetic factors. However, optimum treatment regimen using PPIs isunclear at present, as most previous reports have involved type 2 error. Here, to help clarifythis ideal regimen, we assessed acid inhibitory effects of a number of PPIs across severalCYP2C19 genotypes using different dosing methods in a study involving more than 180rounds of pH monitoring. Methods: Using pH monitoring, we compared acid inhibition ofa number of PPIs (omeprazole at 20 mg, 30 times; lansoprazole at 30 mg, 33 times;rabeprazole at 10 mg, 55 times) in related with different CYP2C19 genotypes. We thenevaluated efficacy of divided treatment with a specific PPI, rabeprazole, using pH monitoring
S-586AGA Abstracts
(rabeprazole at 40 mg sid, 15 times; at 20 mg bid, 20 times; and at 10 mg qid, 35 times).Results: Median (range) 24-h intragastric pH values with omeprazole (20 mg), lansoprazole(30mg), and rabeprazole (10mg)were 4.3 (2.1-7.3), 4.8 (3.6-6.4), 5.5 (3.3-7.5), respectively.Although rabeprazole inhibited gastric acid to a significantly greater degree than omeprazoleand lansoprazole (both p < 0.05, respectively), inhibition over 24-h attained by rabeprazolewas insufficient (median percent time of intragastric pH < 4: 35.6% [3.5%-73.8%]). In ourexamination of the efficacy of divided PPI treatment, median (range) 24-h intragastric pHvalues for rabeprazole 40 mg sid, 20 mg bid, and 10 mg qid were 4.8 (3.6-6.4), 5.7 (4.1-7.4), 6.6 (4.9-8.4), respectively. Although dosing dose a day was same, rabeprazole 40mg,increases in dosing times effectively increased intragastric pH, not only during the day butalso at night (rabeprazole 10 mg qid: percent time of intragastric pH < 4: 3.4% [3.5-9.8%]).In CYP2C19 poor metabolizers, the acid inhibition attained by a PPI was enhanced incomparison with that in CYP2C19 intermediate metabolizers or rapid metabolizers (RMs)for all PPIs. Further, rabeprazole administered at 10 mg qid maintained pH > 4 for 24 hin RMs. Discussion: Although we cannot entirely ignore the influence of CYP2C19 genotypeon acid inhibition, rabeprazole's effect is less influenced by CYP2C19 genotype than omepra-zole and lansoprazole. In addition, PPI sid treatment is difficult to maintain acid secretionfor a full 24-h. However, PPI qid treatment achieved potent acid inhibition, including duringthe night, suggesting its potential usefulness in patients refractory to PPI therapeutic regimens.
Mo1069
Effect of Oral Administration of a New Proton Pump Inhibitor E3710 on 24-hIntra-Gastric pH in Japanese SubjectsHideo Tonomura, Junichi Nagakawa, Carl Trygstad, Fumito Tsuji, Stanford Jhee, SherryUnabia, Mark Yen
Background: Proton pump inhibitors (PPIs) such as omeprazole, lansoprazole, pantoprazole,rabeprazole and esomeprazole are substituted benzimidazoles and the first line of choicefor gastro-esophageal reflux disease (GERD) treatment. Twenty to thirty % of GERD patientsare refractory with these PPIs mostly due to insufficient inhibition of gastric acid secretion.We developed a substituted benzimidazole PPI, E3710, which has a new type of long-lastingmechanism with strong acid-induced split. Aims: To investigate acid secretion inhibitoryactivity of multiple oral doses of E3710 and compare with those of rabeprazole (RPZ) oresomeprazole (EPZ). Methods: This open-label, randomized, 3-way crossover study wasconducted in PAREXEL Early Phase unit in Los Angeles employing 30 healthy, male adultsJapanese (20-50 years of age). Subjects were born in Japan of Japanese parents and Japanesegrandparents and have lived no more than 5 years outside of Japan and have not changedtheir life style or habits, including diet, while living outside of Japan. Subjects were CYP2C19homozygous or heterozygous extensive metabolizers and H. pylori-negative. Intra-gastric 24-h pH monitoring was performed on day 1 and day 5 of consecutive administration of PPIin addition to baseline. RPZ 10 mg, E3710 20 mg, 40 mg and 80 mg, and EPZ 40 mg weretested. Each patient randomly received 3 tests which were separated with 7 days washout.PPIs were administered before breakfast. Results: The mean % of time with pH≥4/24 h(the % / 24-h) at baseline was in the range of 9.9 - 10.3 in 5 tested groups. RPZ 10 mgincreased the % / 24-h to 37.3 on day 1 and 48.0 on day 5. E3710 20 mg increased the% / 24-h to 46.0 on day 1 and 58.9 on day 5. E3710 40 mg increased the % / 24-h to47.8 on day 1 and 63.8 on day 5. E3710 80 mg increased the % / 24-h to 52.6 on day 1and 64.2 on day 5. EPZ 40 mg increased the % / 24-h to 48.8 on day 1 and 63.5 on day5. Thus, the % / 24-h on day 1 and day 5 of E3710 40 mg were significantly greater thanthose of RPZ 10 mg, respectively. Next, we obtained the % of time with pH≥4/8 h from11 PM to 7 AM (the % / 8-h). The % / 8-h at baseline was in the range of 2.2 - 3.5 in 5tested groups. RPZ 10 mg increased the % / 8-h to 23.7 on day 1 and 26.1 on day 5. E371020 mg increased the % / 8-h to 38.0 on day 1 and 28.3 on day 5. E3710 40 mg increasedthe % / 8-h to 31.8 on day 1 and 39.5 on day 5. E3710 80 mg increased the % / 8-h to34.9 on day 1 and 38.2 on day 5. EPZ 40 mg increased the % / 8-h to 23.0 on day 1 and39.2 on day 5. Thus, the %/ 8-h on day 1 nighttime of E3710 20 mg and 40 mg weresignificantly greater than that of RPZ 10mg, and that of E3710 80 mg was significantlygreater than that of EPZ 40 mg. Conclusion: The present results of E3710 on 24-h intra-gastric pH warrant future clinical evaluation of E3710 for GERD treatment.
Mo1070
A Novel PPI Inhibitor E3710 With Acid-Induced Split MechanismHideo Tonomura, Kotaro Kodama, Misako Watanabe, Hideaki Fujisaki, JunichiNagakawa, Noriaki Takeguchi
Background: Proton pump inhibitors (PPIs) are the first choice for treatment of gastroeso-phageal reflux disease (GERD). But, 20-30% patients are refractory to presently availablePPIs and remain unhealed or insufficient from symptom relief. We synthesized a new protonpump inhibitor E3710. The 24-h intragastric pH > 4 holding times after the first doses ofE3710 0.4 mg/kg and esomeprazole (EPZ) 1.6 mg/kg were 82% and 61% of a day, respect-ively, in a cross-over study of gastric fistula dogs (Kodama K et al. J Pharmacol Exp Ther2010). Aim: To study the possible mechanism of long-lasting effect of E3710 in comparisonwith EPZ. Method: In a very low pH environment such as gastric canaliculi, PPIs aretransformed into acid-activated compounds which bind with gastric proton pump. Weexamined the acid-activated chemical transformation process of E3710 and calculated accom-panying change in the physicochemical property of lipophilicity using the PhysChem ver12.01 (Advanced Chemistry Development, Canada). Results: The original and acid-activatedstructures of E3710 and values (D) for the distribution ratio (oil/water) are shown in theattached figure. PPIs including E3710 are absorbed from intestine into blood and reach inthe canalicular space of gastric parietal cells finally crossing the basolateral and apicalmembranes of the parietal cell owing to the highly lipophilic characteristics of PPIs. The Dvalue of E3710 was calculated to be 3.3-fold greater than that of EPZ at neutral pH, indicatingthat E3710 more quickly reach in the canalicular space than EPZ. E3710 has 2, 2-dimethyl-1, 3-dioxane moiety. This dimethyl group is unstable in the strong acidic space and theisopropyl group including the dimethyl group is splitted leaving two OH groups in theremaining main body, which gives a higher hydrophilicity. The D value for the acid activatedE3710 is (1/25)-fold the original compound, while that of EPZ is (1/1.2)-fold. D value of
