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241 Small Molecule Inhibitors Xmd8-92 and Pv1019 Inhibit Pancreatic Tumor Xenograft Growth via a DCLK1 Dependent Mechanism
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Small Molecule Inhibitors Xmd8-92 and Pv1019 Inhibit Pancreatic Tumor Xenograft Growth via a DCLK1 Dependent Mechanism Sripathi M. Sureban, Dongfeng Qu, Parthasarathy Chandrakesan, Randal May, Nathaniel Weygant, Naushad Ali, Panayotis Pantazis, Courtney W. Houchen
Time Trends in Helicobacter pylori Infection and Intestinal Metaplasia Based on the 1970s, 1990s, and 2010s Results in a 40-Year Comparison Study of Japanese Patients Tomoari Kamada, Masanori Ito, Noriaki Manabe, Yoshiki Kimura, Machi Tsukamoto, Takahisa Murao, Hiroshi Matsumoto, Minoru Fujita, Ken-ichi Tarumi, Hiroaki Kusunoki, Yumi Sato, Kazuhiko Inoue, Akiko Shiotani, Jiro Hata, Shinji Tanaka, Ken Haruma
Background: XMD8-92 is a small molecule inhibitor of BMK1/MAPK7 kinase activity, a key member of the MAP kinase cascade, which plays an important role in transmitting oncogenic signals in tumorigenesis. Treatment with XMD8-92 has been reported to inhibit breast and ovarian cancer cell proliferation and tumor xenograft growth. It has also been shown that XMD8-92 binds to DCLK1 (formerly known as DCAMKL-1). Recently, CHK2 (checkpoint kinase) inhibitors have been proposed as chemotherapeutic agents in combination with cytotoxic agents. Treatment with PV1019, a potent and selective CHK2 kinase inhibitor resulted in human ovarian and colorectal cancer cell growth inhibition. The putative intestinal and pancreatic stem cell and Tuft cell marker DCLK1 is upregulated in human pancreatic, esophageal, and colon cancers. Knockdown of DCLK1 with siRNA results in the inhibition of several oncogenes and pluripotency factors, including c-Myc, via microRNA related mechanisms. Aim: To determine whether these small molecule inhibitors regulate pancreatic tumor growth by inhibiting DCLK1. Methods: AsPC-1, human pancreatic cancer cell derived tumor xenografts generated in NOD/SCID mice were injected intraperitoneally with XMD8-92 (50 mg/Kg body weight) and PV1019 (10 mg/Kg). siRNA-targeting DCLK1 encapsulated in poly(lactide-co-glycolide) (PLGA)-based nanoparticles (NP-siDCLK1) and injected directly into tumor xenografts was used as a positive control. Total RNAs isolated from the tumor xenografts and cells from the above experiments were subjected to realtime RT-PCR for mRNA analyses of DCLK1, c-Myc, KRAS, Notch1, EMT, pluripotency factors and CDC25c (downstream target of CHK2 kinase). Protein analyses were carried out by Western blot and immunohistochemistry. Results: XMD8-92, PV1019 and NPsiDCLK1 treatment resulted in AsPC-1 tumor xenograft growth arrest. XMD8-92, PV1019 and NP-siDCLK1 treated tumors demonstrated a statistically significant downregulation (~50%) of DCLK1 and its downstream targets including c-Myc, KRAS, Notch1, ZEB1, ZEB2, Snail, Slug, OCT4, SOX2, LIN28, Nanog, KLF4 and CDC25c. We obtained similar results in vitro following treatment with XMD8-92, PV1019 and NP-siDCLK1. Conclusions: These data taken together demonstrate that small molecule kinase inhibitors like XMD8-92 and PV1019 may regulate pancreatic tumor growth by inhibiting DCLK1 function. Furthermore, these results strengthen the notion that inhibition of DCLK1, a potential central oncogenic regulatory protein, is an effective approach for treating human solid tumor cancers including pancreatic cancer.
Background and aim: It is well known that Helicobacter pylori (H. pylori) infection induces atrophic gastritis and additionally lead to intestinal metaplasia (IM). Moreover, intestinaltype gastric cancer develops in a precancerous gastric mucosa. Recently, the incidence of H. pylori infection in Japan has declined owing to the improvement of economic and hygienic conditions. However, only a few studies have investigated trends in the prevalence of H. pylori infection and IM over long-term periods. Hence, the purpose of our study was to clarify the trends in H. pylori infection and IM in Japanese populations by comparing the 1970s, 1990s, and 2010s results of a 40-year comparison study. Subjects and methods: The prevalence of H. pylori infection and IM grades were evaluated using biopsy specimens from 1381 persons without localized lesions in the upper gastrointestinal tract. The findings were compared between the 1970s (289 subjects: 158 men; mean age, 45 years), 1990s (787 subjects: 430 men; mean age, 44.2 years), and 2010s groups (305 subjects: 163 men; mean age, 53.2 years). Four biopsy specimens were obtained from each patient, 2 from the lesser curvature of the middle antrum and 2 from the anterior and posterior fundus, for evaluating H. pylori infection and IM. Histological IM specimens were evaluated according to the Sydney System, and H. pylori infection was diagnosed by Giemsa staining. Results: The prevalence of H. pylori infection was significantly lower in the 2010s group (35.1%, p , 0.01) than in the 1970s (74.7%) and 1990s groups (53%). In addition, the IM scores for the antrum and fundus were significantly lower in the 2010s group than in the 1970s and 1990s groups. Among the patients with H. pylori infection, those in the 2010s group had a significantly lower IM prevalence rate (antrum, 15%; fundus, 4.7%; p , 0.01) than those in the 1970s (antrum, 64%; fundus, 32.4%) and 1990s groups (antrum, 37.4%; fundus, 21.3%). Conclusions: Our data showed a trend toward a reduced prevalence of H. pylori infection and IM over the 40-year study period, suggesting a possible future decline in the incidence rate of gastric cancer in Japan. 244 A Randomized Controlled Trial of Triple Therapy Versus Sequential Therapy Versus Concomitant Therapy As First Line Treatment for H. pylori Infection Tiing Leong Ang, Kwong Ming Fock, Daphne Ang
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Background: Triple therapy (TT) has been considered a standard treatment for H. pylori infection. However increasing bacterial resistance, especially to clarithromycin, has been reported and there are concerns that the efficacy of TT has decreased. Sequential therapy (ST) and concomitant therapy (CT) are alternative first line treatments that may overcome the problem of bacterial resistance. Currently there are no randomized controlled studies that compare TT with ST or CT in Singapore. Aim: To compare the efficacy of 10-day TT, ST and CT as first line treatment for H. pylori infection in Singapore. Methods: This prospective randomized controlled study was approved by the institutional review board and informed consent was obtained from all patients. Inclusion criteria: patients over 21 years who were newly diagnosed to have H. pylori infection based on a positive carbon urea breath test (CUBT), rapid urease test or histology. Exclusion criteria: 1) known allergy to any of the treatment drugs; 2) previous H. pylori therapy. Patients were randomized to either 10 day TT (proton pump inhibitor [PPI], amoxicillin 1g, clarithromycin 500mg twice daily), 10day ST (PPI and amoxicillin 1 g twice daily x 5 days followed by PPI, clarithromycin 500mg, metronidazole 400mg twice daily x 5days) or 10-day CT (PPI, amoxicillin 1g, clarithromycin 500mg, metronidazole 400mg twice daily). Treatment outcome was assessed by CUBT performed at least 4 weeks after therapy. Results: From Dec 2011 to October 2012, 227 patients (TT: 74, ST: 76, CT: 77) were enrolled. Twenty (8.8%) defaulted leaving 207 for analysis. The mean age was 48.5 years (range: 21 - 87) and 57% were males. The clinical diagnoses were gastritis or functional dyspepsia (80.2%), peptic ulcer disease (19.8%) and gastroesophageal reflux disease (7.2%). All 3 treatment arms were comparable in terms of age, gender distribution, smoking status and clinical diagnoses. There was no statistically significant difference in the H. pylori eradication rate between ST (93.1%), TT (92.5%) and CT (97.1%). The treatment success rates remained similar between all 3 arms when the eradication rate was reanalysed by considering all subjects who defaulted as treatment failure. Conclusion: TT, ST and CT had similar efficacy for H. pylori eradication. All three regimens may be used as first line treatment for H. pylori eradication in Singapore.
14-Day, High-Dose Acid Suppression, Non-Bismuth Quadruple Therapies (Hybrid vs. Concomitant) for Helicobacter pylori Infection: A Randomized Trial Javier Molina-Infante, Marco Romano, Miguel Fernandez Bermejo, Alessandro Federico, Antonietta G. Gravina, Liliana Pozzati, Elena Garcia Abadia, Carmen Martinez-Alcala, Agnese Miranda, Gema Vinagre Rodriguez, Moises Hernandez Alonso, Belen Perez Gallardo, Francisco J. Rancel Medina, Marta Gata Cuadrado, Javier P. Gisbert BACKGROUND&AIM Optimizing triple therapy, through increasing PPI dosage or extending the duration to 14 days, may improve Helicobacter pylori cure rates by 5-10%. Whether these results can be generalizable to non-bismuth quadruple therapies remains unknown. We aimed to evaluate two 14-day, high-dose acid suppression, non-bismuth quadruple regimens in two regions from Spain (Extremadura) and Italy (Naples), with a similarly high (≥20%) clarithromycin resistance rate and cure rates for 10-day sequential therapy ≤80% and for 10-day concomitant therapy , 90%. METHODS Prospective randomized (1:1) multicenter clinical trial, in which consecutive Naïve H. pylori patients were randomized to receive "optimized" non-bismuth quadruple therapies, either hybrid treatment (omeprazole 40 mg b.i.d. and amoxicillin 1 g b.i.d. for 14 days, adding clarithromycin 500 mg b.i.d. and metronidazole/tinidazole 500 mg b.i.d for the final 7 days) or concomitant treatment (same four drugs taken concurrently for 14 days). Antimicrobial resistance was assessed by the E-test in a subset of patients (n=68) undergoing endoscopy. Eradication was confirmed with 13C-urea breath test or histology 8 weeks after treatment. Adverse events and treatment compliance were evaluated with specific questionnaires. RESULTS: 341 patients were finally included (Spain=258, Italy n=83), of whom 327 have completed the study. 95% (310/327) of patients fully complied with treatment. Per-protocol (PP) eradication rates for the hybrid and concomitant treatments were 91% (87-96%) vs. 95% (91%CI=92-99%), p 0.13. Respective intention-to-treat cure rates were 90% (87-96%) vs. 92% (91-98%), p 0.44. Antibiotic resistance rates were: clarithromycin 22% (15/68) (Italy 24 %, Spain 20.5%) and dual resistance 8.8%. Cure rates for both therapies were 100% against clarithromycin resistantmetronidazole susceptible strains (n=9), whereas cure rates against dual resistant strains were 33% (1/3) for hybrid and 100% (3/3) for concomitant therapy. Adverse effects were reported in 47% of patients (45% hybrid vs. 54% concomitant; p 0.07). The most common were metallic taste (39%), epigastralgia/nausea (24%) and diarrhea (20%), with no severe side effects. Overall cure rates were significantly higher (95% vs. 64%, p 0.002, 94% vs. 54%, p ,0.0001 and 93% vs. 41%, p , 0.0001) when compliance with therapy was 100%, 90% or 80%, respectively, albeit without statistical significance in the multivariate analysis CONCLUSION: Both optimized concomitant and hybrid therapies achieved H. pylori cure rates ≥ 90% in settings with clarithromycin resistance rates . 20%, being concomitant therapy highly effective against clarithromycin and dual resistant strains. There were no significant differences between therapies regarding efficacy or compliance, excepting a trend towards better tolerance of the hybrid therapy.
245 Effects of Different Dosing Schedules of Amoxicillin on the Eradication Rates of Helicobacter pylori by Triple Therapy With a Proton Pump Inhibitor, Amoxicillin, and Either Clarithromycin or Metronidazole Takahisa Furuta, Mitsushige Sugimoto, Mihoko Yamade, Takahiro Uotani, Shu Sahara, Hitomi Ichikawa, Takanori Yamada, Satoshi Osawa, Ken Sugimoto Background: Triple therapies with proton pump inhibitor, (PPI), amoxicillin and clarithromycin or metronidazole are standard for Helicobacter pylori infection. While the drugs used in these regimens are normally dosed twice daily, the bactericidal effect of amoxicillin depends on the time-above-MIC, not Cmax or AUC. We therefore examined the influence of different dosing schedules of amoxicillin on the eradication rates of triple therapies. Methods: A total of 245 patients infected with H. pylori infected with clarithromycin-sensitive strains of H. pylori were treated with a PPI, clarithromycin 200 mg bid, and amoxicillin at either 750 mg bid, 500 mg tid, or 500 mg qid for 1 week. Seventy-eight patients infected with clarithromycin-resistant or unknown strains of H. pylori were treated with a PPI, metronidazole 250 mg bid, and amoxicillin at either 750 mg bid, 500 mg tid, or 500 mg qid for 1 week. Results: Nine patients were excluded from analysis. In the clarithromycinsensitive group, eradication rates (PP) were 83.9% (52/62), 97.0% (62/64), and 100.0%
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241
Small Molecule Inhibitors Xmd8-92 and Pv1019 Inhibit Pancreatic Tumor Xenograft Growth via a DCLK1 Dependent Mechanism Sripathi M. Sureban, Dongfeng Qu, Parthasarathy Chandrakesan, Randal May, Nathaniel Weygant, Naushad Ali, Panayotis Pantazis, Courtney W. Houchen
Time Trends in Helicobacter pylori Infection and Intestinal Metaplasia Based on the 1970s, 1990s, and 2010s Results in a 40-Year Comparison Study of Japanese Patients Tomoari Kamada, Masanori Ito, Noriaki Manabe, Yoshiki Kimura, Machi Tsukamoto, Takahisa Murao, Hiroshi Matsumoto, Minoru Fujita, Ken-ichi Tarumi, Hiroaki Kusunoki, Yumi Sato, Kazuhiko Inoue, Akiko Shiotani, Jiro Hata, Shinji Tanaka, Ken Haruma
Background: XMD8-92 is a small molecule inhibitor of BMK1/MAPK7 kinase activity, a key member of the MAP kinase cascade, which plays an important role in transmitting oncogenic signals in tumorigenesis. Treatment with XMD8-92 has been reported to inhibit breast and ovarian cancer cell proliferation and tumor xenograft growth. It has also been shown that XMD8-92 binds to DCLK1 (formerly known as DCAMKL-1). Recently, CHK2 (checkpoint kinase) inhibitors have been proposed as chemotherapeutic agents in combination with cytotoxic agents. Treatment with PV1019, a potent and selective CHK2 kinase inhibitor resulted in human ovarian and colorectal cancer cell growth inhibition. The putative intestinal and pancreatic stem cell and Tuft cell marker DCLK1 is upregulated in human pancreatic, esophageal, and colon cancers. Knockdown of DCLK1 with siRNA results in the inhibition of several oncogenes and pluripotency factors, including c-Myc, via microRNA related mechanisms. Aim: To determine whether these small molecule inhibitors regulate pancreatic tumor growth by inhibiting DCLK1. Methods: AsPC-1, human pancreatic cancer cell derived tumor xenografts generated in NOD/SCID mice were injected intraperitoneally with XMD8-92 (50 mg/Kg body weight) and PV1019 (10 mg/Kg). siRNA-targeting DCLK1 encapsulated in poly(lactide-co-glycolide) (PLGA)-based nanoparticles (NP-siDCLK1) and injected directly into tumor xenografts was used as a positive control. Total RNAs isolated from the tumor xenografts and cells from the above experiments were subjected to realtime RT-PCR for mRNA analyses of DCLK1, c-Myc, KRAS, Notch1, EMT, pluripotency factors and CDC25c (downstream target of CHK2 kinase). Protein analyses were carried out by Western blot and immunohistochemistry. Results: XMD8-92, PV1019 and NPsiDCLK1 treatment resulted in AsPC-1 tumor xenograft growth arrest. XMD8-92, PV1019 and NP-siDCLK1 treated tumors demonstrated a statistically significant downregulation (~50%) of DCLK1 and its downstream targets including c-Myc, KRAS, Notch1, ZEB1, ZEB2, Snail, Slug, OCT4, SOX2, LIN28, Nanog, KLF4 and CDC25c. We obtained similar results in vitro following treatment with XMD8-92, PV1019 and NP-siDCLK1. Conclusions: These data taken together demonstrate that small molecule kinase inhibitors like XMD8-92 and PV1019 may regulate pancreatic tumor growth by inhibiting DCLK1 function. Furthermore, these results strengthen the notion that inhibition of DCLK1, a potential central oncogenic regulatory protein, is an effective approach for treating human solid tumor cancers including pancreatic cancer.
Background and aim: It is well known that Helicobacter pylori (H. pylori) infection induces atrophic gastritis and additionally lead to intestinal metaplasia (IM). Moreover, intestinaltype gastric cancer develops in a precancerous gastric mucosa. Recently, the incidence of H. pylori infection in Japan has declined owing to the improvement of economic and hygienic conditions. However, only a few studies have investigated trends in the prevalence of H. pylori infection and IM over long-term periods. Hence, the purpose of our study was to clarify the trends in H. pylori infection and IM in Japanese populations by comparing the 1970s, 1990s, and 2010s results of a 40-year comparison study. Subjects and methods: The prevalence of H. pylori infection and IM grades were evaluated using biopsy specimens from 1381 persons without localized lesions in the upper gastrointestinal tract. The findings were compared between the 1970s (289 subjects: 158 men; mean age, 45 years), 1990s (787 subjects: 430 men; mean age, 44.2 years), and 2010s groups (305 subjects: 163 men; mean age, 53.2 years). Four biopsy specimens were obtained from each patient, 2 from the lesser curvature of the middle antrum and 2 from the anterior and posterior fundus, for evaluating H. pylori infection and IM. Histological IM specimens were evaluated according to the Sydney System, and H. pylori infection was diagnosed by Giemsa staining. Results: The prevalence of H. pylori infection was significantly lower in the 2010s group (35.1%, p , 0.01) than in the 1970s (74.7%) and 1990s groups (53%). In addition, the IM scores for the antrum and fundus were significantly lower in the 2010s group than in the 1970s and 1990s groups. Among the patients with H. pylori infection, those in the 2010s group had a significantly lower IM prevalence rate (antrum, 15%; fundus, 4.7%; p , 0.01) than those in the 1970s (antrum, 64%; fundus, 32.4%) and 1990s groups (antrum, 37.4%; fundus, 21.3%). Conclusions: Our data showed a trend toward a reduced prevalence of H. pylori infection and IM over the 40-year study period, suggesting a possible future decline in the incidence rate of gastric cancer in Japan. 244 A Randomized Controlled Trial of Triple Therapy Versus Sequential Therapy Versus Concomitant Therapy As First Line Treatment for H. pylori Infection Tiing Leong Ang, Kwong Ming Fock, Daphne Ang
242
Background: Triple therapy (TT) has been considered a standard treatment for H. pylori infection. However increasing bacterial resistance, especially to clarithromycin, has been reported and there are concerns that the efficacy of TT has decreased. Sequential therapy (ST) and concomitant therapy (CT) are alternative first line treatments that may overcome the problem of bacterial resistance. Currently there are no randomized controlled studies that compare TT with ST or CT in Singapore. Aim: To compare the efficacy of 10-day TT, ST and CT as first line treatment for H. pylori infection in Singapore. Methods: This prospective randomized controlled study was approved by the institutional review board and informed consent was obtained from all patients. Inclusion criteria: patients over 21 years who were newly diagnosed to have H. pylori infection based on a positive carbon urea breath test (CUBT), rapid urease test or histology. Exclusion criteria: 1) known allergy to any of the treatment drugs; 2) previous H. pylori therapy. Patients were randomized to either 10 day TT (proton pump inhibitor [PPI], amoxicillin 1g, clarithromycin 500mg twice daily), 10day ST (PPI and amoxicillin 1 g twice daily x 5 days followed by PPI, clarithromycin 500mg, metronidazole 400mg twice daily x 5days) or 10-day CT (PPI, amoxicillin 1g, clarithromycin 500mg, metronidazole 400mg twice daily). Treatment outcome was assessed by CUBT performed at least 4 weeks after therapy. Results: From Dec 2011 to October 2012, 227 patients (TT: 74, ST: 76, CT: 77) were enrolled. Twenty (8.8%) defaulted leaving 207 for analysis. The mean age was 48.5 years (range: 21 - 87) and 57% were males. The clinical diagnoses were gastritis or functional dyspepsia (80.2%), peptic ulcer disease (19.8%) and gastroesophageal reflux disease (7.2%). All 3 treatment arms were comparable in terms of age, gender distribution, smoking status and clinical diagnoses. There was no statistically significant difference in the H. pylori eradication rate between ST (93.1%), TT (92.5%) and CT (97.1%). The treatment success rates remained similar between all 3 arms when the eradication rate was reanalysed by considering all subjects who defaulted as treatment failure. Conclusion: TT, ST and CT had similar efficacy for H. pylori eradication. All three regimens may be used as first line treatment for H. pylori eradication in Singapore.
14-Day, High-Dose Acid Suppression, Non-Bismuth Quadruple Therapies (Hybrid vs. Concomitant) for Helicobacter pylori Infection: A Randomized Trial Javier Molina-Infante, Marco Romano, Miguel Fernandez Bermejo, Alessandro Federico, Antonietta G. Gravina, Liliana Pozzati, Elena Garcia Abadia, Carmen Martinez-Alcala, Agnese Miranda, Gema Vinagre Rodriguez, Moises Hernandez Alonso, Belen Perez Gallardo, Francisco J. Rancel Medina, Marta Gata Cuadrado, Javier P. Gisbert BACKGROUND&AIM Optimizing triple therapy, through increasing PPI dosage or extending the duration to 14 days, may improve Helicobacter pylori cure rates by 5-10%. Whether these results can be generalizable to non-bismuth quadruple therapies remains unknown. We aimed to evaluate two 14-day, high-dose acid suppression, non-bismuth quadruple regimens in two regions from Spain (Extremadura) and Italy (Naples), with a similarly high (≥20%) clarithromycin resistance rate and cure rates for 10-day sequential therapy ≤80% and for 10-day concomitant therapy , 90%. METHODS Prospective randomized (1:1) multicenter clinical trial, in which consecutive Naïve H. pylori patients were randomized to receive "optimized" non-bismuth quadruple therapies, either hybrid treatment (omeprazole 40 mg b.i.d. and amoxicillin 1 g b.i.d. for 14 days, adding clarithromycin 500 mg b.i.d. and metronidazole/tinidazole 500 mg b.i.d for the final 7 days) or concomitant treatment (same four drugs taken concurrently for 14 days). Antimicrobial resistance was assessed by the E-test in a subset of patients (n=68) undergoing endoscopy. Eradication was confirmed with 13C-urea breath test or histology 8 weeks after treatment. Adverse events and treatment compliance were evaluated with specific questionnaires. RESULTS: 341 patients were finally included (Spain=258, Italy n=83), of whom 327 have completed the study. 95% (310/327) of patients fully complied with treatment. Per-protocol (PP) eradication rates for the hybrid and concomitant treatments were 91% (87-96%) vs. 95% (91%CI=92-99%), p 0.13. Respective intention-to-treat cure rates were 90% (87-96%) vs. 92% (91-98%), p 0.44. Antibiotic resistance rates were: clarithromycin 22% (15/68) (Italy 24 %, Spain 20.5%) and dual resistance 8.8%. Cure rates for both therapies were 100% against clarithromycin resistantmetronidazole susceptible strains (n=9), whereas cure rates against dual resistant strains were 33% (1/3) for hybrid and 100% (3/3) for concomitant therapy. Adverse effects were reported in 47% of patients (45% hybrid vs. 54% concomitant; p 0.07). The most common were metallic taste (39%), epigastralgia/nausea (24%) and diarrhea (20%), with no severe side effects. Overall cure rates were significantly higher (95% vs. 64%, p 0.002, 94% vs. 54%, p ,0.0001 and 93% vs. 41%, p , 0.0001) when compliance with therapy was 100%, 90% or 80%, respectively, albeit without statistical significance in the multivariate analysis CONCLUSION: Both optimized concomitant and hybrid therapies achieved H. pylori cure rates ≥ 90% in settings with clarithromycin resistance rates . 20%, being concomitant therapy highly effective against clarithromycin and dual resistant strains. There were no significant differences between therapies regarding efficacy or compliance, excepting a trend towards better tolerance of the hybrid therapy.
245 Effects of Different Dosing Schedules of Amoxicillin on the Eradication Rates of Helicobacter pylori by Triple Therapy With a Proton Pump Inhibitor, Amoxicillin, and Either Clarithromycin or Metronidazole Takahisa Furuta, Mitsushige Sugimoto, Mihoko Yamade, Takahiro Uotani, Shu Sahara, Hitomi Ichikawa, Takanori Yamada, Satoshi Osawa, Ken Sugimoto Background: Triple therapies with proton pump inhibitor, (PPI), amoxicillin and clarithromycin or metronidazole are standard for Helicobacter pylori infection. While the drugs used in these regimens are normally dosed twice daily, the bactericidal effect of amoxicillin depends on the time-above-MIC, not Cmax or AUC. We therefore examined the influence of different dosing schedules of amoxicillin on the eradication rates of triple therapies. Methods: A total of 245 patients infected with H. pylori infected with clarithromycin-sensitive strains of H. pylori were treated with a PPI, clarithromycin 200 mg bid, and amoxicillin at either 750 mg bid, 500 mg tid, or 500 mg qid for 1 week. Seventy-eight patients infected with clarithromycin-resistant or unknown strains of H. pylori were treated with a PPI, metronidazole 250 mg bid, and amoxicillin at either 750 mg bid, 500 mg tid, or 500 mg qid for 1 week. Results: Nine patients were excluded from analysis. In the clarithromycinsensitive group, eradication rates (PP) were 83.9% (52/62), 97.0% (62/64), and 100.0%
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241