Comparison of Helicobacter pylori eradication rates between 7 and 14 days of tailored therapy according to clarithromycin resistance test: A randomized, multicenter, non-inferiority study.

BACKGROUND: Recently, a simple tailored therapy based on clarithromycin resistance has been implemented as Helicobacter pylori (H. pylori) eradication therapy. Nonetheless, despite the tailored therapy and frequent adverse events, studies on treatment period are lacking. This study aimed to compare the H. pylori eradication rates of 7-day and 14-day tailored therapy regimens according to clarithromycin resistance. MATERIALS AND METHODS: This multicenter, prospective, randomized, noninferiority trial enrolled H. pylori-positive patients who were randomly assigned to 7-day and 14-day regimen groups, depending on the presence or absence of clarithromycin resistance by 23S rRNA gene point mutations. Standard triple therapy (STT) (20 mg rabeprazole, 1 g amoxicillin, and 500 mg clarithromycin twice daily) or bismuth quadruple therapy (BQT) (20 mg rabeprazole twice daily, 500 mg metronidazole thrice daily, 120 mg bismuth four times daily, and 500 mg tetracycline four times daily) was assigned by clarithromycin resistance. Eradication rates and adverse events were evaluated. RESULTS: A total of 314 and 278 patients were included in the intention-to-treat (ITT) and per-protocol (PP) analyses, respectively; however, 31 patients were lost to follow-up, whereas five patients violated the protocol. Both the 7-day and 14-day regimens showed similar eradication rates in the ITT (7-day vs. 14-day: 78.3% vs. 78.3%, p > 0.99) and PP (87.9% vs. 89.1%, p = 0.851) analyses. Non-inferiority was confirmed (p < 0.025). A subgroup analysis according to clarithromycin resistance (clarithromycin resistance rate: 28.7%) revealed no significant difference in eradication rates between the 7-day and 14-day STT (90.0% vs. 90.1%, p > 0.99) and BQT (82.5% vs. 86.5%, p = 0.757). Furthermore, adverse events did not significantly differ between the two groups. CONCLUSIONS: The 7-day triple and quadruple therapy according to clarithromycin resistance showed similar eradication rates, as compared to the 14-day therapy.

High-dose dual therapy versus bismuth-containing quadruple therapy for the eradication of Helicobacter pylori: A systematic review and meta-analysis.

OBJECTIVE: To update evidence-based data comparing the efficacy and safety of high-dose dual therapy (HDDT) and bismuth-containing quadruple therapy (BQT) in eradicating Helicobacter pylori infection through meta-analysis. METHODS: Multiple databases were systematically searched for randomized controlled trials (RCTs) published up to May 18, 2023. Dichotomous data were evaluated using risk ratio (RR) and 95% confidence interval (CI). Subgroup analysis, sensitivity analysis, risk of bias assessment, and quality of evidence evaluation were performed. RESULTS: Twenty RCTs containing 7891 subjects were included in the analysis. There was no statistically significant difference in H. pylori eradication rate between HDDT and BQT in the intention-to-treat (ITT) analysis (86.31% vs 84.88%; RR 1.02, 95% CI 1.00-1.04, P = 0.12). In the per-protocol (PP) analysis, the eradication rates for HDDT and BQT were 90.27% and 89.94%, respectively (RR 1.01, 95% CI 0.99-1.03, P = 0.44). Adverse events were significantly lower with HDDT than with BQT (RR 0.44, 95% CI 0.38-0.51, P < 0.00001). Patient adherence was significantly different between the two groups (RR 1.01, 95% CI 1.00-1.03, P = 0.02). Subgroup analysis based on antibiotic combinations within the BQT group showed a significantly higher eradication rate for HDDT than for BQT only when BQT used amoxicillin combined with clarithromycin (P = 0.0009). CONCLUSIONS: HDDT showed comparable efficacy with BQT for H. pylori eradication, with fewer adverse effects and higher compliance. Due to regional differences, antibiotic resistance rates, and combined BQT antibiotics, more studies are needed for further validation and optimization of HDDT.

Dynamic changes in the gut microbiota after bismuth quadruple therapy and high-dose dual therapy for Helicobacter pylori eradication.

BACKGROUND: A novel regimen with high-dose dual therapy (HDDT) has emerged, but its impact on the gut microbiota is not well understood. This study aimed to evaluate the impact of HDDT on the gut microbiota and compare it with that of bismuth quadruple therapy (BQT). METHODS: We enrolled outpatients (18-70 years) diagnosed with Helicobacter pylori infection by either histology or a positive 13C-urea breath test (13C-UBT) and randomly assigned to either the BQT or HDDT group. Subjects consented to provide fecal samples which were collected at baseline, Week 2, and Week 14. Amplification of the V1 and V9 regions of the 16S rRNA was conducted followed by high-throughput sequencing. RESULTS: Ultimately, 78 patients (41 patients in the HDDT group and 37 in the BQT group) were enrolled in this study. Eradication therapy significantly altered the diversity of the gut microbiota. However, the alpha diversity rebounded only in the HDDT group at 12 weeks post-eradication. Immediately following eradication, the predominance of Proteobacteria, replacing commensal Firmicutes and Bacteroidetes, did not recover after 12 weeks. Species-level analysis showed that the relative abundances of Klebsiella pneumoniae and Escherichia fergusonii significantly increased in both groups at Week 2. Enterococcus faecium and Enterococcus faecalis significantly increased in the BQT group, with no significant difference observed in the HDDT group. After 12 weeks of treatment, the relative abundance of more species in the HDDT group returned to baseline levels. CONCLUSION: Eradication of H. pylori can lead to an imbalance in gut microbiota. Compared to BQT, the HDDT is a regimen with milder impact on gut microbiota.

Pretreatment with Ranitidine Bismuth Citrate May Improve Success Rates of Helicobacter pylori Eradication: A Prospective, Randomized, Controlled and Open-Label Study.

Effective Helicobacter pylori (H. pylori) eradication is a major public health concern; however, eradication failure rates with the standard triple therapy remain high. We aimed to investigate the effectiveness and tolerability of ranitidine bismuth citrate (RBC) pretreatment before standard triple therapy for H. pylori eradication. A prospective, randomized, controlled, and open-label clinical trial was conducted from June to December 2019. H. pylori eradication rate, safety, and tolerability were compared between the standard treatment group (esomeprazole, amoxicillin, and clarithromycin for 7 days) and RBC pretreatment group (RBC for 2 weeks before standard triple therapy). This trial ended earlier than estimated owing to the N-nitrosodimethylamine concerns with ranitidine. Success rates of H. pylori eradication were 80.9% and 67.3% in the RBC pretreatment (n = 47) and standard treatment (n = 52) (p = 0.126) groups, respectively. Our trial was discontinued earlier than planned; however, a statistical significance would be achieved by expansion of our data (p = 0.031) if patient enrollment numbers reached those initially planned. Adverse event rates were comparable between groups (25.5% in the pretreatment group vs. 28.8% in the standard treatment group), without serious event. Tolerability was excellent in both groups, recorded as 97.9% and 100% in the pretreatment and standard treatment groups, respectively. Compared with the standard triple regimen, RBC pretreatment for 2 weeks may achieve higher H. pylori eradication rates, with excellent safety and tolerability. However, this study necessitates further validation as it was discontinued early owing to the N-nitrosodimethylamine issues of ranitidine.

Two Different 1-Week Quadruple Therapies Given Back-to-Back Consecutive Therapy for Difficult-to-Treat Helicobacter pylori Infection: A Pilot Study.

INTRODUCTION: We aim to evaluate the efficacy of 2 different 1-week quadruple therapies given back-to-back consecutive therapy in patients with difficult-to-treat Helicobacter pylori infection. METHODS: Patients with proven H. pylori infection were recruited after >3 failed standard quadruple eradication. They received consecutive therapy consisting of esomeprazole 40 mg or rabeprazole 20 mg twice daily, amoxicillin 1,000 mg twice daily, tetracycline 500 mg 4 times daily, and furazolidone 100 mg 3 times daily for the first 7 days, followed by colloidal bismuth pectin 200 mg twice daily in place of furazolidone 100 mg for another 7 days. Eradication rates, treatment-emergent adverse events (TEAEs), and compliance were assessed. RESULTS: Sixty-five patients were enrolled. The mean number of previous eradications was 3.6 (range: 3-7). The intention-to-treat and per-protocol eradication rates were 90.8% (59/65) and 95.1% (58/61). In total, 23.4% (15/64) of patients experienced drug-related TEAEs. No serious adverse events were observed. None of the patients required treatment for TEAEs, and 95.3% (61/64) showed good compliance. Overall, 51 patients (78.5%) were with the available antimicrobial susceptibility testing results. The resistance rates to clarithromycin, metronidazole, levofloxacin, and amoxicillin were 60.8% (31/51), 100% (51/51), 70.6% (36/51), and 2.0% (1/51), respectively. No resistance was detected to either furazolidone or tetracycline. However, in 54.9% of patients (28/51), H. pylori was resistant to 3 antibiotics (metronidazole, levofloxacin, and clarithromycin). DISCUSSION: Consecutive therapy, including amoxicillin, tetracycline, and furazolidone, achieved a good eradication rate (>90%), with desirable compliance and tolerability in difficult-to-treat H. pylori infection.

European Registry on Helicobacter pylori management: Single-capsule bismuth quadruple therapy is effective in real-world clinical practice.

BACKGROUND: There has been resurgence in the use of bismuth quadruple therapy (proton pump inhibitor, bismuth, tetracycline and metronidazole) for treating Helicobacter pylori infection thanks to a three-in-one single-capsule formulation. OBJECTIVE: To evaluate the effectiveness and safety of the single-capsule bismuth quadruple therapy. METHODS: Data were collected in a multicentre, prospective registry of the clinical practice of gastroenterologists on the management of H. pylori infection, where patients were registered at the Asociación Española de Gastroenterologia REDCap database on an electronic case report form until January 2020. Effectiveness by modified intention-to-treat and per-protocol as well as multivariable analysis were performed. Independent factors evaluated were: age, gender, indication, compliance, proton pump inhibitor dose and treatment line. RESULTS: Finally, 2100 patients were prescribed single-capsule bismuth quadruple therapy following the technical sheet (i.e., three capsules every 6 h for 10 days). The majority of these patients were naive (64%), with an average age of 50 years, 64% women and 16% with peptic ulcer. An overall modified intention-to-treat effectiveness of 92% was achieved. Eradication was over 90% in first-line treatment (95% modified intention-to-treat, n = 1166), and this was maintained as a rescue therapy, both in second (89% modified intention-to-treat, n = 375) and subsequent lines of therapy (third to sixth line: 92% modified intention-to-treat, n = 236). Compliance was the factor most closely associated with treatment effectiveness. Adverse events were generally mild to moderate, and 3% of patients reported a severe adverse event, leading to discontinuation of treatment in 1.7% of cases. CONCLUSIONS: Single-capsule bismuth quadruple therapy achieved H. pylori eradication in approximately 90% of patients in real-world clinical practice, both as a first-line and rescue treatment, with good compliance and a favourable safety profile.

Integration of IR-808 and thiol-capped Au-Bi bimetallic nanoparticles for NIR light mediated photothermal/photodynamic therapy and imaging.

Near infrared (NIR) light detonated phototherapy for cancer treatment based on photothermal therapy (PTT) and photodynamic therapy (PDT) has attracted increasing attention owing to its deep tissue penetration. However, the low absorption ability and therapeutic efficiency of the photosensitive drug have restricted the development of phototherapy to a great degree. Herein, a kind of IR808 dye sensitized glutathione (GSH) cladded Au-Bi bimetallic nanoparticles (Au-Bi-GSH@IR808) was prepared to enhance the inhibition effect of tumors. In this nanoplatform, the construction of GSH cladded Au-Bi bimetallic nanoparticles can effectively generate 1O2 while exhibiting outstanding photothermal conversion efficiency (η = 34.2%) upon 808 nm laser irradiation. Furthermore, IR808 as a small molecule dye endows the Au-Bi-GSH@IR808 with a higher 808 nm light absorption ability and stronger photothermal and photodynamic effects. The IR808 sensitized Au-Bi bimetallic nanoparticles with a small size (5 nm), hydrophilia and dispersible nature, exhibit a noticeably enhanced therapeutic peculiarity. Additionally, the prominent CT imaging property of Au-Bi-GSH@IR808 means it is expected to be used as a CT imaging contrast agent in clinical applications. The results of the in vitro and in vivo experiments indicate that the synthesized nanoparticles have an excellent ablation effect on cancer cells, and they are expected to be widely used in the accurate diagnosis and treatment of cancer.

Tailored Synthesis of PEGylated Bismuth Nanoparticles for X-ray Computed Tomography and Photothermal Therapy: One-Pot, Targeted Pyrolysis, and Self-Promotion.

Complex experimental design is a common problem in the preparation of theranostic nanoparticles, resulting in poor reaction control, expensive production cost, and low experiment success rate. The present study aims to develop PEGylated bismuth (PEG-Bi) nanoparticles with a precisely controlled one-pot approach, which contains only methoxy[(poly(ethylene glycol)]trimethoxy-silane (PEG-silane) and bismuth oxide (Bi2O3). A targeted pyrolysis of PEG-silane was achieved to realize its roles as both the reduction and PEGylation agents. The unwanted methoxy groups of PEG-silane were selectively pyrolyzed to form reductive agents, while the useful PEG-chain was fully preserved to enhance the biocompatibility of Bi nanoparticles. Moreover, Bi2O3 not only acted as the raw material of the Bi source but also presented a self-promotion in the production of Bi nanoparticles via catalyzing the pyrolysis of PEG-silane. The reaction mechanism was systematically validated with different methods such as nuclear magnetic resonance spectroscopy. The PEG-Bi nanoparticles showed better compatibility and photothermal conversion than those prepared by the complex multiple step approaches in literature studies. In addition, the PEG-Bi nanoparticles possessed prominent performance in X-ray computed tomography imaging and photothermal cancer therapy in vivo. The present study highlights the art of precise reaction control in the synthesis of PEGylated nanoparticles for biomedical applications.

Long-term changes in the gut microbiota after 14-day bismuth quadruple therapy in penicillin-allergic children.

BACKGROUND: Penicillin-allergic children who are infected with Helicobacter pylori constitute a relatively common subgroup. We aimed to study the short-term and long-term effects of bismuth quadruple therapy on gut microbiota in penicillin-allergic children. METHODS: We prospectively recruited treatment-naive children with H pylori infection and H pylori-negative asymptomatic children as healthy controls. Patients received 14-day bismuth quadruple therapy consisting of omeprazole, clarithromycin, metronidazole, and bismuth. Fecal samples were collected at weeks 0, 2, 6, and 52. Alterations in the gut microbiota were analyzed by 16S rRNA gene sequencing. RESULTS: Twenty-two subjects (14 gastritis patients, 8 duodenal ulcer patients) and 23 controls participated in this study. At week 2, alpha diversity was reduced in both gastritis (P < .05) and ulcer (except P = .16 with Chao 1 index) patients compared with baseline. Some changes persisted at week 6, and all were restored at week 52. Beta diversity was significantly altered 2 weeks after treatment in the gastritis and duodenal ulcer groups (P = .001, P = .002, respectively) and restored at weeks 6 and 52. The mean relative abundance of Bacteroidetes (P < .001, P = .005, respectively) decreased and that of Proteobacteria increased (P < .001, P = .03, respectively). All alterations recovered at week 6 and 52. In both the gastritis and ulcer groups at week 2, some beneficial bacteria were decreased including Bacteroides (P < .001 and P = .003), Faecalibacterium (P < .001 and P = .02), Phascolarctobacterium (P = .002 and P = .004), Roseburia ( P < .001 and P = .13), Bifidobacterium (P = .08 and P = .04), and Blautia (P < .001 and P = .002). Some detrimental bacteria were increased including Escherichia-Shigella (P < .001 and P = .19), Klebsiella (P < .001, and P = .09), Enterococcus (P < .001 and P = .007), and Streptococcus (P = .002 and P = .004). The changes returned to almost the pre-eradication level 1 year after therapy. CONCLUSION: Bismuth quadruple therapy causes short-term dysbiosis of the gut microbiota. Most changes recovered 1-year post-eradication, indicating the long-term safety of H pylori therapy.

Bismuth quadruple regimen with tetracycline or doxycycline versus three-in-one single capsule as third-line rescue therapy for Helicobacter pylori infection: Spanish data of the European Helicobacter pylori Registry (Hp-EuReg).

BACKGROUND: Different bismuth quadruple therapies containing proton-pump inhibitors, bismuth salts, metronidazole, and a tetracycline have been recommended as third-line Helicobacter pylori eradication treatment after failure with clarithromycin and levofloxacin. AIM: To evaluate the efficacy and safety of third-line treatments with bismuth, metronidazole, and either tetracycline or doxycycline. METHODS: Sub-study with Spanish data of the "European Registry on H pylori Management" (Hp-EuReg), international multicenter prospective non-interventional Registry of the routine clinical practice of gastroenterologists. After previous failure with clarithromycin- and levofloxacin-containing therapies, patients receiving a third-line regimen with 10/14-day bismuth salts, metronidazole, and either tetracycline (BQT-Tet) or doxycycline (BQT-Dox), or single capsule (BQT-three-in-one) were included. Data were registered at AEG-REDCap database. Univariate and multivariate analyses were performed. RESULTS: Four-hundred and fifty-four patients have been treated so far: 85 with BQT-Tet, 94 with BQT-Dox, and 275 with BQT-three-in-one. Average age was 53 years, 68% were women. Overall modified intention-to-treat and per-protocol eradication rates were 81% (BQT-Dox: 65%, BQT-Tet: 76%, BQT-three-in-one: 88%) and 82% (BQT-Dox: 66%, BQT-Tet: 77%, BQT-three-in-one: 88%), respectively. By logistic regression, higher eradication rates were associated with compliance (OR = 2.96; 95% CI = 1.01-8.84) and no prior metronidazole use (OR = 1.96; 95% CI = 1.15-3.33); BQT-three-in-one was superior to BQT-Dox (OR = 4.46; 95% CI = 2.51-8.27), and BQT-Tet was marginally superior to BQT-Dox (OR = 1.67; 95% CI = 0.85-3.29). CONCLUSION: Third-line H pylori eradication with bismuth quadruple treatment (after failure with clarithromycin and levofloxacin) offers acceptable efficacy and safety. Highest efficacy was found in compliant patients and those taking 10-day BQT-three-in-one or 14-day BQT-Tet. Doxycycline seems to be less effective and therefore should not be recommended.

Optimizing the MIC breakpoints of amoxicillin and tetracycline for antibiotic selection in the rescue therapy of H. pylori with bismuth quadruple regimen.

PURPOSE: H. pylori with triple-drug resistance (TR) to clarithromycin, metronidazole, and levofloxacin limits the success of rescue therapy. We aimed to identify the optimal breakpoints of antibiotic minimal inhibitory concentration (MIC) to predict the success of rescue therapy for TR H. pylori infection. METHODS: We consecutively enrolled 430 patients with at least one course of failed H. pylori eradications to receive an H. pylori culture for antibiotic MIC test. Seventy-three (17%) had TR H. pylori infection (MIC of clarithromycin > 0.5, levofloxacin > 1, and metronidazole > 8 mg/L, respectively). Sixty-nine cases with TR H. pylori infection received rescue therapy with either ATBP (amoxicillin, tetracycline, bismuth, and PPI) or MTBP (metronidazole, tetracycline, bismuth and PPI) for 7-14 days. Fourteen patients with positive 13C-urea breath test after the first rescue therapy were retreated with a crossover second rescue therapy. RESULTS: The MTBP regimen had higher eradication success than the ATBP regimen as the first rescue therapy for TR H. pylori (intent-to-treat (ITT) analysis, 70.3 vs. 46.9%, p = 0.048; per protocol (PP) analysis, 78.8% vs. 51.7%, p = 0.025). For MTBP regimen, tetracycline MIC ≤ 0.094 mg/L (p < 0.001) with a 14-day treatment duration (p = 0.037) could predict eradication success with 100% accuracy. For the ATBP regimen, amoxicillin MIC selected as ≤ 0.032 mg/L could optimally determine eradication success (72.2 vs. 33.3%, p = 0.025). CONCLUSION: Optimizing the MIC breakpoints of amoxicillin and tetracycline resistance better predicts the outcome of bismuth quadruple therapy. Further prospective studies using the revised MIC breakpoints to select antibiotics are warranted.

Prospective comparative study between two first-line regimens for Helicobacter pylori eradication: Non-bismuth quadruple versus bismuth quadruple therapy.

BACKGROUND: The Maastricht V Consensus recommends quadruple therapies as first-line Helicobacter pylori treatment in high clarithromycin (CLA) resistance areas. AIMS: To compare efficacy, side effects and compliance between quadruple concomitant non-bismuth vs bismuth quadruple therapy. METHOD: Prospective study enrolling H. pylori-positive patients. Omeprazol and a three-in-one formulation of bismuth-metronidazol-tetracycline (OBMT-3/1) for 10 days, or combination of omeprazol-clarithromycin-amoxicillin-metronidazol (OCAM) for 14 days, were prescribed. Eradication outcome was assessed by urea breath test or histology. Side effects and compliance were recorded during the treatment period with specific questionnaires. RESULTS: 404 patients were recruited (median age 53 years; 62.87% women). In 382 (183 with OCAM, 199 with OBMT-3/1) the post-treatment test result was available. The eradication rates were 85.94% (CI95%: 80.20-90.52) with OCAM and 88.21% (CI95%: 83.09-92.22) with OBMT-3/1 (p=0.595) in intention-to-treat analysis, whilst in per protocol analysis they were 91.12% (CI95%: 85.78-94.95) and 96.17% (CI95%: 92.28-98.45) respectively (p=0.083). Compliance over 90% was 91.35% with OCAM and 92.04% with OBMT-3/1 (p=0.951). Some side effect was present in 94.02% with OCAM and in 88.89% with OBMT-3/1 (p=0.109), being longer (12 vs 7 days, p<0.0001) and more severe (p<0.0001) with OCAM. CONCLUSIONS: In a high CLA-resistance area, there are no differences between OBMT-3/1 and OCAM in H. pylori eradication and compliance rates, but OBMT-3/1 achieves a higher safety profile.

14-Day High-Dose Amoxicillin- and Metronidazole-Containing Triple Therapy With or Without Bismuth as First-Line Helicobacter pylori Treatment.

BACKGROUND: Amoxicillin, metronidazole, proton pump inhibitor, bismuth quadruple therapy had been shown to reliably achieve high eradication rates. The role of individual components remains undefined. AIM: To identify the additional benefit/role of bismuth in amoxicillin, metronidazole, proton pump inhibitor, bismuth quadruple therapy for Helicobacter pylori (H. pylori) treatment. METHODS: This was a non-inferiority factorial design trial. Treatment-naive H. pylori-infected subjects were randomly (1:1) assigned to receive 14-day amoxicillin- and metronidazole-containing triple therapy consisting of esomeprazole 20 mg twice a day, amoxicillin 1 g, and metronidazole 400 mg both thrice daily with or without 220 mg bismuth twice a day. Six weeks after treatment, H. pylori eradication was assessed by 13C-urea breath test. Antimicrobial susceptibility was assessed by the twofold agar dilution method. RESULTS: From July 2018 to June 2019, a total of two hundred and sixteen subjects were randomized. Both therapies achieved high eradication rates. Per-protocol with bismuth = 97.9% (94/96, 95% CI 95.1-100%) and without bismuth = 94.7% (90/95, 95% CI 90.3-99.1%) (P = 0.43). Intent-to-treat analysis = 90.7% (98/108, 95% CI 85.2-96.2%) versus 88.9% (96/108, 95% CI 82.8-95.0%) with and without bismuth (P = 0.65). The two regimens were not inferior by intent-to-treat or per-protocol analyses. Metronidazole resistance did not affect the efficacy of either therapy. CONCLUSION: Neither the presence nor absence of bismuth or metronidazole resistance reduced the effectiveness of triple therapy containing esomeprazole 20 mg twice a day, amoxicillin 1 g, and metronidazole 400 mg thrice daily in this population. The clinical trial was registered with ClinicalTrials.gov, NCT03557437.

Upregulation of nuclear factor (erythroid-derived 2)-like 2 protein level in the human colorectal adenocarcinoma cell line DLD-1 by a heterocyclic organobismuth(III) compound: Effect of organobismuth(III) compound on NRF2 signaling.

An increasing number of metal-based compounds, including arsenic trioxide, auranofin, and cisplatin, have been reported to have antitumor activity. Their beneficial effects are controlled by a transcription factor, nuclear factor (erythroid-derived 2)-like 2 (NRF2). In response to oxidative stress, NRF2 induces the expression of cytoprotective genes. NRF2 protein levels are regulated by Kelch-like ECH-associated protein 1 (KEAP1) via ubiquitination. Bi-chlorodibenzo[c,f][1,5]thiabismocine (compound 3), a bismuth compound, is known for its potent anti-proliferative activity against various cancer cell lines. In the present study, we investigated the effect of compound 3 on NRF2 signaling in the human colorectal adenocarcinoma cell line DLD-1 in terms of cell viability as well as mRNA and protein expression levels of NRF2. Compound 3 upregulated NRF2 protein levels in a time- and concentration-dependent manner, accompanied by a marked increase in heme-oxygenase-1 (HO-1) mRNA and protein levels. We observed that brusatol, an NRF2 inhibitor, as well as small interfering RNA (siRNA)-mediated knockdown of NRF2 in DLD-1 cells suppressed compound 3-induced HO-1 expression. The anticancer activity of compound 3 was enhanced by compounds that downregulate NRF2. These results suggest that compound 3 upregulates HO-1 via NRF2 activation and that the NRF2-HO-1 pathway is the cellular response to compound 3. We also discovered that compound 3 slightly downregulated KEAP1; thus, NRF2 activation may be associated with KEAP1 modification. Collectively, our results indicate that compound 3 simultaneously activates an anti-oxidative stress pathway, such as NRF2 and HO-1, and a pro-cell death signal in DLD-1 cells. Our findings may provide useful information for the development of a potent anticancer organobismuth(III) compound.

Treatment of Helicobacter pylori infection and its long-term impacts on gut microbiota.

The rising prevalence of antibiotic resistance and the long-term safety following eradication therapy are important issues in the management of Helicobacter pylori infection. The prevalence of clarithromycin, levofloxacin, and metronidazole resistance of H. pylori has increased to 21%, 27%, and 45%, respectively, in the Asia-Pacific region. Personalized treatment guided by susceptibility testing may provide a reliably excellent eradication rate in the first-line treatment but is costly and not widely available. Population-specific empirical therapy according to the local prevalence of antibiotic resistance may be an alternative strategy. Levofloxacin-based therapy and bismuth quadruple therapy are the recommended second-line rescue therapy. Susceptibility testing or genotypic resistance-guided therapy is the preferred treatment for refractory H. pylori infection, but empirical therapy may be an acceptable alternative. Eradication of H. pylori leads to short-term perturbation of gut microbiota. The diversity of gut microbiota can be restored months after eradication therapy, but the speed of recovery varies with regimens. The short-term increases of antibiotic resistance of Escherichia coli and Klebsiella pneumoniae may be restored to basal states months after H. pylori eradication. Future studies that apply in-depth sequencing, such as shotgun metagenomics sequencing, are needed to clarify whether the compositions of gut microbiota at the species level are fully restored.

Recent progress in Helicobacter pylori treatment.

The main challenge in the field of Helicobacter pylori (H. pylori) infection is antibiotic resistance, which influences the efficacy of eradication regimens. Bismuth-containing quadruple therapy has been confirmed as an effective regimen for eradicating H. pylori, especially in strains with antibiotic resistance. High-dose proton-pump inhibitor-amoxicillin dual therapy could decrease the use of unnecessary antibiotics, which is a promising alternative approach. Adjuvant therapy (specific probiotic or vitamin) also showed good results, although more evidence is needed. Novel anti-H. pylori drugs are needed, and the establishment of the H. pylori database is an effective way to acknowledge the real-time information of H. pylori management. This review provides the recent progress of H. pylori treatment, and further studies are needed to address the role of different regimens in improving H. pylori eradication rate, especially in strains with antibiotics resistance.

Combination of Bismuth and Standard Triple Therapy Eradicates Helicobacter pylori Infection in More than 90% of Patients.

BACKGROUND & AIMS: Due to the poor eradication rates of standard triple therapy, the addition of bismuth salts has been proposed for first-line eradication of Helicobacter pylori. We assessed the effectiveness and safety of the combination of bismuth and the standard, clarithromycin-containing triple therapy in eradication of H pylori infection, using data from a large multi-center registry. METHODS: We performed an interim analysis of data from the European Registry on H pylori Management, a prospective trial registering clinical data and outcomes from infected patients from 27 countries in Europe since 2013. We extracted data on 1141 treatment-naïve patients who received first-line treatment with bismuth salts (240 mg) and a proton pump inhibitor (57% received esomeprazole, 18% received omeprazole, 11% received pantoprazole, and 14% received rabeprazole), amoxicillin (1 g), and clarithromycin (500 mg), all taken twice daily. RESULTS: Intention to treat and per-protocol rates of eradication were 88% and 94%, respectively. Intention to treat eradication increased to 93% in patients who received 14-day treatments. Adverse events occurred in 36% of patients; 76% of these events were mild, with a mean duration of 6 days. In multivariate analysis, eradication was associated with treatment compliance (odds ratio [OR], 13.0), a double dose (equivalent to 40 mg omeprazole) of proton pump inhibitor (OR, 4.7), and 14-day duration of treatment (OR, 2.0). CONCLUSIONS: In an analysis of data from a large multi-center registry, we found the addition of bismuth to 14-day standard triple therapy with clarithromycin and amoxicillin to eradicate H pylori infection in more than 90% of patients, based on intention to treat analysis, with an acceptable safety profile and level of adherence. ClinicalTrials.gov no: NCT02328131.

Mathematical Modeling of Preclinical Alpha-Emitter Radiopharmaceutical Therapy.

Preclinical studies, in vivo, and in vitro studies, in combination with mathematical modeling can help optimize and guide the design of clinical trials. The design and optimization of alpha-particle emitter radiopharmaceutical therapy (αRPT) is especially important as αRPT has the potential for high efficacy but also high toxicity. We have developed a mathematical model that may be used to identify trial design parameters that will have the greatest impact on outcome. The model combines Gompertzian tumor growth with antibody-mediated pharmacokinetics and radiation-induced cell killing. It was validated using preclinical experimental data of antibody-mediated 213Bi and 225Ac delivery in a metastatic transgenic breast cancer model. In modeling simulations, tumor cell doubling time, administered antibody, antibody specific-activity, and antigen-site density most impacted median survival. The model was also used to investigate treatment fractionation. Depending upon the time-interval between injections, increasing the number of injections increased survival time. For example, two administrations of 200 nCi, 225Ac-labeled antibody, separated by 30 days, resulted in a simulated 31% increase in median survival over a single 400 nCi administration. If the time interval was 7 days or less, however, there was no improvement in survival; a one-day interval between injections led to a 10% reduction in median survival. Further model development and validation including the incorporation of normal tissue toxicity is necessary to properly balance efficacy with toxicity. The current model is, however, useful in helping understand preclinical results and in guiding preclinical and clinical trial design towards approaches that have the greatest likelihood of success. SIGNIFICANCE: Modeling is used to optimize αRPT.

High Effective of 14-Day High-Dose PPI- Bismuth-Containing Quadruple Therapy with Probiotics Supplement for Helicobacter Pylori Eradication: A Double Blinded-Randomized Placebo-Controlled Study.

Background: Helicobacter pylori (H. pylori) infection is important risk factors for chronic gastritis, peptic ulcer and gastric cancer. Bismuth-containing quadruple therapy has recently been the first-line regimen recommended in many European countries but has limited efficacy in ASEAN especially Thailand. This study was aim to evaluate efficacy of high dose PPI Bismuth-containing quadruple therapy with probiotics supplement for H. pylori eradication. Methods: In this double-blind randomized placebo-controlled study, H. pylori infected patients were randomized to receive 7-or 14-day high dose PPI- bismuth-containing quadruple therapy with or without probiotics supplement. Probiotic was 37.5 mg Lactobacillus reuteri (Biogaia®) in tablet twice daily. CYP2C19 genotyping and antibiotic susceptibility tests were also done. H. pylori eradication was defined as a negative 13C-urea breath test at least 4 weeks after treatment. Results: 100 subjects were enrolled (72 females, 28 males, mean age=54 years). Antibiotic resistance was 15.6% for clarithromycin, 34.1% for metronidazole. CYP2C19 genotyping was performed in both group and revealed 13%, 50% and 37% for poor, intermediate and rapid metabolizers, respectively. Overall eradication rates of 7-day and 14-day regimens with probiotic were 68% and 96%; P value=0.027. The eradication rate for all patients with poor and rapid metabolizers were 100% with 14-day regimen. 14-day regimen with probiotics can provide 100% eradication with clarithromycin resistance, metronidazole resistance or dual clarithromycin and metronidazole resistance group. Furthermore, the incidence of nausea and vomiting, abdominal discomfort, and bitter taste were significantly lower in patients with probiotics group compared with placebo (6%vs.26%, P=0.002,OR=0.126,95% CI=0.03-0.53; 4%vs.18.0%, P=0.017, OR= 0.155,95% CI=0.03-0.81 and 4%vs.26%, P= 0.001,OR= 0.08, 95%CI= 0.016-0.41, respectively). Conclusions: The 14-day high dose PPI- bismuth-containing quadruple therapy with probiotic can provide an excellent cure rate for H. pylori infection as first line treatment irrespective of CYP2C19 and antibiotic resistance pattern. Adding probiotic also significantly reduced treatment-related adverse events and improve the patients' compliance.