Efficacy of Acetylcysteine-containing Triple Therapy in the First Line of Helicobacter Pylori Infection
Efficacy of Acetylcysteine-containing Triple Therapy in the First Line of Helicobacter Pylori Infection
Helicobacter pylori infection has been shown to be associated with the development of gastric
 cancer and peptic ulcer diseases. Eradication of H. pylori infection could reduce the
 occurence or recurrence of these diseases. The triple treatment including a proton pump
 inhibitor, clarithromycin, and amoxicillin or metronidazole to treat H pylori infection,
 proposed at the first Maastricht conference has become universal since all the consensus
 conferences and guidelines around the world recommended it. However, the eradication rate of
 clarithromycin-based triple therapy has been declining in recent years, probably related to
 the increasing resistant rate to clarithromycin. It was estimated that 15-20% of patients
 would fail from first line standard eradication therapy and need second line rescue therapy.

 The H. pylori persistence in human infections and its resistance to the drugs commonly used
 in antimicrobial therapy have been attributed not only to genetic variability, but also to
 ability of H. pylori to form biofilm as a strategy to overcome environmental stress and to
 protect itself. Several recent reports indicate that H. pylori forms biofilm either in vitro
 or in vivo, N-acetylcysteine (NAC) were thought to reduce and prevent biofilm formation. Two
 small-scale clinical trials showed NAC offers additive effect on eradication effects of H.
 pylori therapy. A recent trial showed N-acetylcysteine pre-treatment before a culture-guided
 antibiotic regimen is effective in treating refractory H. pylori infection.

 Aims: Therefore, we aim to assess

 1. Whether triple therapy containing N-acetyl cysteine is more effective than standard
 triple therapy

 2. the impact of antibiotic resistance and cytochrome P450 C19(CYP2C19) polymorphism on the
 eradication rate of triple therapy containing N-acetyl cysteine.
Helicobacter pylori infection has been shown to be associated with the development of gastric
 cancer and peptic ulcer diseases. Eradication of H. pylori infection could reduce the
 occurrence or recurrence of these diseases. The triple treatment including a proton pump
 inhibitor, clarithromycin, and amoxicillin or metronidazole to treat H pylori infection,
 proposed at the first Maastricht conference has become universal since all the consensus
 conferences and guidelines around the world recommended it. However, the eradication rate of
 clarithromycin-based triple therapy has been declining in recent years, probably related to
 the increasing resistant rate to clarithromycin. It was estimated that 15-20% of patients
 would fail from first line standard eradication therapy and need second line rescue therapy.
 Measures to improved H. pylori eradication rate include (1) increase treatment duration, (2)
 add other antibiotics or use antibiotics not previously used, (3) introducing new therapeutic
 agents, and (4) potent acid inhibition. Our group has shown the 10- or 14-day sequential
 therapy, which consists of a proton-pump inhibitor and amoxicillin for the first 5 or 7 days,
 followed by a proton-pump inhibitor plus clarithromycin and metronidazole (or tinidazole) for
 another 5 or 7days, provides good eradication in first line H. pylori eradication. However,
 complexity of sequential therapy is complex and adverse effect resulted from adding one more
 antibiotic may have poor effect on compliance and leads to treatment failure. A simplified
 regimen for H. pylori infection is worthy of investigation.

 Introducing new therapeutic agents The H. pylori persistence in human infections and its
 resistance to the drugs commonly used in antimicrobial therapy have been attributed not only
 to genetic variability, but also to ability of H. pylori to form biofilm as a strategy to
 overcome environmental stress and to protect itself. A biofilm is a dense aggregation of
 microbial cells bound together by a slimy extracellular matrix of polysaccharide and protein.
 When bacteria group together in these multicellular communities, they are able to tolerate
 antimicrobial challenges that normally eradicate free-floating individual cells. It is
 currently accepted that biofilms are implicated in over 80% of the chronic infections caused
 by bacteria, including middle ear otitis, endocarditis, urinary tract infections and lung
 infections of patients with cystic fibrosis. The importance of biofilm in medicine is due to
 its role in persistence of the infection because biofilm is not removed and bacteria in
 biofilms are 1000 more resistant to antibiotics and host defenses as compared to those free
 living bacteria.

 Several recent reports indicate that H. pylori forms biofilm either in vitro or in vivo, Cole
 et al studied the ability of 19 H. pylori clinical isolates and reference strains in Brain
 Heart Infusion broth supplemented with 0.1% β-cyclodextrin. Both strains were able to form
 biofilm and the biofilm produced had a similar progression when compared to biofilm formed by
 other bacterial species. The first evidence of in vivo biofilm formation arose in 2006. The
 authors compared, by scanning electron microscopy, gastric biopsies from urease positive and
 negative patients, detecting the presence of dense mature biofilm in the pathogen positive
 biopsies while biofilm was absent in the urease negative biopsies, which is indicative that
 H. pylori is able to form biofilm in the human gastric mucosa. To this context, it is notable
 that stress conditions stimulate H. pylori to enter coccoid forms that when the antibiotic
 concentration reduces, can resuscitate and repopulate the biofilm and the infection relapses.
 In vitro study, H. pylori biofilm formation decreases the susceptibility to clarithromycin
 and that H. pylori clarithromycin resistance mutations are more frequently generated in
 biofilms than in planktonic cells.

 Because antibacterial susceptibility of a particular strain is favored when the biofilm is
 destabilized, it is believed that a combination of antimicrobial agents and anti-biofilm
 molecules should be synergistic. N-acetylcysteine (NAC) being both a mucolytic agent and a
 thiol-containing antioxidant agent was successfully used in medical practice for the
 treatment of patients with chronic respiratory tract infections. The NAC positive effects
 were thought to be due not only to mucus-dissolving properties, but also, interestingly, to
 the capability to reduce and prevent biofilm formation. NAC was able to avoid biofilm
 formation and to destabilize the already formed biofilm at concentrations over 10 mg/mL,
 similar to results observed with other pathogens. On the other hand, in vivo studies with two
 groups of 20 individuals each, one group (treated) received N-acetyl-cysteine for one week
 before the anti-H. pylori treatment for refractory H. pylori infection while the other group
 (untreated controls) did not received the destabilizing agent, showed eradication of the
 infection in 65% of the cases for the N-acetyl-cysteine treated group as detected by the urea
 breath test. The control group showed only 20% of successful eradication, suggesting that
 N-acetyl-cysteine act as a biofilm destabilizing agent that favor in vivo the activity of
 antibiotic substances.

 Potent acid inhibition Acid inhibition has also proven an important component of eradication
 therapy. The antibiotics, particularly clarithromycin, which is used against H. pylori, are
 subject to pH-dependent degradation. This degradation is reduced by increasing gastric pH.
 Achieving a pH above 4 maximizes the efficacy of the antibiotic. Second, proton pump
 inhibitors (PPIs) may alter the transport of antibiotics from the plasma to the gastric juice
 and mucosa by altering the pH or by affecting active transport processes. The minimum
 inhibitory concentration (MIC) of the antibiotics against H. pylori is often lower at higher
 pHs. Finally, because H. pylori is sensitive to changes in gastric pH, PPI-induced elevations
 of pH, the gastric contents may become less hospitable to H. pylori. The importance of
 achieving adequate acid inhibition has been highlighted by recent studies. First, increasing
 the PPI dose was found to raise cure rates when used in dual anti-Helicobacter pylori
 therapies. Second, a previous meta-analysis by our group showed that triple therapy using a
 standard dose of PPI twice a day achieves higher cure rates than the same antibiotics plus
 the PPI once daily. Previous meta-analyses show that H. pylori treatment achieves lower cure
 rates in extensive metabolizers than in poor PPI metabolizers. All this evidence supports the
 hypothesis that achieving a potent acid inhibition can improve cure rates of H. pylori
 treatment.

 Lansoprazole, a proton pump inhibitor that specifically inhibits H+K+-ATPase in the gastric
 parietal cell, effectively inhibits both basal- and gastric-stimulated acid secretion. Our
 studies have proved lansoprazole-based H. pylori eradication achieved high successful rate.
 Dexlansoprazole modified release (MR), a new generation of proton pump inhibitor, is a novel
 modified release formulation of dexlansoprazole, an enantiomer of lansoprazole.
 Dexlansoprazole MR employs an innovative Dual Delayed Release (DDR) technology designed to
 prolong the plasma concentration-time profile of dexlansoprazole and extend the duration of
 acid suppression. In a phase 1 pharmacokinetic/pharmacodynamic study of Dexlansoprazole MR 60
 and 90 mg once daily also produced significant increases in the percentage of time with
 intragastric pH >4 over 24-h postdose compared with lansoprazole 30 mg once daily (∼70% for
 dexlansoprazole MR vs. 60% for lansoprazole, P < 0.05). Since acid inhibition is crucial in
 H. pylori treatment. Whether a more potent PPI, Dexlansoprazole MR could improve the efficacy
 of H. pylori treatment has not been investigated.

 Therefore, the primary purpose of the proposed study is to compare the efficacy of
 dexlansoprazole MR based triple therapy with or without N-acetyl cysteine for helicobacter
 pylori eradication
Inclusion Criteria:

 -  H. pylori infected patients who have willingness to receive eradication therapy

 Exclusion Criteria:

 -  (1) history of gastrectomy, (2)gastric malignancy, including adenocarcinoma and
 lymphoma, (3) previous allergic reaction to antibiotics (amoxicillin, clarithromycin),
 N-acetyl cysteine and prompt pump inhibitors (dexlansoprazole), (4)contraindication to
 treatment drugs, (5) pregnant or lactating women, (6) severe concurrent disease. (7)
 phenylketonuria (8) Patients who cannot give informed consent by himself or herself.