Amoxicillin and Clarithromycin Mucoadhesive Delivery System for Helicobacter pylori Infection in a Mouse Model: Characterization, Pharmacokinetics, and Efficacy

Helicobacter pylori is the main pathogen responsible for gastric ulcers and a predisposing factor of stomach cancer. Although current treatment is usually successful, it requires high doses and frequent administration. An innovative mucoadhesive system (Mucolast®) loaded with amoxicillin and clarithromycin is proposed to improve the efficacy of treatment against H. pylori. The drug product was optimized based on its viscoelastic properties to obtain long-term stability of the vehicle. The drug release mechanisms were different for both antibiotics based on their solubilization status. A systemic and stomach pharmacokinetic profile was obtained after three different doses were administered to mice, obtaining similar systemic exposure levels but an increase in drug concentration in the stomach. The efficacy results in mice infected with H. pylori also demonstrated the superiority of the antibiotics when administered in Mucolast®, as shown by the bacterial count in stomach tissue and under histopathological and biochemical evaluation. The proposed treatment was efficacious and safe and is presented as a realistic alternative to current treatment options to improve patient compliance and to reduce bacterial resistance.

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Perfil Epidemiológico de Pacientes Submetidos à Biópsia Gástrica em um Hospital Escola do Sul de Minas Gerais/ Epidemiological Profile of Patients Undergo Gastric Biopsy in a School Hospital of Minas Gerais

REVISTA CIÊNCIAS EM SAÚDE ◽

10.21876/rcsfmit.v4i3.229 ◽

1970 ◽

Vol 4 (3) ◽

pp. 48-57

Author(s):

Isabela Maria A. Ribeiro Simões ◽

Ana Carolina Mauad Coli ◽

Roseane de Souza Candido Irulegui

Keyword(s):

Helicobacter Pylori ◽

Age Groups ◽

Epidemiological Data ◽

Minas Gerais ◽

Gastric Biopsy ◽

Gastric Ulcers ◽

Histopathological Diagnosis ◽

Gastric Diseases ◽

H Pylori ◽

Epidemiological Profile

Objetivo: Determinar a prevalência de lesões benignas e neoplasia gástrica através do estudo de biópsias realizadas em um Hospital Escola do Sul de Minas Gerais, no período entre 2007 e 2011. Materiais e Métodos: A pesquisa documental foi quantitativa e retrospectiva, baseada na análise dos registros de biópsias e prontuários. Realizou-se o levantamento de dados referentes à idade, gênero, cor, profissão, diagnóstico histopatológico e presença de Helicobacter pylori nas amostras. Resultados: O número total de biópsias gástricas analisadas foi de 1225, cujo perfil populacional encontrado foi: idade média de 56,75 anos, sexo masculino (52%), cor branca (81,9 %), aposentado (30%). Os diagnósticos mais frequentes foram: gastrites (71,9%), pólipos (14,2%), adenocarcinomas (5,9%), úlceras gástricas (6%), linfomas (0,4%), sem alterações (0,4%) e outros (1,2%). Em outros, encontram-se achados de malignidade, metaplasia e xantelasma gástrico. Em relação à presença de Helicobacter pylori nas amostras, o resultado encontrado foi de24% positivas, 46% negativas e 30% não pesquisadas. Conclusão: Os resultados confirmam a alta frequência das doenças gástricas e sua incidência nas diversas faixas etárias, além do envolvimento do H. pylori em tais afecções. É de grande importância a caracterização dos dados epidemiológicos, o que permite prováveis direcionamentos para programas de prevenção e informação para a população. Palavras-chave: biópsia gástrica, gastropatia, perfil epidemiológico. ABSTRACTObjective: To determine the prevalence of benign lesions and gastric cancer through study of biopsies performed at a school hospital in southern Minas Gerais, in the period between 2007 and 2011.Materials and Methods: The research was quantitative and retrospective, based on analysis of biopsies records and medical records. We conducted the survey data regarding age, sex, color, profession, histopathological diagnosis and the presence of Helicobacter pylori in the samples. Results: The total number of gastric biopsies analyzed was 1225. Population listing was found: mean age of 56.75 years, male (52%), white (81.9%), retired (30%). The most frequent diagnoses were gastritis (71.9%), polyps (14.2%), adenocarcinomas (5.9%), gastric ulcers (6%), lymphoma (0.4%), unchanged (0, 4%) and others (1.2%). In others, there are: findings of malignancy, metaplasia, gastric xanthelasma. Regarding the presence of Helicobacter pylori in the sample, the result was: 24% positive, 46% negative, 30% non searched. Conclusion: The results confirm the high frequency of gastric diseases and their incidence in the various age groups additionally to the involvement of H. pylori in such conditions. It is of great importance to characterize the epidemiological data, allowing probable directions for prevention and information programs for population. Keywords: gastric biopsy, gastropathy, epidemiological profile

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Selective killing of Helicobacter pylori with pH-responsive helix–coil conformation transitionable antimicrobial polypeptides

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1710408114 ◽

2017 ◽

Vol 114 (48) ◽

pp. 12675-12680 ◽

Cited By ~ 36

Author(s):

Menghua Xiong ◽

Yan Bao ◽

Xin Xu ◽

Hua Wang ◽

Zhiyuan Han ◽

...

Keyword(s):

Helicobacter Pylori ◽

Triple Therapy ◽

Helical Structure ◽

Commensal Bacteria ◽

Gastric Ulcers ◽

Normal Tissues ◽

Minimal Toxicity ◽

Antimicrobial Polypeptides ◽

H Pylori ◽

Drug Resistant Strains

Current clinical treatment of Helicobacter pylori infection, the main etiological factor in the development of gastritis, gastric ulcers, and gastric carcinoma, requires a combination of at least two antibiotics and one proton pump inhibitor. However, such triple therapy suffers from progressively decreased therapeutic efficacy due to the drug resistance and undesired killing of the commensal bacteria due to poor selectivity. Here, we report the development of antimicrobial polypeptide-based monotherapy, which can specifically kill H. pylori under acidic pH in the stomach while inducing minimal toxicity to commensal bacteria under physiological pH. Specifically, we designed a class of pH-sensitive, helix–coil conformation transitionable antimicrobial polypeptides (HCT-AMPs) (PGA)m-r-(PHLG-MHH)n, bearing randomly distributed negatively charged glutamic acid and positively charged poly(γ-6-N-(methyldihexylammonium)hexyl-l-glutamate) (PHLG-MHH) residues. The HCT-AMPs showed unappreciable toxicity at physiological pH when they adopted random coiled conformation. Under acidic condition in the stomach, they transformed to the helical structure and exhibited potent antibacterial activity against H. pylori, including clinically isolated drug-resistant strains. After oral gavage, the HCT-AMPs afforded comparable H. pylori killing efficacy to the triple-therapy approach while inducing minimal toxicity against normal tissues and commensal bacteria, in comparison with the remarkable killing of commensal bacteria by 65% and 86% in the ileal contents and feces, respectively, following triple therapy. This strategy renders an effective approach to specifically target and kill H. pylori in the stomach while not harming the commensal bacteria/normal tissues.

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TIFA Signaling in Gastric Epithelial Cells Initiates the cag Type 4 Secretion System-Dependent Innate Immune Response to Helicobacter pylori Infection

mBio ◽

10.1128/mbio.01168-17 ◽

2017 ◽

Vol 8 (4) ◽

Cited By ~ 54

Author(s):

Alevtina Gall ◽

Ryan G. Gaudet ◽

Scott D. Gray-Owen ◽

Nina R. Salama

Keyword(s):

Immune Response ◽

Helicobacter Pylori ◽

Epithelial Cells ◽

Inflammatory Response ◽

Secretion System ◽

Innate Immune ◽

Gastric Ulcers ◽

Bacterial Clearance ◽

Gastric Epithelial Cells ◽

H Pylori

ABSTRACT Helicobacter pylori is a bacterial pathogen that colonizes the human stomach, causing inflammation which, in some cases, leads to gastric ulcers and cancer. The clinical outcome of infection depends on a complex interplay of bacterial, host genetic, and environmental factors. Although H. pylori is recognized by both the innate and adaptive immune systems, this rarely results in bacterial clearance. Gastric epithelial cells are the first line of defense against H. pylori and alert the immune system to bacterial presence. Cytosolic delivery of proinflammatory bacterial factors through the cag type 4 secretion system ( cag -T4SS) has long been appreciated as the major mechanism by which gastric epithelial cells detect H. pylori . Classically attributed to the peptidoglycan sensor NOD1, recent work has highlighted the role of NOD1-independent pathways in detecting H. pylori ; however, the bacterial and host factors involved have remained unknown. Here, we show that bacterially derived heptose-1,7-bisphosphate (HBP), a metabolic precursor in lipopolysaccharide (LPS) biosynthesis, is delivered to the host cytosol through the cag -T4SS, where it activates the host tumor necrosis factor receptor-associated factor (TRAF)-interacting protein with forkhead-associated domain (TIFA)-dependent cytosolic surveillance pathway. This response, which is independent of NOD1, drives robust NF-κB-dependent inflammation within hours of infection and precedes NOD1 activation. We also found that the CagA toxin contributes to the NF-κB-driven response subsequent to TIFA and NOD1 activation. Taken together, our results indicate that the sequential activation of TIFA, NOD1, and CagA delivery drives the initial inflammatory response in gastric epithelial cells, orchestrating the subsequent recruitment of immune cells and leading to chronic gastritis. IMPORTANCE H. pylori is a globally prevalent cause of gastric and duodenal ulcers and cancer. H. pylori antibiotic resistance is rapidly increasing, and a vaccine remains elusive. The earliest immune response to H. pylori is initiated by gastric epithelial cells and sets the stage for the subsequent immunopathogenesis. This study revealed that host TIFA and H. pylori -derived HBP are critical effectors of innate immune signaling that account for much of the inflammatory response to H. pylori in gastric epithelial cells. HBP is delivered to the host cell via the cag -T4SS at a time point that precedes activation of the previously described NOD1 and CagA inflammatory pathways. Manipulation of the TIFA-driven immune response in the host and/or targeting of ADP-heptose biosynthesis enzymes in H. pylori may therefore provide novel strategies that may be therapeutically harnessed to achieve bacterial clearance.

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Efficacy of and Resistance to Rifaximin-based Quadruple Therapy in Helicobacter pylori Eradication

The Korean Journal of Helicobacter and Upper Gastrointestinal Research ◽

10.7704/kjhugr.2020.0021 ◽

2020 ◽

Vol 20 (3) ◽

pp. 218-224

Author(s):

Hyun Soo Kim ◽

Hyuk Yoon ◽

Dong Woo Shin ◽

Dong Jun Oh ◽

Mingu Kwon ◽

...

Keyword(s):

Helicobacter Pylori ◽

Rescue Therapy ◽

Treatment Options ◽

Treatment Protocol ◽

Resistance Rate ◽

Quadruple Therapy ◽

Minimal Inhibitory Concentrations ◽

Intention To Treat ◽

H Pylori ◽

Triple Regimen

Background/Aims: The treatment options for Helicobacter pylori (H. pylori) infection are in a state of flux: traditional triple therapies have started to fail, and new treatments are unable to achieve optimal eradication rates. Rifaximin and rifabutin are new antibiotics. The aim of this study was to evaluate the efficacy and safety of adding rifaximin to the standard triple regimen and of a rifabutin-based triple regimen as a rescue therapy for H. pylori eradication.Materials and Methods: We enrolled 27 H. pylori-positive patients who were treated with a proton pump inhibitor, amoxicillin, clarithromycin, and rifaximin for 14 days. H. pylori eradication was assessed by a 13C-urea breath test performed 4 weeks after therapy completion. The efficacy of the therapy was based on intention-to-treat (ITT) and per-protocol (PP) analysis. We also investigated the resistance rate, compliance, and side effects associated with rifaximin therapy. Minimal inhibitory concentrations and resistance to rifabutin were evaluated using the agar dilution method.Results: Of the 27 patients, 22 completed the treatment protocol with 100% compliance; five patients withdrew. The ITT and PP eradication rates for the rifaximin-containing quadruple therapy were 70.4% (19/27) and 86.3% (19/22), respectively. Adverse events were observed in five of 22 patients (22.7%). The resistance rates to rifaximin and rifabutin were 66.7% (2/3) and 0% (0/3), respectively.Conclusions: The findings of this study show the limitations of rifaximin-based quadruple therapy and suggest the benefits of a rifabutin-based rescue regimen in South Korea.

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Prevalence of Helicobacter pylori infection among patients undergoing upper gastrointestinal endoscopy

Asian Journal of Health Sciences ◽

10.15419/ajhs.v3i1.405 ◽

2015 ◽

Vol 3 (1) ◽

Author(s):

Vudumula Vijaya Lakshmi

Keyword(s):

Duodenal Ulcer ◽

Helicobacter Pylori ◽

Normal Population ◽

Gastric Ulcers ◽

Upper Gastrointestinal Endoscopy ◽

Contributing Factors ◽

Duodenal Ulcers ◽

Female Ratio ◽

Ulcer Disease ◽

H Pylori

Helicobacter pylori (H. pylori) has a role in the multifactorial etiology of peptic ulcer disease. A link between H. pylori infection and duodenal ulcer disease is now established. Other contributing factors and their interaction with the organism may initiate the ulcerative process. The fact that eradication of H. pylori infection leads to a long-term cure in the majority of duodenal ulcer patients and the fact that the prevalence of infection is higher in ulcer patients than in the normal population are cogent arguments in favor of it being the primary cause of the ulceration. This study was under taken at the Department of surgery, Narayana medical college, Nellore from January 2007 to July 2008. A total of 150 patients with duodenal ulcers, gastric ulcers, antral gastritis, gastric carcinoma and dyspepsia of any kind were studied. Maximum number of cases were in the age group of 31 years to 50 years among both sexes and number of cases gradually decreased after 50 years of age in males and females. Males were more in number and male to female ratio is (2.75:1) approximately 3:1.

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Expressions of MMPs and TIMP-1 in Gastric Ulcers May DifferentiateH. pylori-Infected from NSAID-Related Ulcers

The Scientific World JOURNAL ◽

10.1100/2012/539316 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Hsiu-Chi Cheng ◽

Hsiao-Bai Yang ◽

Wei-Lun Chang ◽

Wei-Ying Chen ◽

Yi-Chun Yeh ◽

...

Keyword(s):

Helicobacter Pylori ◽

Gastric Ulcer ◽

Epithelial Cells ◽

Matrix Metalloproteinases ◽

Matrix Metalloproteinase ◽

Immunohistochemical Staining ◽

Gastric Ulcers ◽

Matrix Metalloproteinase 1 ◽

Two Factors ◽

H Pylori

Background. Two major causes of gastric ulcers areHelicobacter pylori(H. pylori) infection and nonsteroidal anti-inflammatory drug (NSAID) use.Aims. This study aimed to determine if there were different expressions of matrix metalloproteinases (MMPs) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) betweenH. pylori-infected and NSAID-related ulcers.Methods. The 126 gastric ulcer patients (H. pyloriinfectedn=46; NSAID relatedn=30; combined with two factorsn=50) provided ulcer and nonulcer tissues for assessment of MMP-3, -7, and -9 and TIMP-1 expression by immunohistochemical staining.Results. Gastric ulcer tissues had significantly higher MMP-3, -7, and -9 and TIMP-1 expressions than nonulcer tissues (P<0.05).H. pylori-infected gastric ulcers had even higher MMP-7, MMP-9, and TIMP-1 expressions in epithelial cells than NSAID-related gastric ulcers (P<0.05). In patients with the two combined factors, gastric ulcers expressed similar proportions of antral ulcers and MMP-7 and MMP-9 intensities to NSAID-related gastric ulcers, but lower MMP-9 and TIMP-1 thanH. pylori-infected gastric ulcers (P<0.05).Conclusions. H. pylori-infected gastric ulcers express higher MMP-7, MMP-9, and TIMP-1 than NSAID-related ulcers. In patients with the two combined factors, ulcer location and MMP-7 and MMP-9 intensities are similar to NSAID use.

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Mechanisms of the Epithelial–Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer

Cells ◽

10.3390/cells9041055 ◽

2020 ◽

Vol 9 (4) ◽

pp. 1055 ◽

Cited By ~ 11

Author(s):

Jacek Baj ◽

Izabela Korona-Głowniak ◽

Alicja Forma ◽

Amr Maani ◽

Elżbieta Sitarz ◽

...

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Epithelial Mesenchymal Transition ◽

Treatment Strategies ◽

Gastric Ulcers ◽

Heparin Binding ◽

Human Pathogens ◽

Mesenchymal Transition ◽

Cytotoxin Associated Gene A ◽

H Pylori

Helicobacter pylori (H. pylori) is one of the most common human pathogens, affecting half of the world’s population. Approximately 20% of the infected patients develop gastric ulcers or neoplastic changes in the gastric stroma. An infection also leads to the progression of epithelial–mesenchymal transition within gastric tissue, increasing the probability of gastric cancer development. This paper aims to review the role of H. pylori and its virulence factors in epithelial–mesenchymal transition associated with malignant transformation within the gastric stroma. The reviewed factors included: CagA (cytotoxin-associated gene A) along with induction of cancer stem-cell properties and interaction with YAP (Yes-associated protein pathway), tumor necrosis factor α-inducing protein, Lpp20 lipoprotein, Afadin protein, penicillin-binding protein 1A, microRNA-29a-3p, programmed cell death protein 4, lysosomal-associated protein transmembrane 4β, cancer-associated fibroblasts, heparin-binding epidermal growth factor (HB-EGF), matrix metalloproteinase-7 (MMP-7), and cancer stem cells (CSCs). The review summarizes the most recent findings, providing insight into potential molecular targets and new treatment strategies for gastric cancer.

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Dietary Composition Influences Incidence of Helicobacter pylori-Induced Iron Deficiency Anemia and Gastric Ulceration

Infection and Immunity ◽

10.1128/iai.00479-16 ◽

2016 ◽

Vol 84 (12) ◽

pp. 3338-3349 ◽

Cited By ~ 11

Author(s):

Amber C. Beckett ◽

M. Blanca Piazuelo ◽

Jennifer M. Noto ◽

Richard M. Peek ◽

M. Kay Washington ◽

...

Keyword(s):

Helicobacter Pylori ◽

Iron Deficiency ◽

Iron Deficiency Anemia ◽

Gastric Ulceration ◽

High Salt ◽

Gastric Ulcers ◽

Deficiency Anemia ◽

Content Type ◽

H Pylori

Epidemiologic studies have provided conflicting data regarding an association betweenHelicobacter pyloriinfection and iron deficiency anemia (IDA) in humans. Here, a Mongolian gerbil model was used to investigate a potential role ofH. pyloriinfection, as well as a possible role of diet, inH. pylori-associated IDA. Mongolian gerbils (eitherH. pyloriinfected or uninfected) received a normal diet or one of three diets associated with increasedH. pylorivirulence: high-salt, low-iron, or a combination of a high-salt and low-iron diet. In an analysis of all infected animals compared to uninfected animals (independent of diet),H. pylori-infected gerbils had significantly lower hemoglobin values than their uninfected counterparts at 16 weeks postinfection (P< 0.0001). The mean corpuscular volume (MCV) and serum ferritin values were significantly lower inH. pylori-infected gerbils than in uninfected gerbils, consistent with IDA. Leukocytosis and thrombocytosis were also detected in infected gerbils, indicating the presence of a systemic inflammatory response. In comparison to uninfected gerbils,H. pylori-infected gerbils had a higher gastric pH, a higher incidence of gastric ulcers, and a higher incidence of fecal occult blood loss. Anemia was associated with the presence of gastric ulceration but not gastric cancer. Infected gerbils consuming diets with a high salt content developed gastric ulcers significantly more frequently than gerbils consuming a normal-salt diet, and the lowest hemoglobin levels were in infected gerbils consuming a high-salt/low-iron diet. These data indicate thatH. pyloriinfection can cause IDA and that the composition of the diet influences the incidence and severity ofH. pylori-induced IDA.

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Impact of Helicobacter pylori Eradication Therapy on Platelet Counts in Patients With Chronic Idiopathic Thrombocytopenic Purpura

Global Journal of Health Science ◽

10.5539/gjhs.v8n7p35 ◽

2015 ◽

Vol 8 (7) ◽

pp. 35 ◽

Cited By ~ 2

Author(s):

Mohamadreza Amiri

Keyword(s):

Helicobacter Pylori ◽

Platelet Count ◽

Eradication Therapy ◽

Current Treatment ◽

Thrombocytopenic Purpura ◽

Stool Antigen Test ◽

Platelet Counts ◽

Before And After ◽

History Of ◽

H Pylori

This study was a before and after clinical evaluation of Helicobacter pylori eradication on platelet counts in a group of 23 patients with chronic Idiopathic (Autoimmune) thrombocytopenic purpura (CITP). H. pylori infection was identified in patients by a 13C-urea breath test and confirmed by an H. pylori stool antigen test. Eradication was conducted in patients testing positive. Infected (n = 10) and uninfected (n = 13) patient groups did not differ with respect to age, gender, history of previous splenectomy, treatment with anti-D, current treatment with corticosteroids, or initial platelet counts. H pylori eradication was successful in eight infected CITP patients, with two patients not responsive to treatment. Compared to the uninfected group, patients in the infected group who responded to eradication therapy had significantly increased platelet counts after six months (56.2 ± 22.2 vs. 233 ± 85.6 ×103 million cells/L; P < 0.01), whereas platelet counts in the non-responding patients and uninfected group did not differ after this period of time. H. pylori eradication promotes significant platelet count improvement in patients with CITP. Thus, all patients with CITP should be tested and treated for H. pylori infections.

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Natural History of Gastric Mucosal Cytokine Expression in Helicobacter pylori Gastritis in Mongolian Gerbils

Infection and Immunity ◽

10.1128/iai.73.4.2205-2212.2005 ◽

2005 ◽

Vol 73 (4) ◽

pp. 2205-2212 ◽

Cited By ~ 40

Author(s):

Yoshio Yamaoka ◽

Kazuyoshi Yamauchi ◽

Hiroyoshi Ota ◽

Atsushi Sugiyama ◽

Satoshi Ishizone ◽

...

Keyword(s):

Helicobacter Pylori ◽

Gastric Ulcers ◽

Mongolian Gerbils ◽

Mrna Levels ◽

Hyperplastic Polyps ◽

Fundic Mucosa ◽

Reverse Transcription Pcr ◽

Pyloric Mucosa ◽

Ifn Γ ◽

H Pylori

ABSTRACT Data regarding the chronological changes in gastric mucosal cytokines in the different phases of Helicobacter pylori infection are unavailable. We examined Mongolian gerbils for up to 52 weeks after H. pylori (ATCC 43504) inoculation. Levels of mRNAs of mucosal cytokines (interleukin-1β [IL-1β], gamma interferon [IFN-γ], IL-4, IL-6, and IL-10) were assessed using real-time reverse transcription-PCR. Starting 26 weeks after H. pylori inoculation, two clinicohistologic patterns appeared: gastric ulcers in 32% and hyperplastic polyps in 68% of gerbils. High levels of mucosal IL-1β mRNA were observed early in the infection, reaching maximum at 4 weeks and then rapidly declining. Mucosal IFN-γ mRNA also reached maximal levels at 4 weeks but remained high thereafter. Both IL-1β and IFN-γ mRNA levels were consistently higher in the pyloric mucosa than in the fundic mucosa. In contrast, IL-4, IL-6, and IL-10 mRNA levels peaked at 8 to 26 weeks and levels were similar in the pyloric mucosa and the fundic mucosa. IFN-γ mRNA levels were significantly higher in gerbils with ulcers than in those with hyperplastic polyps (median IFN-γ/glyceraldehyde-3-phosphate dehydrogenase ratio × 100,000 = 650 versus 338, respectively [antrum], and 172 versus 40, respectively [corpus]) (P < 0.05). We propose that the different outcomes (e.g., ulcers or hyperplastic polyps) might relate to imbalances among cytokines.

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