Alginate/polyethylene glycol diacrylate shape memory hydrogel films for gastric retention and antibiotic delivery in H. pylori infection

Helicobacterpylori (H. pylori)infection affects about half the worldpopulation, and if left untreated, can cause painful sores in thestomach lining and intestinal bleeding, leading to peptic ulcer disease(PUD) and stomach cancer. Treatment of H. pylori infection is always a challenge to the treating doctor because ofthe treatment inefficiency resulting from the poor bioavailabilityof the drug at the inner layers of the gastric mucosa, where the bacteriareside. This also results in the development of antibiotic resistance.In this work, we developed a mucoadhesive gastroretentive drug deliverysystem (M-GRDDS) for the effective delivery of antibiotics and piperineto the gastric mucosa. The GRDDS system was formulated by using theion-gelation method and was evaluated for its entrapment efficiency,particle size, swelling behavior, drug release, mucoadhesion property,and H. pylori eradication efficacy.The efficacy of the drug-loaded mucoadhesive GRDDS formulation wascompared with that of the free drug. Results showed that the percentageentrapment efficiency was more than 80% for all the drugs. M-GRDDSbeads showed controlled release at pH 1.2 and 7.4. The optimized mucoadhesivebeads showed good in vitro mucoadhesion in X-rayphotography, with a mean gastric residence time of more than 8 h inrabbits. Tissue distribution study in rats revealed local deliveryof the drugs to the gastric mucosa from the M-GRDDS beads. The in vivo efficacy study performed on Sprague–Dawleyrats showed that the colony-forming units in the group treated withthe novel GRDDS formulation were fewer than those in the group treatedwith the free drugs. Biochemical tests, gene expression studies, andhistopathology studies corroborated the enhanced efficacy of the M-GRDDSformulation in eradicating the infection and curing peptic ulcers.The results conclude that the developed M-GRDDS formulation holdssignificant potential for improving local bioavailability, contributingto the more effective eradication of H. pylori-based gastric ulcers.

We present a bioinspired design strategy to engineer bacteria-targeting and membrane-disruptive nanoparticles for the effective antibiotic therapy of Helicobacter pylori (H. pylori) infection. Antibacterial nanoparticles were self-assembled from highly exfoliated montmorillonite (eMMT) and cationic linear polyethyleneimine (lPEI) via electrostatic interactions. eMMT functions as a bioinspired 'sticky' building block for anchoring antibacterial nanoparticles onto the bacterial cell surface via bacteria-secreted extracellular polymeric substances (EPS), whereas membrane-disruptive lPEI is able to efficiently lyse the bacterial outer membrane to allow topical transmembrane delivery of antibiotics into the intracellular cytoplasm. As a result, eMMT-lPEI nanoparticles intercalated with the antibiotic metronidazole (MTZ) not only efficiently target bacteria via EPS-mediated adhesion and kill bacteria in vitro, but also can effectively remain in the stomach where H. pylori reside, thereby serving as an efficient drug carrier for the direct on-site release of MTZ into the bacterial cytoplasm. Importantly, MTZ-intercalated eMMT-lPEI nanoparticles were able to efficiently eradicate H. pylori in vivo and to significantly improve H. pylori-associated gastric ulcers and the inflammatory response in a mouse model, and also showed superior therapeutic efficacy as compared to standard triple therapy. Our findings reveal that bacterial adhesion plays a critical role in promoting efficient antimicrobial delivery and also represent an original bioinspired targeting strategy via specific EPS-mediated adsorption. The bacteria-adhesive eMMT-lPEI nanoparticles with membrane-disruptive ability may constitute a promising drug carrier system for the efficacious targeted delivery of antibiotics in the treatment of bacterial infections.

Strategies to improve antibiotic treatment of Helicobacter pylori infection are hampered by lack of knowledge about the route of antibiotic delivery. Post-prandial dosing with antibiotics prolongs their gastric residence time and improves their intragastric distribution, leading to improved local delivery compared with pre-prandial dosing. We aimed to assess whether pre- or post-prandial dosing. with amoxycillin suspension was more effective for H. pylori eradication in an amoxycillin/omeprazole regimen. Seventy-nine patients with H. pylori infection were treated with omeprazole 40 mg o.m. for 28 days and amoxycillin suspension 500 mg q.d.s. for days 15-28, the amoxycillin being randomized to either 1 h before or immediately after food. The H. pylori eradication rate, for those completing the trial, was 67% (22/33) when amoxycillin suspension was given pre-prandially, compared with 39% (15/38) when it was given post-prandially (P < 0.05). Good compliance was achieved, with H. pylori eradication in 59% (28/46) of good compliers compared with 36% (9/25) of others completing the protocol (P < 0.05). When given with omeprazole, pre-prandial dosing with amoxycillin suspension is more effective for H. pylori eradication than post-prandial dosing. This is consistent with the hypothesis that systemic rather than local delivery of amoxycillin is important for H. pylori eradication.

We designed a bacteria-targeting and membrane disrupting nanocomposite for successful antibiotic treatment of Helicobacter pylori (H. pylori) infections in the present study. The antibacterial nanocomposite was prepared from thiolated-ureido-chitosan (Cys-U-CS) and anionic poly (malic acid) (PMLA) via electrostatic interaction decorated with dual functional ammonium citrate carbon quantum dots (CDs). Cys-U-CS serves as a targeting building block for attaching antibacterial nanocomposite onto bacterial cell surface through Urel-mediated protein channel. Simultaneously, membrane disrupting CDs generate ROS and lyse the bacterial outer membrane, allowing antibiotics to enter the intracellular cytoplasm. As a result, Cys-U-CS/PMLA@CDs nanocomposite (UCPM-NPs) loaded with the antibiotic amoxicillin (AMX) not only effectively target and kill bacteria in vitro via Urel-mediated adhesion but also efficiently retain in the stomach where H. pylori reside, serving as an effective drug carrier for abrupt on-site release of AMX into the bacterial cytoplasm. Furthermore, since thiolated-chitosan has a mucoadhesive property, UCPM-NPs may adhere to the stomach mucus layer and pass through it swiftly. According to our results, bacterial targeting is crucial for guaranteeing successful antibiotic treatment. The bacteria targeting UCPM-NPs with membrane disruptive ability may establish a promising drug delivery system for the effective targeted delivery of antibiotics to treat H. pylori infections.

Background: Gastrointestinal (GI) symptoms are common in patients with chronic renal failure (CRF). Delayed gastric emptying might be a possible pathophysiological mechanism. The aims of this study were to evaluate gastric emptying in patients with CRF and to correlate the findings with GI symptoms and evaluate the impact of Helicobacter pylori infection in CRF patients on gastric emptying. Methods: Thirty‐nine patients with CRF (17 F, 22 M) were compared with 131 healthy subjects (74 F, 57 M). A standardized breakfast was given with 20 spherical, radiopaque markers (ROMs). The emptying was followed by fluoroscopy after 4, 5 and 6 h. Gastric emptying was assessed by calculating the individual mean percentual gastric retention of markers, 4 to 6 h after the meal. The perceived severity of GI symptoms was assessed with a validated questionnaire. Because of gender differences in gastric emptying, men and women were compared separately and a percentile of 95 was chosen as the upper reference value. H. pylori infection was assessed using a serological method. Results: Delayed gastric emptying was found in 14 out of 39 (36%) of the CRF patients. There was no relationship between delayed gastric emptying and age, GI symptoms, H. pylori infection or underlying renal disease. However, a higher proportion of patients in peritoneal dialysis demonstrated delayed gastric emptying compared with predialytic patients (6 of 9 versus 2 of 13, P = 0.026). Men with CRF had a higher gastric retention compared with healthy men (16.6 (0–63.3)% versus 0 (0–2.1)%, P < 0.0001), and 10 men with CRF had delayed gastric emptying (P < 0.0001). There was no significant difference in mean gastric retention between women with CRF and healthy women (13.3 (0–55.4)% versus 10.8 (0–30.0)%, P = 0.93), but 4 women with CRF had delayed gastric emptying (P = 0.02). Eighteen of the CRF patients had GI symptoms (6 F, 12 M) and 21 were asymptomatic (11 F, 10 M). There was no difference in mean gastric retention in patients with CRF with and without GI symptoms (M: 13.3 (0–55.0)% versus 47.5 (5.0–65.0)%, P = 0.51, F: 16.6 (0–63.3)% versus 13.3 (0–59.2)%, P = 0.96). Gastric emptying in CRF patients with and without H. pylori infection showed no difference. Conclusions: Delayed gastric emptying is common in patients with chronic renal failure, particularly in men. The delay was not associated with the presence of GI symptoms, underlying renal disease or H. pylori infection. However, the dialytic status might have an impact on gastric emptying in patients with CRF.

Inspired by the natural pathogen-host interactions and adhesion, this study reports on the development of a novel targeted nanotherapeutics for the treatment of Helicobacter pylori (H. pylori) infection. Specifically, plasma membranes of gastric epithelial cells (e.g. AGS cells) are collected and coated onto antibiotic-loaded polymeric cores, the resulting biomimetic nanoparticles (denoted AGS-NPs) bear the same surface antigens as the source AGS cells and thus have inherent adhesion to H. pylori bacteria. When incubated with H. pylori bacteria in vitro, the AGS-NPs preferentially accumulate on the bacterial surfaces. Using clarithromycin (CLR) as a model antibiotic and a mouse model of H. pylori infection, the CLR-loaded AGS-NPs demonstrate superior therapeutic efficacy as compared the free drug counterpart as well as non-targeted nanoparticle control group. Overall, this work illustrates the promise and strength of using natural host cell membranes to functionalize drug nanocarriers for targeted drug delivery to pathogens that colonize on the host cells. As host-pathogen adhesion represents a common biological event for various types of pathogenic bacteria, the bioinspired nanotherapeutic strategy reported here represents a versatile delivery platform that may be applied to treat numerous infectious diseases.

Lack of association of Helicobacter pylori infection with gastric hypersensitivity or delayed gastric emptying in functional dyspepsia

Thirty-seven patients aged 36-75 years with cirrhosis of the liver secondary to chronic hepatitis were included in the study. They were divided into three groups according to the modified Child's classification for cirrhotic severity, where A = good, B = fair and C = poor. In addition, the patients were divided according to the presence or absence of each of the following: ascites, splenomegaly and oesophageal varices. Radionuclide-labelled solid meals were used to evaluate gastric emptying and the 14C-urea breath test was used to detect Helicobacter pylori infection. Gastric emptying was represented by the gastric retention ratio of the solid meal at 90 min (RR90) and calculated using the following formula: the residual radioactivity within the region of interest (ROI) covering the whole stomach at 90 min divided by the initial radioactivity within the ROI at 0 min. We found that 75.7% (28/37) of the patients had abnormal gastric emptying and 45.9% (17/37) had H. pylori infection. No significant correlation was found between abnormal gastric emptying and H. pylori infection. There were no significant differences among the three groups regarding gastric emptying or H. pylori infection according to the modified Child's classification. However, the highest rates of abnormal gastric emptying and H. pylori infection were in patients in Child's class C. The differences in RR90 among patients with and without ascites, and patients with and without splenomegaly, were not significant (P > 0.05). However, there was a significant difference between the patients with and without oesophageal varices (P < 0.05). In addition, poor correlations (R2 < 0.01) were found between RR90 and serum levels of bilirubin and albumin.

Helicobacter pylori (H. pylori) colonizes not only the surface of the surface mucous cells but also the surface mucous gel layer (SMGL). Thus, we examined the possible value of pronase, a mucolytic agent, as a potential eradication therapy. One hundred and thirty-five patients were randomly assigned to two treatment groups. Sixty-eight patients received 30 mg of lansoprazole once daily, 500 mg of amoxicillin and 250 mg of metronidazole thrice daily for 2 weeks (LAM group), while the other 67 patients received the same dosage of those agents plus 18,000 tyrosine units of pronase thrice daily for 2 weeks (LAMP group). Eradication was assessed 4-6 weeks after treatment by immunohistochemical tests and cultures. We also determined the in vitro activity of pronase against H. pylori, and evaluated the synergistic effects between pronase and the other three drugs. To investigate the effect of pronase on the structure of the SMGL, surgically removed stomachs obtained from patients who had taken pronase were examined histopathologically. The cure rates for H. pylori infection in the LAMP group were significantly higher than those in the LAM group (intention to treat analysis: 94.0 vs. 76.5%, p =.0041). Pronase exhibited no antibacterial activity against H. pylori., and no in vitro synergistic effects were observed. In the patients who took pronase before surgery, the SMGL was thinner than in the patients who did not take pronase, and the structure of the SMGL was markedly disrupted. Pronase has an additive effect in curing H. pylori infection. Pronase has no apparent in vitro activity against H. pylori, but may improve the local delivery of antibiotics by virtue of its removal and disruption of the SMGL.

Low prevalence of H. pylori infection in patients with gastroparesis

The prevalence of drug-resistant bacteria presents a significant challenge to the antibiotic treatment of Helicobacter pylori (H. pylori), while traditional antimicrobial agents often suffer from shortcomings such as poor gastric retention, inadequate alleviation of inflammation, and significant adverse effects on the gut microbiota. Here, a selenized chitosan (CS-Se) modified bismuth-based metal-organic framework (Bi-MOF@CS-Se) nanodrug is reported that can target mucin through the charge interaction of the outer CS-Se layer to achieve mucosal adhesion and gastric retention. Additionally, the Bi-MOF@CS-Se can respond to gastric acid and pepsin degradation, and the exposed Bi-MOF exhibits excellent antibacterial properties against standard H. pylori as well as clinical antibiotic-resistant strains. Remarkably, the Bi-MOF@CS-Se effectively alleviates inflammation and excessive oxidative stress by regulating the expression of inflammatory factors and the production of reactive oxygen species (ROS), thereby exerting therapeutic effects against H. pylori infection. Importantly, this Bi-MOF@CS-Se nanodrug does not affect the homeostasis of gut microbiota, providing a promising strategy for efficient and safe treatment of H. pylori infection.

Preparation and properties of pH-responsive, self-assembled colloidal nanoparticles from guanidine-containing polypeptide and chitosan for antibiotic delivery

Anti-Helicobacterpylori effectiveness and targeted delivery performance of amoxicillin-UCCs-2/TPP nanoparticles based on ureido-modified chitosan derivative

In the present work, sustained release gastroretentive minimatrices of amoxicillin have been designed and optimized using central composite design. Effect of amount of xanthan gum, rate controlling polymers (HPMC K100M CR/PEO coagulant (1:1)), carbopol 974P, and gas generating couple (sodium bicarbonate/citric acid (3:1)) was studied on dependent (response) variables, i.e., buoyancy lag time, drug release at 1 h, time required for 95% drug release, swelling index, and bioadhesive strength. Minimatrices were prepared by non aqueous granulation method using solution of PVP K30 in isopropyl alcohol. All the formulations were found to contain 99.2% to 100.9% of amoxicillin per minimatrix. Optimum formulation (Formulation number AGT09) containing high level of the independent variables was having buoyancy lag time of 7 min and drug release at 1 h was 32.5%. It required 9.39 h for 95% drug release while swelling index and bioadhesive strength were 341 and 17.9 dyn/cm(2), respectively. This formulation was said to be optimum because it has minimum buoyancy lag time, requires maximum time for 95% drug release, and has higher bioadhesive capabilities. In vitro results of an optimized formulation indicate its sustained drug release and gastric retention capability, which may be very useful for effective treatment of H. pylori infection.

Design and synthesis of multifunctional polymeric micelles for targeted delivery in Helicobacter pylori infection