Duodenal Ulcer Healing Research Articles

A comparison of efficacy and safety of potassium-competitive acid blocker and proton pump inhibitor in gastric acid-related diseases: A systematic review and meta-analysis.

Potassium-competitive acid blocker (PCAB) is a recent alternative to proton pump inhibitor (PPI) for potent acid suppression. The current systematic review and meta-analysis aimed to compare the efficacy and safety of PCAB versus PPI in treating gastric acid-related diseases. We searched up to June 5, 2022, for randomized controlled trials of gastric acid-related diseases that included erosive esophagitis, symptomatic gastroesophageal reflux disease (GERD), peptic ulcers, and Helicobacter pylori infection. The pooled risk ratio (RR) was evaluated for the efficacy outcome and treatment-emergent adverse events (TEAEs) as the safety outcome. Sensitivity analyses were performed to test the robustness of the study findings. Of the 710 screened studies, 19 studies including 7023 participants were analyzed. The RRs for the healing of erosive esophagitis with Vonoprazan versus PPI were 1.09 (95% confidence interval [CI] 1.03-1.14), 1.03 (95% CI 1.00-1.07), and 1.02 (95% CI 1.00-1.05) in Weeks 2, 4, and 8, respectively. There were no differences in the improvement of GERD symptoms and healing of gastric and duodenal ulcers between PCAB and PPI. The pooled eradication rates of H.pylori were significantly higher in Vonoprazan versus PPI first-line treatment (RR 1.13; 95% CI 1.04-1.22). The overall RR of TEAEs with Vonoprazan versus PPI was 1.08 (95% CI 0.89-1.31). Overall, the risk of bias was low to some concerns. Furthermore, sensitivity analyses confirmed the robustness of the study's conclusion. Vonoprazan is superior to PPI in first-line H.pylori eradication and erosive esophagitis but non-inferior in other gastric acid-related diseases. Likewise, short-term safety is comparable in both treatment groups.

An Unusual Case of Refractory Peptic Ulcer Disease

An Unusual Case of Refractory Peptic Ulcer Disease

Preformulation Studies of Pantoprazole: Fundamental Part of Formulation Design

Once the novel molecule is planted, preformulation study is one of the fractions that is started. In a larger sense, it covers with research on a molecule's physical, chemical, analytical, and medicinal properties and offers suggestions for effective modifications that could be made to improve performance. The study of preformulation factors can contribute to the development of pharmaceutical formulations that are dependable, safe, stable, and efficacious. Pantoprazole is an irreversible proton pump inhibitor (PPI) that reduces gastric acid secretion. PPIs, pantoprazole binds to the proton pump (H+,K+ -adenosine triphosphatase) in the parietal cells to exercise its pharmacodynamic effects; however, in comparison to other PPIs, its binding may be more specific for the proton pump. When given as an enteric-coated, delayed-release tablet, pantoprazole is well absorbed and has a 77 % oral bioavailability. It is metabolized by the liver's cytochrome P2C19 into the inactive metabolite hydroxypantoprazole, which is then subjected to sulphate conjugation. Independent of dose, the elimination half-life ranges from 0.9 to 1.9 hours. Similar to other PPIs, pantoprazole is effective in promoting the healing of gastric and duodenal ulcers. In the present works overall objective of preformulation studies of Pantoprazole is to engender information useful in developing stable and Bioavailable dosage forms.

Vonoprazan Fumarate for the Treatment of Gastric Ulcers: A Short Review on Emerging Data.

Potassium-competitive acid blockers (P-CABs), such as vonoprazan, represent a novel and heterogeneous class of drugs that competitively block the potassium binding site of gastric H+/K+ ATPase, thus potentially overcoming the limitations of proton-pump inhibitors. Different studies evaluated the efficacy of vonoprazan versus proton-pump inhibitors (PPIs) for the treatment of acid-related disorders, and, therefore, P-CABs present the same indications of PPIs: gastroesophageal reflux disease, gastric and duodenal ulcer healing, management of upper gastrointestinal bleeding, non-steroidal anti-inflammatory drug (NSAID)-associated ulcers and Helicobacter pylori eradication therapy. The aim of this review was to evaluate the role of vonoprazan for the treatment of peptic ulcer disease (PUD) and the management of gastric ulcer occurring after endoscopic submucosal dissection (ESD). Indeed, vonoprazan (at the dose of both 10 and 20mg) showed similar results to PPIs in patients taking long-term NSAIDs, in the absence of severe adverse effects, and provided a more rapid and effective treatment of ulcers induced by ESD. However, studies in medical literature are heterogeneous, mainly performed with a retrospective design, and often carried out in Japan only. For these reasons, further prospective, randomized studies are warranted in order to help physicians, patients, and policymakers regarding the use of vonoprazan in clinical practice.

2529 A Case of Cytomegalovirus Causing Duodeno-Colonic Fistula in Immune Competent Patient

INTRODUCTION: Cytomegalovirus (CMV) is a common opportunistic infection in immune compromised patients. Within the gastro-intestinal tract, it is a known cause of esophagitis and colitis. A rare presentation of CMV infection is an enteric fistula with only a few cases reported. We present a case of duodena-colonic fistula secondary to CMV in an immune competent host. CASE DESCRIPTION/METHODS: 86-year gentleman with past medical history of dementia who presented with complaints of feeling tired, jaundice and colorless diarrhea, significant weight loss for two months. He denied alcohol use and was not taking any prescription medications. He denied family history of cancer or liver disease. His initial labs showed non-specific elevation in the liver enzymes along with mild anemia. He underwent an MRI abdomen that showed duodenal swelling but no obstructive mass or bile duct dilation. Endoscopic ultrasound showed a large duodenal ulcer with duodena-colonic fistula that was large enough for the scope to pass through. Biopsies were taken from the fistula and liver which showed cytoplasmic inclusion bodies characteristic of CMV. HIV antibodies were negative and CMV blood titres were elevated. His acute liver injury was attributed to CMV hepatitis. He completed 6 weeks of anti-viral treatment with ganciclovir. A repeat endoscopy 2 months later showed healing duodenal ulcer with no fistula present. Blood CMV level was negative at the time of completion of anti-viral treatment. He was seen later in the immunology clinic to evaluate why he had such a severe infection from CMV. His labs were significant for only mildly reduced B lymphocyte count – 47 (normal 100-700) with slightly lower immunoglobulin G level 748 (normal 762-1488) and immunoglobulin M level 25 (normal 38-328). Rest of the labs were unremarkable including a complete blood picture, lymphocyte subsets and lymphocyte proliferation studies. It was felt that his CMV infection was isolated and because he had no recurrent infections it was decided by the patient and the immunologist to forego any further investigations of immune deficiency. DISCUSSION: In clinical practice, it is important to exclude CMV infection as a cause of intestinal ulcers even in immune competent patients. Especially if they are accompanied by an enteric fistula. Treatment of the CMV enteric fistula involves both anti-viral therapy and surgical closure of the fistula. Rarely such as in our patient, healing of the fistula can take place without any invasive procedures.

Membrane-bound ATP-dependent Energy Systems, as Extra- and Intracellular Key Signals for Gastrointestinal Functions and their Regulations in the Gastrointestinal Mucosa.

Our research group has carried out various biochemical examinations in rat gastric ulcer models and in human gastrointestinal resecates obtained from patient who underwent gastric intervention due to peptic ulcer disease. Biochemical methods gave excellent possibility to approach the biochemical events taking place in tissues, cellular and subcellular regulatory levels during of ulcer development and of its prevetions. This paper gives a brief summary of these biochemical examinations conducted during this study period started from the 1960's up till now. 1. The decreased action of gastric acid secretory responses is not needed for duodenal and gastric ulcer healing in patients with peptic ulcer; 2. The surgical and chemical vagotomy resulted in various biochemical changes in the rat stomach; 3. The presence of Na+-K+-dependent ATPase and adenylate cyclase can be demostrated both in the rat and human gastric fundic mucosa; 4. The mitocondrial ATP is a common substrate for these membrane-bound ATP-dependent enzymes, and a multiple feedback mechanism existing between these two membrane-bound enzymes altered by mediators, hormones and drugs; 5. This feedback mechanism exists in the GI mucosa under different pathological conditions and during certain drug actions; 6. The development of mucosal damage and prevention depends on the actual regulatory state of above mentioned feedback mechanism between the membrane-bound ATP-dependent energy systems; 7.The drug actions depend on the actual functional state of target organ; 8. Biochemical gradients exist between the biochemical structure of the fundic, antral, duodenal and jejunal mucosa in patients with gastric hyperacidity, which is gradually downregulated by the decrease of gastric acid secretory responses, and totally disappears in patients with hypacidity; 9. No biochemically proven tissue hypoxia - around the chronic ulcer, duodenal and jejunal ulcers - exists in patients with chronic peptic ulcer; 10. The cellular and tissue protection differ from each other in the gastrointestinal tract; 11. Helicobacter pylori does not produce damage at the level of cell membrane, mitochondrion and DNA - given alone or in combination with indomethacin - on freshly isolated rat gastric mucosal cells. 12. A biochemical explanation is given to ulcer development in humans and in different animal models.

Vonoprazan for the Prevention of Recurrent NSAID Ulcers

The potassium-competitive acid blocker vonoprazan is as effective as proton-pump inhibitors (PPIs) in healing gastric and duodenal ulcers (Aliment

Synthesis of 1,2,3-Triazolo[4,5-h]quinolone Derivatives with Novel Anti-Microbial Properties against Metronidazole Resistant Helicobacter pylori.

Helicobacter pylori infection can lead to gastritis, peptic ulcer, and the development of mucosa associated lymphoid tissue (MALT) lymphoma. Treatment and eradication of H. pylori infection can prevent relapse and accelerate the healing of gastric and duodenal ulcers as well as regression of malignancy. Due to the increasing emergence of antibiotic resistance among clinical isolates of H. pylori, alternative approaches using newly discovered antimicrobial agents in combination with the standard antibiotic regimens for the treatment of H. pylori are of major importance. The purpose of the present study was to investigate the effect of newly synthesized 8-amino 7-substituted fluoroquinolone and their correspondent cyclized triazolo derivatives when either alone or combined with metronidazole against metronidazole-resistant H. pylori. Based on standard antimicrobial susceptibility testing methods and checkerboard titration assay, all of the tested compounds showed interesting antimicrobial activity against 12 clinical strains of H. pylori, with best in vitro effect for compounds 4b and 4c. Fractional inhibitory concentration (FIC) mean values showed synergistic pattern in all compounds of Group 5. In addition, additive activities of some of the tested compounds of Group 4 were observed when combined with metronidazole. In contrast, the tested compounds showed no significant urease inhibition activity. These results support the potential of new fluoroquinolone derivatives to be useful in combination with anti-H. pylori drugs in the management of H. pylori-associated diseases.

Synthesis of New Nitrofluoroquinolone Derivatives with Novel Anti-Microbial Properties against Metronidazole Resistant H. pylori.

One of the major therapeutic approaches to preventing relapse and accelerating the healing of duodenal and gastric ulcers is the eradication of Helicobacter pylori. Due to the emergence of antibiotic resistance among clinical strains of H. pylori, alternative approaches using newly discovered antimicrobial agents in combination with the standard regimens for the treatment of H. pylori are increasingly needed. The purpose of the present study was to investigate the effect of newly synthesized 8-nitroflouroqunolone derivatives when used either alone or when combined with metronidazole against metronidazole-resistant H. pylori. Based on the standard antimicrobial susceptibility testing methods and checkerboard titration assay, all of the tested compounds showed interesting antimicrobial activity against 12 clinical strains of H. pylori, with the best in vitro effect for compound 3c. In addition, synergistic and additive activities of some of the tested compounds were observed when combined with metronidazole. Furthermore, among the tested nitroflouroquinolone derivatives, compound 3b showed significant urease inhibition activity with IC50 of 62.5 µg/mL. These results suggest that 8-nitroflouroquinolone derivatives may have a useful role in combination with anti-H. pylori drugs in the management of H. pylori-associated diseases.

Eradication therapy for peptic ulcer disease in Helicobacter pylori-positive people.

Peptic ulcer disease is the cause of dyspepsia in about 10% of people. Ninety-five percent of duodenal and 70% of gastric ulcers are associated with Helicobacter pylori. Eradication of H. pylori reduces the relapse rate of ulcers but the magnitude of this effect is uncertain. This is an update of Ford AC, Delaney B, Forman D, Moayyedi P. Eradication therapy for peptic ulcer disease in Helicobacter pylori-positive patients. Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD003840. DOI: 10.1002/14651858.CD003840.pub4. To assess the proportion of peptic ulcers healed and the proportion of participants who remained free from relapse with eradication therapy against placebo or other pharmacological therapies in H. pylori-positive people.To assess the proportion of participants that achieved complete relief of symptoms and improvement in quality of life scores.To compare the incidence of adverse effects/drop-outs (total number for each drug) associated with the different treatments.To assess the proportion of participants in whom successful eradication was achieved. In this update, we identified trials by searching the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE (1950 to March 2016) and Ovid EMBASE (1980 to March 2016). To identify further relevant trials, we handsearched reference lists from trials selected by electronic searching, and published abstracts from conference proceedings from the United European Gastroenterology Week (published in Gut) and Digestive Disease Week (published in Gastroenterology). The search was last updated in March 2016. We contacted members of Cochrane Upper GI and Pancreatic Diseases,and experts in the field and asked them to provide details of outstanding clinical trials and any relevant unpublished materials. We analysed randomised controlled trials of short- and long-term treatment of peptic ulcer disease in H. pylori-positive adults. Participants received at least one week of H. pylori eradication compared with ulcer healing drug, placebo or no treatment. Trials were included if they reported assessment from two weeks onwards. We collected data on ulcer healing, recurrence, relief of symptoms and adverse effects. We calculated the risk ratio (RR) with 95% confidence intervals (CI) using both fixed-effect and random-effects models with Review Manager software (RevMan 5.3) based on intention-to-treat analysis as far as possible. A total of 55 trials were included for one or more outcomes for this review.In duodenal ulcer healing, eradication therapy was superior to ulcer healing drug (UHD) (34 trials, 3910 participants, RR of ulcer persisting = 0.66, 95% confidence interval (CI) 0.58 to 0.76; 381/2286 (adjusted proportion: 12.4%) in eradication therapy plus UHD versus 304/1624 (18.7%) in UHD; low quality evidence) and no treatment (two trials, 207 participants, RR 0.37, 95% CI 0.26 to 0.53; 30/125 (adjusted proportion: 21.7%) in eradication therapy versus 48/82 (58.5%) in no treatment; low quality evidence).In gastric ulcer healing, the differences were imprecise between eradication therapy and UHD (15 trials, 1974 participants, RR 1.23, 95% CI 0.90 to 1.68; 220/1192 (adjusted proportion: 16.0%) in eradication therapy plus UHD versus 102/782 (13.0%) in UHD; very low quality evidence). In preventing duodenal ulcer recurrence the differences were imprecise between maintenance therapy with H.pylori eradication therapy and maintenance therapy with UHD (four trials, 319 participants, RR of ulcer recurring 0.73; 95% CI 0.42 to 1.25; 19/159 (adjusted proportion: 11.9%) in eradication therapy versus 26/160 (16.3%) in UHD; very low quality evidence), but eradication therapy was superior to no treatment (27 trials 2509 participants, RR 0.20, 95% CI 0.15 to 0.26; 215/1501 (adjusted proportion: 12.9%) in eradication therapy versus 649/1008 (64.4%) in no treatment; very low quality evidence).In preventing gastric ulcer recurrence, eradication therapy was superior to no treatment (12 trials, 1476 participants, RR 0.31, 95% CI 0.22 to 0.45; 116/697 (adjusted proportion: 16.3%) in eradication therapy versus 356/679 (52.4%) in no treatment; very low quality evidence). None of the trials reported proportion of people with gastric ulcer not healed after initial therapy between H.pylori eradication therapy and no active treatment or the proportion of people with recurrent gastric ulcer or peptic ulcers during maintenance therapy between H.pylori eradication therapy and ulcer healing drug therapy. Adding a one to two-week course of H. pylori eradication therapy is an effective treatment for people with H. pylori-positive duodenal ulcer when compared to ulcer healing drugs alone and no treatment. H. pylori eradication therapy is also effective in preventing recurrence of duodenal and gastric ulcer compared to no treatment. There is currently no evidence that H. pylori eradication therapy is an effective treatment in people with gastric ulcer or that it is effective in preventing recurrence of duodenal ulcer compared to ulcer healing drug. However, confidence intervals were wide and significant benefits or harms of H. pylori eradication therapy in acute ulcer healing of gastric ulcers compared to no treatment, and in preventing recurrence of duodenal ulcers compared to ulcer healing drugs cannot be ruled out.

Is There Any Difference in the Eradication Rate of Helicobacter pylori Infection According to the Endoscopic Stage of Peptic Ulcer Disease?

The eradication rate of Helicobacter pylori (H. pylori) infection might be affected by the degree of inflammation of gastric mucosa represented by the endoscopic stage of peptic ulcer disease (PUD). The aims of this study were to evaluate the eradication rates of H. pylori infection according to the endoscopic stage of PUD and to document whether early eradication in the active stage could yield a higher eradication rate in patients with peptic ulcer bleeding (PUB). A total of 1,177 patients with PUD (380 gastric ulcer, 710 duodenal ulcer, and 87 combined ulcer) who received proton-pump inhibitor (PPI)-based triple therapy were included, and the eradication rates were compared by ulcer stage. Univariate and multivariate analyses were conducted to identify factors influencing eradication rate. In PUB, the eradication rates between the early eradication group (≤7 days) and the late eradication group (>7 days) were compared. The eradication rates according to endoscopic stage were significantly different in gastric ulcer (active vs healing vs scarring; 84.8% vs 82.7% vs 70.6%, p = .014, respectively), but there were no significant differences in duodenal ulcer (active vs healing vs scarring; 87.6% vs 80.9%% vs 80.9% p = .169, respectively). In multivariate analyses, active ulcer as well as age younger than 50 was a significantly independent predictor of successful eradication (Odds ratio; 2.799, 95% CI; 1.659-4.723, p = .0001). The eradication rate of the early eradication group was significantly higher than the late eradication group in PUB (89.2% vs 71.9%, 95% CI; 1.265-8.269, p = .011). There was a significant difference in the eradication rate according to the endoscopic stage of gastric ulcer. Active ulcer was an independent predictor of successful eradication. Furthermore, early H. pylori eradication should be considered in patients with PUB to yield a higher eradication rate.

Almagate suspension in combination with esomeprazole for duodenal ulcer patients positive in Helicobacter pylori

Objective To observe the effect of almagate suspension in combination with esomeprazole for duodenal ulcer patients positive in Helicobacter pylori.Methods 124 duodenal ulcer patients positive in Helicobacter pylori were randomized into two groups.The control group was given esomeprazole alone after 7-day's anti-H.pylori triple therapy including esomeprazole,amoxicillin,and clarithromycin.The treatment group was treated with the same therapy plus almagate suspension.Four weeks after the treatment.both groups returned to recheck the duodenal ulcer healing by gastroscope.14C-urea breath test was (rechek) four weeks after the end of the treatment.The ulcer healing rates,total effective rates,and H.pylori eradication rates were compared between the two groups.Results There was no statistical difference in the duodenal ulcer healing rate between these two groups (61.29％ vs.66.13％,P ＞ 0.05).There was statistical difference in the duodenal ulcer total effective rate between these two groups (82.26％ vs.95.16％,x 2=5.153,P ＜ 0.05).There was no statistical difference in the duodenal ulcer H.pylori eradication rate between these two groups (82.26％ vs.79.03％,P ＞ 0.05).Conclusions Almagate suspension in combination with esomeprazole is a more effective therapy method for duodenal ulcer patients positive in Helicobacter pylori than esomeprazole alone. Key words: Duodenal ulcer; Helicobacter pylori; Almagate suspension; Esomeprazole

New, pathogenesis‐based pharmacologic approaches to gastrointestinal ulcers: Gene therapy with egr‐1 & cell therapy with bone marrow‐derived stem cells

Our recent studies showed that the immediate‐early gene early growth response (egr‐1) that regulates the expression of angiogenic growth factors (e.g., VEGF, bFGF, PDGF) & neovascularization play a mechanistic role in experimental duodenal ulceration (DU). We thus hypothesized that gene therapy with adenovirus (AV) encoding egr‐1 & local administration of bone marrow‐derived stem cells (BMSC) may accelerate the healing of both upper & lower gastrointestinal ulcers, i.e., DU & ulcerative colitis (UC). Groups of rats were given cysteamine‐HCl (C, 85 mg/100g, x1, gavage) to induce DU or 6% iodoacetamide (IA, 0.1ml/rat, x1, enema) to cause UC. A single dose of either AV‐egr‐1 (2 × 109 pfu/rat) or BMSC (1 × 106 cells/rat) was given intraduodenally at laparotomy in DU rats on the 3rd day after C or intracolonically in UC rats on the 2nd day after IA. The rats were euthanized on the 7th or 14th day after C or IA administration. We found that DU & UC lesion areas were significantly reduced in rats treated with AV‐egr‐1 or BMSC compared to controls in both 7 & 14 days (p < 0.05). Increased levels (2‐ to 4‐folds) of growth factors VEGF, PDGF and bFGF were also seen at days 7 and 14 in the rats treated with AV‐egr‐1 or BMSC compared to the controls.Conclusionslocal egr‐1 gene or stem cell therapies seem to be a new option to achieve a rapid healing of DU & UC, possibly by promoting angiogenesis/vasculogenesis & restoring mucosal integrity.(This work was supported by the Veterans Health Administration Merit Review Grants to S. Szabo and Zs. Sandor).

Increasing gastric juice pH level prior to anti-Helicobacter pylori therapy may be beneficial to the healing of duodenal ulcers

The aim of this study was to observe the efficacy of clarithromycin-based triple therapy for Helicobacter pylori (Hp)-infected duodenal ulcer when combined with different pH levels of gastric juices. A total of 160 patients with Hp-infected duodenal ulcers were randomly allocated into two groups. Patients in the treatment group (n=80) were administered a 20-mg dose of omeprazole twice daily for 1 week and then the treatment and control groups (n=80) received therapy for Hp infection and duodenal ulcers. We observed the ulcer healing stage, the content of anti-Hp IgA in gastric juice and the Hp eradication rate before and after proton pump inhibitor therapy in the two groups. Results revealed that the Hp eradication rate in the treatment group was 93% compared with 81% in the control group, and the difference was statistically significant (P<0.05). The ulcer healing rate in the treatment group was 93%, compared with 70% in the control group (P<0.05). A positive linear correlation was observed between gastric pH and the content of anti-Hp IgA in gastric juice (P<0.05). Increasing gastric pH prior to anti-Hp therapy may be beneficial to the eradication of Hp and for promoting the healing of duodenal ulcers.

Novel Pharmacologic Approaches to the Prevention and Treatment of Ulcerative Colitis

Ulcerative colitis (UC) is a chronic, relapsing inflammatory disorder of the colonic mucosa followed by poor quality of healing and recurring lesions. Recent studies demonstrated that the poor healing and chronic inflammation in colon of UC could be the result of microvascular dysfunction and endothelial barrier defect, resulting in sustained tissue hypoperfusion and ischemia in the colon. Long before angiogenesis became a popular research topic, our laboratory was the first to postulate that stimulation of angiogenesis alone might be sufficient to accelerate ulcer healing in the gastrointestinal tract. Our earlier studies demonstrated that therapy with genes or peptides of angiogenic growth factors, e.g., bFGF, PDGF and VEGF significantly accelerated healing of experimental duodenal ulcers (DU), while blockade of these angiogenic factors resulted in impaired healing of DU. However, unlike the angiogenesis in DU, increasing evidences from us and others indicate that angiogenesis plays a pathogenic role in UC, e.g., VEGF induces an abnormal "pathologic" angiogenesis which interferes with UC healing. Recently, another angiogenic factor, placental growth factor (PlGF), has also been suggested to be a marker of pathologic angiogenesis and may play a critical role in pathogenesis of UC. Although inhibition of pathologic angiogenesis by, e.g., anti-VEGF or -PlGF, was demonstrated to be a new approach to attenuate UC development, additional data of our and others showed that stimulating angiogenesis by administration of PDGF or bFGF significantly accelerated healing of UC. Also, activation of Rac1, a small GTPase, markedly improved VEGF-induced neovessel architecture defect and reduced vascular permeability (VP) in an angiogenic model. Thus, it seems that both angiogenic and anti-angiogenic therapies may be used in various stages of UC. More recently, we demonstrated that increased VP in colonic mucosa is an early and essential element in the initiation and progression of UC. The increased VP is initiated by early release of histamine and maintained/aggravated by VEGF, leading to perivascular edema, vascular stasis, hypoxia, inflammatory cell infiltration, and colonic erosions/ulcers. Inhibition of increased VP prevents or reduces development and progression of UC. In this review, we discuss novel pharmacologic approaches to prevent UC, differential actions of angiogenic growth factors in UC pathogenesis and blocking the early increase in VP in UC development, these new findings may provide new insights into the regulation of angiogenesis in UC and may lead to development of VP-related drugs to accelerate the healing of UC.

Novel Pharmacologic Approaches to the Prevention and Treatment of Ulcerative Colitis

Ulcerative colitis (UC) is a chronic, relapsing inflammatory disorder of the colonic mucosa followed by poor quality of healing and recurring lesions. Recent studies demonstrated that the poor healing and chronic inflammation in colon of UC could be the result of microvascular dysfunction and endothelial barrier defect, resulting in sustained tissue hypoperfusion and ischemia in the colon. Long before angiogenesis became a popular research topic, our laboratory was the first to postulate that stimulation of angiogenesis alone might be sufficient to accelerate ulcer healing in the gastrointestinal tract. Our earlier studies demonstrated that therapy with genes or peptides of angiogenic growth factors, e.g., bFGF, PDGF and VEGF significantly accelerated healing of experimental duodenal ulcers (DU), while blockade of these angiogenic factors resulted in impaired healing of DU. However, unlike the angiogenesis in DU, increasing evidences from us and others indicate that angiogenesis plays a pathogenic role in UC, e.g., VEGF induces an abnormal “pathologic” angiogenesis which interferes with UC healing. Recently, another angiogenic factor, placental growth factor (PlGF), has also been suggested to be a marker of pathologic angiogenesis and may play a critical role in pathogenesis of UC. Although inhibition of pathologic angiogenesis by, e.g., anti-VEGF or –PlGF, was demonstrated to be a new approach to attenuate UC development, additional data of our and others showed that stimulating angiogenesis by administration of PDGF or bFGF significantly accelerated healing of UC. Also, activation of Rac1, a small GTPase, markedly improved VEGF-induced neovessel architecture defect and reduced vascular permeability (VP) in an angiogenic model. Thus, it seems that both angiogenic and anti-angiogenic therapies may be used in various stages of UC. More recently, we demonstrated that increased VP in colonic mucosa is an early and essential element in the initiation and progression of UC. The increased VP is initiated by early release of histamine and maintained/aggravated by VEGF, leading to perivascular edema, vascular stasis, hypoxia, inflammatory cell infiltration, and colonic erosions/ulcers. Inhibition of increased VP prevents or reduces development and progression of UC. In this review, we discuss novel pharmacologic approaches to prevent UC, differential actions of angiogenic growth factors in UC pathogenesis and blocking the early increase in VP in UC development, these new findings may provide new insights into the regulation of angiogenesis in UC and may lead to development of VP-related drugs to accelerate the healing of UC. Keywords: Angiogenesis, angiogenic growth factors, bFGF, PDGF, VEGF, PlGF, Rac-1, pathologic angiogenesis, histamine, Src kinase, VE-cadherin, vascular permeability, ulcer healing, ulcerative colitis

Su1735 Effects of Melatonin and Tryptophan on Healing of Gastric and Duodenal Ulcers With Helicobacter pylori Infection in Humans

Melatonin (MT) and its precursor L-tryptophan (TRP) are implicated in the protection of gastric mucosa against aspirininduced lesions and in the acceleration of healing of idiopathic gastro-duodenal ulcers, but no information is available whether these agents are also effective in healing of gastroduodenal ulcers accompanied by Helicobacter pylori (H. pylori) infection. In this study three groups A, B and C, each including 7 H. pylori-positive patients with gastric ulcers and 7 H. pylori-positive patients with duodenal ulcers, aging 28-50 years, were randomly assigned for the treatment with omeprazole 20 mg twice daily combined with placebo (group A), MT administered in a dose of 5 mg twice daily (group B) or TRP applied in a dose of 250 mg twice daily (group C). All patients underwent routine endoscopy at day 0 during which the gastric mucosa was evaluated and gastric biopsies were taken for the presence of H. pylori and histopathological evaluation. The rate of ulcer healing was determined by gastroduodenoscopy at day 0, 7, 14 and 21 after the initiation of the therapy. Plasma MT, gastrin, ghrelin and leptin were measured by specific RIA. At day 21, all ulcers were healed in patients of groups B and C but only 3 out of 7 in group A of gastric ulcers and 3 out of 7 in duodenal ulcers. Initial plasma MT showed similar low levels in all three groups but it increased several folds above initial values in ulcer patients at day 7, 14 and 21. Plasma gastrin and leptin levels showed a significant rise over initial values in patients treated with omeprazole and placebo, MT or TRP while plasma ghrelin levels were not significantly affected by these treatments. We conclude that MT or TRP added to omeprazole treatment, significantly accelerates healing rate of H. pylori infected chronic gastroduodenal ulcers over that obtained with omeprazole alone and this likely depends upon the significant rise in plasma MT and possibly also in leptin levels, both hormones involved in the mechanism of gastroprotection and ulcer healing.

Mechanistic and pharmacologic role of placental growth factor in experimental ulcerative colitis in rats

We demonstrated that vascular endothelial growth factor accelerated the healing of experimental duodenal ulcer but aggravated ulcerative colitis (UC), probably because of the differences in ulcer healing. Since placental growth factor (PlGF) enhances abnormal (“pathologic”) angiogenesis, we measured its expression and role in experimental UC. Groups of rats were given iodoacetamide (IA) to cause UC and they were euthanized at 0.5, 2, 6, 12, 24, 48, and 84 hr after IA. Additional groups of rats were given neutralizing anti‐PlGF antibody, IgG (50ug/rat, i.m.) or saline on 2nd and 5th days and euthanized 7th day after IA when the extent of UC was evaluated macroscopically and by microscopy. Mucosal scrapings of distal colon were obtained at autopsy. Expression of PlGF was measured by Western blotting.ResultsExpression of PlGF protein was enhanced at 2 hr, with further increases (+50–80%) until 7 days. Inhibition of PlGF significantly reduced the levels of colonic PlGF, i.e., 2‐ to 3‐folds compared to control. Colonic lesions were also decreased from 323.2±44.1 (controls) to 209.8±31.2 mm2 (anti‐PlGF) (p &lt; 0.05).Conclusions1) The sustained increase in expression of PlGF in UC may indicate an abnormal (pathologic) angiogenesis occurring in the development of UC. 2) Inhibition of PlGF attenuated experimental UC development. 3) Thus, PlGF may play a pathogenic &amp; therapeutic role in the development &amp; healing of UC.(This work was supported by the Veterans Health Administration Merit Review Grants to Zs. Sandor and S. Szabo)

Ghrelin accelerates the healing of cysteamine-induced duodenal ulcers in rats

SummaryBackgroundPrevious studies have shown that administration of ghrelin exhibits protective and therapeutic effects in the gut. The aim of the present investigation was to examine the influence of ghrelin administration on the course of cysteamine-induced duodenal ulcers, as well as effects on mucosal production of oxygen free radicals and duodenal antioxidant defense.Material/MethodsDuodenal ulcers were induced in male Wistar rats by cysteamine administered intragastrically at the dose of 200 mg/kg in 1 ml of saline, 3 times at 4-h intervals. Starting 24 h after the first dose of cysteamine, rats were treated intraperitoneally twice a day with saline or ghrelin given at the dose of 4, 8 or 16 nmol/kg/dose. Seven days after administration of the first dose of cysteamine, the study was terminated.ResultsInduction of ulcers by cysteamine was accompanied by a reduction in duodenal blood flow, mucosal DNA synthesis and mucosal activity of superoxide dismutase (SOD); whereas mucosal concentration of interleukin-1β and malonyldialdehyde (MDA – an index of lipid peroxidation) were increased. Treatment with ghrelin increased healing rate of duodenal ulcers and enhanced duodenal blood flow, mucosal DNA synthesis and mucosal activity of SOD, and reduced mucosal concentration of interleukin-1β and MDA.ConclusionsTreatment with ghrelin increases the healing rate of duodenal ulcers and this effect is related, at least in part, to improvement of duodenal mucosal blood flow, mucosal cell proliferation and antioxidant defense, as well as being related to reduction in mucosal oxidative stress and inflammatory response.

Peter John Banfield

The release of immunoreactive prostaglandin E2 (PGE2) and leukotriene C4 (LTC4) from antral and duodenal mucosal biopsy specimens taken from 20 patients with duodenal ulcer disease was measured by radioimmunoassay...