Esophagoprotective Activity of Angiotensin-(1-7) in Rat Model of Acute Reflux Esophagitis. Role of Sensory Neuropetides and Proinflammatory Cytokines Michael W. Pawlik, Slawomir Kwiecien, Robert Pajdo, Agata Ptak-Belowska, Danuta Drozdowicz, Wieslaw W. Pawlik, Stanislaw Konturek, Tomasz Brzozowski
Nighttime GERD and Esophageal Erosions are Independent Factors to Explain Acute Improvement of Symptoms Severity Measured With ReQuest® During Magnesium Pantoprazole Treatment. a Report From the Mexican GERD Working Group Miguel Morales-Arámbula, oscar teramoto, Julio-Cesar Soto-Perez, Gualberto Mateos, Arturo Jimenez, Jazmin Chiu-Ugalde, Juan C. Lopez-Alvarenga, Jose-Antonio Vargas
The pathogenesis of reflux esophagitis results from an imbalance between aggressive factors damaging the esophagus and the natural antireflux barriers. The local renin-angiotensin system (RAS) exists in esophageal mucosa, however, its contribution to the mechanism of esophageal integrity has not been clarified. Angiotensin-(1-7) (Ang-(1-7)) which is an important component of the RAS, was recently implicated in gastroprotection but its effect on damage induced by reflux esophagitis (RE) has not been explored. We evaluated the possible protective effect of Ang-(1-7) against mucosal lesions induced by the acute RE induced in anesthetized rats by ligating of the pylorus and the limiting ridge (transitional region between the forestomach and the corpus of stomach). Rats were pretreated 30 min before induction of RE either with 1) vehicle (saline), 2) Ang-(1-7) (5 - 75 μg/kg i.p.), 3) Ang-(1-7) (50 μg/ kg i.p.) without and with A 779 (2.5 mg/kg i.p.), a selective antagonist of Ang-(1-7) Mas receptor, 4) Ang 1-7 (50 μg/kg i.p.) without and with capsaicin (125 mg/kg s.c.) to induce functional ablation of sensory nerves, and 5) antisecretory treatment with PPI inhibitor, pantoprazole (10 mg/kg i.g.). Four hrs after induction of esophagitis, the damage was graded with mucosal lesion index (LI) from 0-6, the esophageal blood flow (EBF) was determined by H2-gas clearance technique and the RT-PCR expression and plasma levels of proinflammatory cytokines IL-1β and TNF-α was determined by ELISA. The esophageal LI and wet weight in esophagitis were significantly higher and the EBF was decreased by 35% as compared with the intact mucosa Pretreatment with Ang-(1-7) which in intact rats increased the EBF by 25% without any damage and alteration in plasma IL-1β and TNF-α levels, almost completely prevented, similarly as pantoprazole, the esophageal mucosal injury and significantly increased EBF by about 18% as compared to that in vehicle-controls with RE. The esophagoprotective effects and the rise in EBF induced by Ang-(1-7) were completely abolished by A779. Capsaicin denervation which by itself failed to affect the esophageal lesions, also reduced the esophagoprotective and hyperemic effects of Ang-(1-7) and both protection and hyperemia were restored by co-treatment with CGRP (10 μg/kg s.c.). Ang(1-7) significantly decreased the RE-induced increase in mRNA expression and plasma IL1β and TNF-α levels and these effects were also abolished by pretreatment with A779 and capsaicin-sensory denervation. We conclude that Ang-(1-7), a potent vasodilatatory member of angiotensin family peptides, exhibits esophagoprotection against the esophageal damage induced by reflux esophagitis via mechanism involving activation of Mas receptor, the stimulation of sensory nerves releasing of vasodilatatory CGRP and the suppression of expression and release of IL-1β and TNF-α.
Background: We previously published that nighttime GERD (NT GERD) is associated with extraesophageal symptoms, but we did not analyzed if the esophageal erosions severity is related to nighttime symptoms or if both, erosions and symptoms can improve with pantoprazole magnesium (PMg) 40 mg during the very first week of treatment. Aim: To evaluate the influence of esophageal lesions and NT GERD over the improvement of GERD symptoms severity, during the first week of PMg treatment. Methods: 383 patients with NT GERD and 554 patients with diurnal symptoms (controls) were included. NT GERD was defined as awakening at night by heartburn or any other symptom associated with GERD. All patients filled a ReQuest® 10 cm-visual analog scale questionnaire, every day during the first week of treatment with PMg. They also underwent endoscopy and esophageal erosions were classified by Los Angeles (LA) classification. MANOVA for repeated measurements was performed, including fixed factors (NT-GERD and esophageal lesions by LA) and covariates (BMI and age). Results: A mean improvement of 51% in ReQuest® overall symptoms score was observed after a week of treatment. Patients with NT-GERD showed an effect size 15% higher than controls (ReQuest® overall score 22.4±1 vs 24.3±0.96, p< 0.043). The prevalence of esophageal lesions was as follows: erosions grade A, 47.5%; B 27.5%; C D 3.4% and 21.6% presented with no esophageal lesions. There was no association between LA grades and presence of nighttime GERD. Nevertheless, improvement in symptom severity can be predicted by esophageal lesions, i.e. patients with lesions grades C D had slower amelioration than patients without lesions and grades A-B (altogether); the effect size of this difference was 15%. Conclusions: Improvement of symptoms during the first week of PMg treatment was independently predicted by esophageal erosions and nighttime GERD. Nighttime symptoms are associated with reflux at recumbent position, however, no association was found with LA grades. Patients with NT GERD have the better response to PMg treatment. Independently of LA grade and symptom severity, all patients improved with 7 days PMg treatment. References: Lopez L, et al. Gastroenterology 2008; 134(Suppl 1): A-176. Morales-Arambula M, et al. Gastroenterology 2009; 13 (Suppl 1): A-428. Mo1090 Long-Term Treatment With High Dose, but Not Regular Dose of PPI is Necessary for Management of PPI-Resistant Erosive GERD Yoshikazu Kinoshita, Kazuma Fujimoto, Tetsuo Arakawa
Background and Aims In our previous study, treatment with rabeprazole twice daily of total 20 mg for 8 weeks is shown to be effective for erosive gastroesophageal reflux disease (GERD) refractory to regular dose PPI (PPI-resistant erosive GERD) (Twice Study, Am J Gastro 2011). However, it is unknown how much dose the maintenance treatment should be done. This study was done to elucidate an adequate maintenance therapy for PPI-resistant erosive GERD. Subjects and Methods Patients who enrolled in Twice study were examined retrospectively the situation after the study. Among them, the 65 patients who were given a PPI for at least 1 year and underwent esophagogastroduodenoscopy (EGD) before and 1 year after maintenance therapy were allocated to this follow-up study. At the initial EGD as the endpoint of Twice study, esophageal mucosal break disappeared in 49 patients (responder) and remained in 16 patients (nonresponder) after 8-week treatment with doubledose rabeprazole. The 43 patients were given regular dose of PPI and 22 were given high dose as maintenance therapy. Proportion of regular and high dose regimen was almost the same between responder (31/18) and nonresponder (12/4). Results The mucosal break was found in 34 patients out of 65 (52.3%) after 1-year maintenance therapy with PPI. Among them, incidence of the mucosal break was higher in nonresponder (81.3%, 13/16) than responder (42.9%, 21/49) (P = 0.0097). The incidence was smaller in patients who were given high dose PPI than those given regular dose (36.4% vs. 60.5%, P=0.057). Regular dose PPI maintenance therapy allowed existence of mucosal break in nonresponder compared to responder (91.7% vs. 48.4%, P = 0.013), while high dose reduced incidence of mucosal break in nonresponder as well as responder (50.0% vs. 33.3%, P = 0.5475). Multivariate analysis identified only nonresponder to initial treatment with double-dose rabeprazole as a significant risk factor for the mucosal break after 1-year maintenance therapy (odds 5.750: 1.032-32.024, P=0.046). A tendency was found for age ≥ 65 years (odds 0.291, P=0.067), and regular dose PPI (odds 4.545, P=0.053). Conclusions Incidence of mucosal break at esophagus is high in patients with erosive GERD refractory to regular dose of PPI even after 1-year maintenance therapy with PPI. High dose of PPI may be needed to reduce the mucosal break during maintenance therapy for such intractable patients.
The Effect of Anti-Reflux Treatment on Acid Reflux and Conscious Awakenings From Sleep in Patients With Gastroesophageal Reflux Disease Lokesh K. Jha, Tiberiu Hershcovici, Rakshith Gadam, Ofer Z. Fass, Marcia R. Webster, Ronnie Fass Background: More than 50% of the GERD patients report having heartburn that awakens them from sleep during the night. Sleep induction and awakenings from sleep are vulnerable periods for acid reflux to occur. Thus far, there are no studies that assessed the effect of anti-reflux treatment on sleep induction (recumbent awake) and conscious awakenings. Aim: To assess the effect of esomeprazole 40 mg once daily for 7 days on gastroesophageal reflux during the recumbent awake period and conscious awakenings. Method: Patients with heartburn and/or regurgitation at least 3 times a week were included in this study. Patients were evaluated by demographic, Epworth Sleepiness Scale, Berlin and GERD symptom checklist questionnaires. Subjects underwent an upper endoscopy followed by esophageal pH testing concomitantly with actigraphy. Patients with normal endoscopy and pH monitoring, as well as those with sleep apnea, were excluded. Novel software simultaneously integrated raw actigraphy and pH data matched by time to determine the relationship between recumbent awake period, as well as conscious awakenings from sleep and acid reflux events. Subsequently, subjects were given esomeprazole 40 mg once daily (am) for 7 days. On day 7, subjects underwent a second pH testing concomitantly with actigraphy. Result: 20 GERD patients (mean age of 48.95 + 18.7, age range 20-81 years, F/M 11/9) were enrolled. The mean number of acid reflux events during the recumbent-awake period was significantly lower after treatment with esomeprazole 40 mg once daily, as compared to baseline (5.0 + 6.1 vs 1.56 + 4.7, P=0.005). Similarly, the mean number of conscious awakenings with acid reflux event was significantly lower after treatment with esomeprazole as compared to baseline (2 + 2.1 min vs 1 + 1.5 min, P=0.02). Mean duration of an acid reflux event in both the conscious awakenings and recumbent awake periods were significantly shorter after treatment as compared to baseline (8.9 + 13.0min vs 1.1 + 2.3min, P=0.01, and 0.34 + 0.5 min vs 0.1 + 0.4min, P=0.006, respectively). Reported GERD-related symptoms were also significantly reduced during recumbent-awake and conscious awakening periods after treatment as compared to baseline. However, there was no statistically significant difference in the mean duration of the recumbent awake period, as well as the mean number and duration of conscious awakenings from sleep during treatment as compared to baseline. Conclusion: Treatment with esomeprazole 40 mg significantly reduced esophageal acid exposure during both conscious awakenings and the recumbent awake period. However, esomeprazole had no effect on duration and number of conscious awakenings from sleep during the night.