Synergistic protective effects between docosahexaenoic acid and omeprazole on the gastrointestinal tract in the indomethacin‐induced injury model

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used drugs due to their antipyretic, anti-inflammatory, and analgesic properties. However, NSAIDs can cause adverse reactions, mainly gastrointestinal damage. Omeprazole (OMP) exhibits gastroprotective activity, but its protection is limited at the intestinal level. For this reason, it is essential to utilize a combination of therapies that provide fewer adverse effects, such as the combined treatment of OMP and docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid with anti-inflammatory, analgesic, and gastroprotective activities. The objective of this study was to evaluate the pharmacological interaction between DHA and OMP in a murine model of indomethacin-induced gastrointestinal damage. The gastroprotective and enteroprotective effects of DHA (0.3-10 mg/kg, p.o.), OMP (1-30 mg/kg, p.o.), or the combination treatment of both compounds (3-56.23 mg/kg, p.o.) were evaluated in the indomethacin-induced gastrointestinal damage model (30 mg/kg, p.o.). Since DHA and OMP exhibited a protective effect in a dose-responsive fashion, the ED 30 for each individual compound was determined and a 1:1 combination of DHA and OMP was tested. Isobolographic analysis was used to determine any pharmacodynamic interactions. Since the effective experimental dose ED 30 (Zexp) of the combined treatment of DHA and OMP was lower than the theoretical additive dose (Zadd; p < .05) in both the stomach and small intestine their protective effects were considered synergistic. These results indicate that the synergistic protective effects from combined treatment of DHA and OMP could be ideal for mitigating damage generated by NSAIDs at the gastrointestinal level.

Alpha‐lipoic acid: A promising adjuvant for nonsteroidal anti‐inflammatory drugs therapy with improved efficacy and gastroprotection

“…Moreover, it is also well established that production of reactive oxygen species (ROS) and lipid peroxidation due to activation of inflammatory process are responsible for NSAID-induced gastric ulcers (Sinha et al, 2013;Suleyman et al, 2010;Wallace, 2008). In clinic, the current optimal approach to the prevention and treatment of NSAID-related gastric damage is a combined use of NSAID with gastroprotective agents such as proton pump inhibitors (PPIs) (Becker et al, 2004;Bindu et al, 2020;Sánchez-Trigueros et al, 2020;Sinha et al, 2013). Despite the wide usage and relatively high protective capability, these gastroprotective agents have a potential to be the increased risk of vitamin deficiency, bone fractures, colitis and gastric cancer especially in long term usage (Cheung & Leung, 2019;Kinoshita et al, 2018).…”

The influence of different proton pump inhibitors and potassium‐competitive acid blockers on indomethacin‐induced small intestinal injury

“…Currently, previous publications suggest that the influence of GAIs on NSAID-induced small intestinal injury is controversial. For OPZ, Sanchez-Trigueros et al 31 reported that the OPZ-treated group exhibited enteroprotective capacity. Another study 32 showed that OPZ failed to protect the small intestine from IND-induced injury in animal experiments.…”

“…Different GAIs were administrated to the intervention groups intragastrically for 5 days, including OPZ (10 mg/kg), IPZ (5 mg/kg), RPZ (10 mg/kg), and VPZ (10 mg/kg), according to previous studies. 11 On the last day, 1 h after the different GAIs were applied, the intervention groups received IND by oral gavage again. During the study, the weights of the mice were recorded every day, and the small intestinal content of the mice was collected at the end of the experiment.…”

Hybrid Nanobeads for Oral Indomethacin Delivery

“…That is the case of INDO, a NSAID largely prescribed for the management of chronic pain and inflammatory conditions. Side effects are even more accentuated in prolonged therapies, decreasing the patient compliance [ 2 ].…”

“…However, severe side effects in the gastrointestinal system (e.g., nausea, indigestion, vomit, diarrhea and abdominal ache) are associated to the oral administration, due to the first-pass metabolism. These effects are exacerbated in chronic diseases, in which an extended treatment is required [2]. Considering the huge number of INDO prescriptions (>1 million/per year, only in the USA), new approaches to minimize INDO systemic toxicity and improve its efficacy are required [3].…”