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The main indications for PPIs use include the treatment of gastroesophageal reflux disease, peptic ulcer disease, functional dyspepsia, Barrett esophagus, eosinophilic esophagitis, and hypersecretory diseases such as gastrinoma and Zollinger-Ellison syndrome. Their contribution to eradication therapy for Helicobacter pylori is also important. However, the long-term use of PPIs has been associated with various adverse drug reactions and complications, such as the development of fundic gland polyposis, atrophic gastritis, gastric cancer, vitamin B12 deficiency, hypomagnesemia, osteoporosis\/ fractures, changes in the microbiome, increased risk of infection, necrotizing enterocolitis, renal injury, and other conditions. Thus, administration of PPIs should be based on scientific evidence of their efficacy and safety. Their long-term administration should be cautious, and continuation reassessed frequently. Caution should be exercised when administering PPIs to neonates and infants. 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