{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T06:36:06Z","timestamp":1776753366304,"version":"3.51.2"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:00:00Z","timestamp":1776729600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Gastroesophageal reflux (GER) is a common physiological phenomenon in infants, typically self-limited, but often a source of parental concern. When non-pharmacological measures fail to improve symptoms, thickened formulas are commonly used. Zinc-L-carnosine (Polaprezinc) is a mucosal protectant with anti-inflammatory and antioxidant properties. It is widely used in gastrointestinal disorders in adults but has not yet been extensively studied in infants. We aim to evaluate the clinical effectiveness and cost impact of a Zinc-L-carnosine-based supplement (Hepilor liquido\u00ae) compared to thickened formula in infants with persistent regurgitation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This was a two-center, prospective, single-blind, randomized, non-inferiority study conducted in two Italian pediatric hospitals. Infants aged 4 weeks to 7 months with persistent regurgitation despite appropriate nutritional and behavioral management were randomized to receive either Hepilor liquido\u00ae or thickened formula for 8 weeks. The primary outcome was symptom improvement based on the I-GERQ-R (Infant Gastro-Esophageal Reflux Questionnaire-Revised) score. Secondary outcomes included a reduction in regurgitation frequency and treatment cost analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Sixty infants aged 4 weeks to 7 months were randomized to receive either Hepilor liquido\u00ae (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200930, 50%) or thickened formula (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200930, 50%) for 8 weeks. Both groups showed significant improvement in I-GERQ-R scores at 8 weeks. Although no statistically significant difference was observed in overall symptomatic remission, the Hepilor liquido\u00ae group demonstrated a greater reduction in regurgitation frequency. Notably, the average treatment cost was significantly lower in the Hepilor\u00ae group compared to the thickened formula. No severe adverse events were recorded in both groups.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Zinc-L-carnosine is a safe and effective alternative to thickened formula in treating persistent infant regurgitation, after the failure of non-pharmacological measures. Its lower cost and promising clinical effect support further investigation in larger pediatric cohorts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical Trial Registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/clinicaltrials.gov\/study\/NCT06678997<\/jats:ext-link>\n                      , identifier: NCT06678997.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fped.2026.1754324","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T05:36:00Z","timestamp":1776749760000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Zinc-L-Carnosine (Polaprezinc) in managing infant regurgitation: a two-center randomized controlled trial"],"prefix":"10.3389","volume":"14","author":[{"given":"Marisa","family":"Piccirillo","sequence":"first","affiliation":[{"name":"Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sapienza University of Rome","place":["Rome, Italy"]},{"name":"Pediatric Unit, Sant'Andrea University Hospital","place":["Rome, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maurizio","family":"Mennini","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sapienza University of Rome","place":["Rome, Italy"]},{"name":"Pediatric Unit, Sant'Andrea University Hospital","place":["Rome, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enrico","family":"Felici","sequence":"additional","affiliation":[{"name":"Pediatric Unit, Children's Hospital, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo","place":["Alessandria, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela","family":"Mauro","sequence":"additional","affiliation":[{"name":"Rheumatology Unit, Department of Childhood and Developmental Medicine, ASST Fatebenefratelli-Sacco","place":["Milano, MI, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luca","family":"Bernardo","sequence":"additional","affiliation":[{"name":"Rheumatology Unit, Department of Childhood and Developmental Medicine, ASST Fatebenefratelli-Sacco","place":["Milano, MI, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Elisabetta","family":"Baldassarre","sequence":"additional","affiliation":[{"name":"Department of Interdisciplinary Medicine, Neonatology and Neonatal Intensive Care Unit, \u201cAldo Moro\u201d University of Bari","place":["Bari, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erika","family":"Renzi","sequence":"additional","affiliation":[{"name":"Department of Public Health and Infectious Diseases, Sapienza University of Rome","place":["Rome, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Corrado","family":"De Vito","sequence":"additional","affiliation":[{"name":"Department of Public Health and Infectious Diseases, Sapienza University of Rome","place":["Rome, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Furio","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sapienza University of Rome","place":["Rome, Italy"]},{"name":"Pediatric Unit, Sant'Andrea University Hospital","place":["Rome, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Graziani","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sapienza University of Rome","place":["Rome, Italy"]},{"name":"Pediatric Unit, Sant'Andrea University Hospital","place":["Rome, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanna","family":"Quatrale","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sapienza University of Rome","place":["Rome, Italy"]},{"name":"Pediatric Unit, Sant'Andrea University Hospital","place":["Rome, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandro","family":"Ferretti","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sapienza University of Rome","place":["Rome, Italy"]},{"name":"Pediatric Unit, Sant'Andrea University Hospital","place":["Rome, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni","family":"Di Nardo","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sapienza University of Rome","place":["Rome, Italy"]},{"name":"Pediatric Unit, Sant'Andrea University Hospital","place":["Rome, Italy"]},{"name":"Pediatric Gastroenterology and Endoscopy Unit, Department of Pediatric Specialties, Santobono Pausilipon Children's Hospital","place":["Naples, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1093\/pch\/pxac068","article-title":"Medical management of gastro-esophageal reflux in healthy infants","volume":"27","author":"Chevalier","year":"2022","journal-title":"Paediatr Child Health"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1542\/peds.109.6.1061","article-title":"Natural history and familial relationships of infant spilling to 9 years of age","volume":"109","author":"Martin","year":"2002","journal-title":"Pediatrics"},{"key":"B3","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1097\/mpg.0000000000002280","article-title":"Prevalence of gastroesophageal reflux disease symptoms in infants and children: a systematic review","volume":"68","author":"Singendonk","year":"2019","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"B4","doi-asserted-by":"publisher","first-page":"84","DOI":"10.4253\/wjge.v15.i3.84","article-title":"Gastroesophageal reflux disease in children: what's New right now?","volume":"15","author":"Sintusek","year":"2023","journal-title":"World J Gastrointest Endosc"},{"key":"B5","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1097\/mpg.0000000000001889","article-title":"Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition","volume":"66","author":"Rosen","year":"2018","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1456","DOI":"10.1053\/j.gastro.2016.02.015","article-title":"Functional disorders: children and adolescents","volume":"150","author":"Hyams","year":"2016","journal-title":"Gastroenterology"},{"key":"B7","doi-asserted-by":"crossref","first-page":"e015594","DOI":"10.1136\/bmjopen-2016-015594","article-title":"The costs of functional gastrointestinal disorders and related signs and symptoms in infants: a systematic literature review and cost calculation for England","volume":"7","author":"Mahon","year":"2017","journal-title":"BMJ Open"},{"key":"B8","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1007\/s40272-018-0314-0","article-title":"The effect of alginate in gastroesophageal reflux in infants","volume":"20","author":"Salvatore","year":"2018","journal-title":"Paediatr Drugs"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1445","DOI":"10.3892\/etm.2021.10880","article-title":"Recent advances on polaprezinc for medical use (review)","volume":"22","author":"Li","year":"2021","journal-title":"Exp Ther Med"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1984","DOI":"10.1002\/ijc.25200","article-title":"Polaprezinc prevents oral mucositis associated with radiochemotherapy in patients with head and neck cancer","volume":"127","author":"Watanabe","year":"2010","journal-title":"Int J Cancer"},{"key":"B11","first-page":"7271","article-title":"Polaprezinc prevents oral mucositis in patients treated with high-dose chemotherapy followed by hematopoietic stem cell transplantation","volume":"34","author":"Hayashi","year":"2014","journal-title":"Anticancer Res"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1387","DOI":"10.1002\/hed.24446","article-title":"Effect of polaprezinc on oral mucositis, irradiation period, and time to discharge in patients with head and neck cancer","volume":"38","author":"Suzuki","year":"2016","journal-title":"Head Neck"},{"key":"B13","doi-asserted-by":"publisher","first-page":"4691","DOI":"10.21873\/anticanres.12775","article-title":"Prophylactic effect of polaprezinc, a zinc-L-carnosine, against chemotherapy-induced oral mucositis in pediatric patients undergoing autologous stem cell transplantation","volume":"38","author":"Funato","year":"2018","journal-title":"Anticancer Res"},{"key":"B14","doi-asserted-by":"publisher","first-page":"4126","DOI":"10.3390\/nu14194126","article-title":"Efficacy and safety of polaprezinc-based therapy versus the standard triple therapy for Helicobacter pylori eradication: a systematic review and meta-analysis of randomized controlled trials","volume":"14","author":"Mahmoud","year":"2022","journal-title":"Nutrients"},{"key":"B15","doi-asserted-by":"publisher","first-page":"7050","DOI":"10.3390\/jcm11237050","article-title":"The effect of quadruple therapy with polaprezinc or bismuth on gut Microbiota after Helicobacter pylori eradication: a randomized controlled trial","volume":"11","author":"Wu","year":"2022","journal-title":"J Clin Med"},{"key":"B16","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1186\/1471-230x-13-108","article-title":"Effectiveness of polaprezinc for low-dose aspirin-induced small-bowel mucosal injuries as evaluated by capsule endoscopy: a pilot randomized controlled study","volume":"13","author":"Watari","year":"2013","journal-title":"BMC Gastroenterol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"g7703","DOI":"10.1136\/bmj.g7703","article-title":"Gastro-oesophageal reflux disease in children: NICE guidance","volume":"350","author":"Davies","year":"2015","journal-title":"BMJ (Clinical Research ed)"},{"key":"B18","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1016\/j.cgh.2006.02.016","article-title":"The infant gastroesophageal reflux questionnaire revised: development and validation as an evaluative instrument","volume":"4","author":"Kleinman","year":"2006","journal-title":"Clin Gastroenterol Hepatol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1136\/adc.2008.156497","article-title":"A preliminary report on the efficacy of the multicare AR-bed in 3-week-3-month-old infants on regurgitation, associated symptoms and acid reflux","volume":"95","author":"Vandenplas","year":"2010","journal-title":"Arch Dis Child"},{"key":"B20","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1097\/MPG.0b013e31815667d7","article-title":"Clinical response to 2 dosing regimens of lansoprazole in infants with gastroesophageal reflux","volume":"46","author":"Khoshoo","year":"2008","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"B21","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.foodchem.2014.02.168","article-title":"Effect of adding different thickening agents on the viscosity properties and in vitro mineral availability of infant formula","volume":"159","author":"Gonz\u00e1lez-Berm\u00fadez","year":"2014","journal-title":"Food Chem"},{"key":"B22","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.nut.2017.10.010","article-title":"Thickened infant formula: what to know","volume":"49","author":"Salvatore","year":"2018","journal-title":"Nutrition"},{"key":"B23","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1016\/j.bbrc.2006.08.088","article-title":"Expression of HSP72 in the gastric mucosa is regulated by gastric acid in rats\u2014correlation of HSP72 expression with mucosal protection","volume":"349","author":"Wada","year":"2006","journal-title":"Biochem Biophys Res Commun"},{"key":"B24","doi-asserted-by":"publisher","first-page":"174","DOI":"10.3164\/jcbn.11-26","article-title":"Heat shock protein 70-dependent protective effect of polaprezinc on acetylsalicylic acid-induced apoptosis of rat intestinal epithelial cells","volume":"49","author":"Qin","year":"2011","journal-title":"J Clin Biochem Nutr"},{"key":"B25","doi-asserted-by":"publisher","first-page":"6178","DOI":"10.3748\/wjg.v12.i38.6178","article-title":"Polaprezinc protects human colon cells from oxidative injury induced by hydrogen peroxide: relevant to cytoprotective heat shock proteins","volume":"12","author":"Ohkawara","year":"2006","journal-title":"World J Gastroenterol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1254\/jphs.09056fp","article-title":"Polaprezinc (zinc L-carnosine) is a potent inducer of anti-oxidative stress enzyme, heme oxygenase (HO)-1 - a new mechanism of gastric mucosal protection","volume":"110","author":"Ueda","year":"2009","journal-title":"J Pharmacol Sci"},{"key":"B27","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1007\/s00535-010-0213-9","article-title":"Reactive oxygen species-quenching and anti-apoptotic effect of polaprezinc on indomethacin-induced small intestinal epithelial cell injury","volume":"45","author":"Omatsu","year":"2010","journal-title":"J Gastroenterol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"103860","DOI":"10.1016\/j.medengphy.2022.103860","article-title":"Efficacy and safety of polaprezinc in the treatment of gastric ulcer: a multicenter, randomized, double-blind, double-dummy, positive-controlled clinical trial","volume":"110","author":"Shen","year":"2022","journal-title":"Med Eng Phys"},{"key":"B29","doi-asserted-by":"publisher","first-page":"83","DOI":"10.3390\/ijerph17010083","article-title":"Magnesium alginate in gastro-esophageal reflux: a randomized multicenter cross-over study in infants","volume":"17","author":"Baldassarre","year":"2019","journal-title":"Int J Environ Res Public Health"},{"key":"B30","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1097\/mpg.0000000000000521","article-title":"Effect of magnesium alginate plus simethicone on gastroesophageal reflux in infants","volume":"60","author":"Ummarino","year":"2015","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"B31","doi-asserted-by":"publisher","first-page":"101954","DOI":"10.1016\/j.clinre.2022.101954","article-title":"The role of zinc L-carnosine in the prevention and treatment of gastrointestinal mucosal disease in humans: a review","volume":"46","author":"Efthymakis","year":"2022","journal-title":"Clin Res Hepatol Gastroenterol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1007\/bf01540402","article-title":"Effects of zinc L-carnosine on gastric mucosal and cell damage caused by ethanol in rats. Correlation with endogenous prostaglandin E2","volume":"35","author":"Arakawa","year":"1990","journal-title":"Dig Dis Sci"},{"key":"B33","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1097\/mpg.0000000000002841","article-title":"Distress in infants and young children: don't Blame acid reflux","volume":"71","author":"Salvatore","year":"2020","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"B34","doi-asserted-by":"publisher","first-page":"G571","DOI":"10.1152\/ajpgi.00454.2009","article-title":"Inflammatory mediators in gastroesophageal reflux disease: impact on esophageal motility, fibrosis, and carcinogenesis","volume":"298","author":"Rieder","year":"2010","journal-title":"Am J Phys Gastrointest Liver Physiol"}],"container-title":["Frontiers in Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2026.1754324\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T05:36:05Z","timestamp":1776749765000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2026.1754324\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,21]]},"references-count":34,"alternative-id":["10.3389\/fped.2026.1754324"],"URL":"https:\/\/doi.org\/10.3389\/fped.2026.1754324","relation":{},"ISSN":["2296-2360"],"issn-type":[{"value":"2296-2360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,21]]},"article-number":"1754324"}}