{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T05:29:40Z","timestamp":1786685380496,"version":"build-2736575974"},"reference-count":45,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T00:00:00Z","timestamp":1783900800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T00:00:00Z","timestamp":1783900800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacology Res &amp;amp; Perspec"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Opioids, most intravenous anesthetics and various illicit substances can cause fatal respiratory depression by depressing central respiratory networks. ENA\u2010001, a ventilatory modulator targeting the carotid bodies, has emerged as a potential countermeasure without impairing analgesia or hypnosis. We conducted a literature review to evaluate the efficacy and safety of ENA\u2010001. This scoping review summarizes the current evidence base for ENA\u2010001 from in\u00a0vitro, animal experiments, and human volunteer studies. A comprehensive search was conducted across several electronic databases to identify all available literature describing its effects as a respiratory stimulant and as a reversal agent of drug\u2010induced respiratory depression. We identified eight relevant publications, four describing data in humans and four using animal models (mice, rats, and non\u2010human primates). ENA\u2010001 increased ventilation and attenuated respiratory depression induced by morphine and the combination of xylazine and fentanyl. The primary site of action was localized to the carotid bodies, specifically the pore\u2010forming \u03b1\u2010subunit of the KCa1.1 (BK) channel. In humans, ENA\u2010001 increased minute ventilation and reduced end\u2010tidal carbon dioxide under poikilocapnic conditions. In experimental human models of alfentanil\u2010 and propofol\u2010induced respiratory depression, ENA\u2010001 significantly improved isohypercapnic minute ventilation and fully restored the hypoxic ventilatory response, respectively, without impairing sedation or analgesia. Across all studies, the safety profile was favorable, with no serious adverse events reported. In conclusion, ENA\u2010001 is a first\u2010in\u2010class, peripherally acting respiratory stimulant that effectively reverses drug\u2010induced respiratory depression. These findings support its continued clinical development for opioid\u2010 and anesthetic\u2010induced respiratory compromise.<\/jats:p>","DOI":"10.1002\/prp2.70297","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T06:57:42Z","timestamp":1784012262000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting the Carotid Body Function With Big\u2010K\n                    <sup>+<\/sup>\n                    \u2010Channel Blocker\n                    <scp>ENA<\/scp>\n                    \u2010001 in Opioid\u2010Induced Respiratory Depression: A Scoping Review"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3296-3373","authenticated-orcid":false,"given":"Jimmy J.","family":"Arevalo","sequence":"first","affiliation":[{"name":"Department of Anesthesiology Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0289-6432","authenticated-orcid":false,"given":"Monique","family":"van Velzen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine Erasmus University Medical Center  Rotterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone C.","family":"Jansen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8767-1824","authenticated-orcid":false,"given":"Maarten","family":"van Lemmen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4403-3815","authenticated-orcid":false,"given":"Elise","family":"Sarton","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Amsterdam University Medical Center  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3161-3945","authenticated-orcid":false,"given":"Albert","family":"Dahan","sequence":"additional","affiliation":[{"name":"Outcomes Research Consortium  Houston Texas USA"},{"name":"MediD Consultancy Group  Amsterdam the Netherlands"},{"name":"Centre for Human Drug Research  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Olofsen","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph F.","family":"Cotten","sequence":"additional","affiliation":[{"name":"Department of Anesthesia, Critical Care, and Pain Medicine Massachusetts General Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2822-7509","authenticated-orcid":false,"given":"Marieke","family":"Niesters","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine Erasmus University Medical Center  Rotterdam the Netherlands"},{"name":"Centre for Human Drug Research  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1422-3830","authenticated-orcid":false,"given":"Rutger M.","family":"van der Schrier","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,13]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chest.2019.05.015"},{"key":"e_1_2_10_3_1","first-page":"987","article-title":"The Global Burden of Disease Attributable to Alcohol and Drug Use in 195 Countries and Territories, 1990\u20102016: A Systematic Analysis for the Global Burden of Disease Study 2016","volume":"5","author":"GBD Collaborators","year":"2016","journal-title":"Lancet Psychiatry"},{"key":"e_1_2_10_4_1","volume-title":"Provisional Drug Overdose Death Counts","author":"Ahmad F. B. C. J.","year":"2025"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpubh.2024.1346109"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12871-021-01307-8"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00017.2021"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bjae.2023.12.007"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/neuro.05.023.2009"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.07.043"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnsyn.2022.902319"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0889-8537(05)70008-0"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00012.2009"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1213\/00000539-198101000-00015"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/aes494"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2018.07.018"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1990.sp018223"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/function\/zqaf020"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1152\/function.078.2025"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0000000000005931"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13181-019-00750-x"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0000000000004096"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1213\/ANE.0b013e318284469d"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(80)90155-7"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0000000000000368"},{"issue":"4","key":"e_1_2_10_26_1","first-page":"421","article-title":"Competitive Study of the Effects of Naloxone and of Almitrine on Fentanyl Analgesia in the Anesthetized Dog: Effects on the Muzzle Opening Reflex and Blood Gases","volume":"21","author":"Dauthier C.","year":"1980","journal-title":"Annales Fran\u00e7aises D'anesth\u00e9sie et de R\u00e9animation"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/54.6.617"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1987.63.1.66"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0000000000000844"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1527-3458.2006.00236.x"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.601"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0505270102"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-18440-1_41"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.46658\/JBIMES-20-12"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.7326\/M18-0850"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2288-14-43"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.l4898"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom10020188"},{"key":"e_1_2_10_39_1","article-title":"ENA\u2010001 Reverses Xylazine\/Fentanyl Combination\u2010Induced Respiratory Depression in Rats: A Qualitative Pilot Study","volume":"16","author":"Miller T. L.","year":"2024","journal-title":"Cureus"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/aeu182"},{"key":"e_1_2_10_41_1","article-title":"A Single Ascending\u2010Dose Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Respiratory Stimulant ENA\u2010001","volume":"16","author":"Pergolizzi J.","year":"2024","journal-title":"Cureus"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.SA.0000460956.97061.e0"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0000000000004915"},{"issue":"5","key":"e_1_2_10_44_1","article-title":"Combination of the BK\u2010Channel Antagonist ENA\u2010001 and Naloxone Is More Effective Than Either Agent Alone in Reversing Fentanyl\u2010Induced Respiratory Suppression in Rats","volume":"18","author":"Phay M.","year":"2026","journal-title":"Cureus"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.99"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-59932-7"}],"container-title":["Pharmacology Research &amp; Perspectives"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/prp2.70297","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/prp2.70297","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/prp2.70297","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T05:19:15Z","timestamp":1786684755000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1002\/prp2.70297"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,13]]},"references-count":45,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1002\/prp2.70297"],"URL":"https:\/\/doi.org\/10.1002\/prp2.70297","archive":["Portico"],"relation":{},"ISSN":["2052-1707","2052-1707"],"issn-type":[{"value":"2052-1707","type":"print"},{"value":"2052-1707","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,13]]},"assertion":[{"value":"2026-01-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-01","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-13","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70297"}}