{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T09:32:53Z","timestamp":1793179973099,"version":"4.5.0"},"reference-count":46,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Br J Clin Pharmacol"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>Time to onset of reversal is critical when treating opioid\u2010induced respiratory depression and hypoxia. This study aimed to develop a formulation of the opioid antagonist nalmefene with an increased absorption rate and reduced time to onset of reversal following intramuscular administration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Several absorption enhancers were screened in rats, followed by confirmatory studies in dogs. Subsequently, nalmefene formulations with a range of MgCl\n                      <jats:sub>2<\/jats:sub>\n                      concentrations were evaluated in a two\u2010part translational clinical study in healthy participants. In Part 1 (\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u200917), pharmacokinetic parameters were assessed following intramuscular injections of nalmefene formulated with MgCl\n                      <jats:sub>2<\/jats:sub>\n                      (0.47%\u20134.7%) or NaCl (0.9%). In Part 2 (\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u20096), participants received intravenous fentanyl to produce opioid\u2010induced respiratory depression. They were then dosed with intramuscular nalmefene formulated with 0.94% MgCl\n                      <jats:sub>2<\/jats:sub>\n                      , intranasal naloxone or placebo (intramuscular saline) in a randomized six\u2010period crossover sequence with each treatment administered on two separate occasions. Minute ventilation, oxygen saturation and carbon dioxide were monitored continuously, and pharmacokinetic and pharmacodynamic parameters were evaluated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Pharmacokinetic profiles from animals indicated that MgCl\n                      <jats:sub>2<\/jats:sub>\n                      within a range of concentrations enhanced the nalmefene absorption rate. In the clinical studies, a nalmefene 1.5 mg formulation containing 0.94% MgCl\n                      <jats:sub>2<\/jats:sub>\n                      demonstrated more rapid absorption compared with a formulation containing 0.9% NaCl and also produced faster, more robust reversal of opioid\u2010induced respiratory depression compared with intranasal naloxone.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These preclinical and clinical studies demonstrate that a nalmefene formulation containing magnesium chloride produced more rapid nalmefene absorption after intramuscular injection, which is advantageous for the treatment of opioid overdose in settings where life support is not immediately available.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/bcp.70685","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T02:35:24Z","timestamp":1784082924000},"page":"3914-3925","source":"Crossref","is-referenced-by-count":0,"title":["Development of a nalmefene formulation suitable for a community\u2010use auto\u2010injector"],"prefix":"10.1002","volume":"92","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-5460-4623","authenticated-orcid":false,"given":"Alessandra","family":"Cipriano","sequence":"first","affiliation":[{"name":"Knoa Pharma LLC  Stamford Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manjunath S.","family":"Shet","sequence":"additional","affiliation":[{"name":"Knoa Pharma LLC  Stamford Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugh","family":"Huang","sequence":"additional","affiliation":[{"name":"Elacon LLC  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronnie","family":"Ortiz","sequence":"additional","affiliation":[{"name":"Knoa Pharma LLC  Stamford Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garth T.","family":"Whiteside","sequence":"additional","affiliation":[{"name":"Knoa Pharma LLC  Stamford Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Glen","family":"Apseloff","sequence":"additional","affiliation":[{"name":"Ohio Clinical Trials LLC  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8128-0806","authenticated-orcid":false,"given":"Stephen C.","family":"Harris","sequence":"additional","affiliation":[{"name":"Knoa Pharma LLC  Stamford Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"e_1_2_11_2_1","first-page":"11","article-title":"Drug overdose deaths in the United States, 2002\u20132022","volume":"491","author":"Spencer MR","year":"2024","journal-title":"NCHS Data Brief"},{"key":"e_1_2_11_3_1","article-title":"Estimates of drug overdose deaths involving fentanyl, methamphetamine, cocaine, heroin, and oxycodone: United States, 2021","volume":"27","author":"Spencer MR","year":"2021","journal-title":"Vital Stat Rapid Release"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm7348a2"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.40736"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/YCO.0000000000000717"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugpo.2017.06.010"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12630\u2010019\u201001294\u2010y"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm6905a2"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12954\u2010024\u201000994\u2010z"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dadr.2024.100223"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/acem.13034"},{"key":"e_1_2_11_13_1","unstructured":"US Food and Drug Administration.FDA approves first over\u2010the\u2010counter naloxone nasal spray2023Available online at:https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-approves-first-over-counter-naloxone-nasal-spray"},{"key":"e_1_2_11_14_1","unstructured":"US Food and Drug Administration.FDA approves second over\u2010the\u2010counter naloxone nasal spray product2023Available online at:https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-approves-second-over-counter-naloxone-nasal-spray-product"},{"key":"e_1_2_11_15_1","unstructured":"US Food and Drug Administration.FDA approves higher dosage of naloxone nasal spray to treat opioid overdose [press release]. 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