{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T18:00:56Z","timestamp":1791655256990,"version":"4.3.4"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:00:00Z","timestamp":1781568000000},"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. Cardiovasc. Med."],"abstract":"<jats:sec>\n                    <jats:title>Backgrounds\/aims<\/jats:title>\n                    <jats:p>\n                      Synthetic stimulants represent the largest group of new psychoactive substances and include the aminorex class, which possess anorectic properties and a pharmacological profile similar to that of amphetamine. Among these, 4,4\u2032-dimethylaminorex (4,4\u2032-DMAR) is one of the best-known synthetic stimulants with a chiral structure, which gives rise to two stereoisomers [(\u00b1)\n                      <jats:italic>cis<\/jats:italic>\n                      -4,4\u2032-DMAR and (\u00b1)\n                      <jats:italic>trans<\/jats:italic>\n                      -4,4\u2032-DMAR] with distinct pharmacological and toxicological characteristics. This substance has been detected in cases of intoxication and deaths among adults and adolescents. Although 4,4\u2032-DMAR can also induce respiratory impairments, tachycardia, and sudden cardiac death\/arrest, clinical and preclinical investigations of its cardiorespiratory toxicity remain limited. Thus, this study aimed to investigate the cardiorespiratory effects of (\u00b1)\n                      <jats:italic>cis<\/jats:italic>\n                      -4,4\u2032-DMAR (1, 3, and 10\u2005mg\/kg) administration and the coadministration of 1\u2005mg\/kg (\u00b1)\n                      <jats:italic>cis<\/jats:italic>\n                      -4,4\u2032-DMAR and 30\u2005mg\/kg (\u00b1)\n                      <jats:italic>trans<\/jats:italic>\n                      -4,4\u2032-DMAR in awake CD-1 male mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We evaluated heart rate, breathing rate, and cardiac (ECG) and respiratory (plethysmography) electrical parameters. The most severe effects were observed after administration of 10\u2005mg\/kg (\u00b1)\n                      <jats:italic>cis<\/jats:italic>\n                      -4,4\u2032-DMAR and coadministration of 1\u2005mg\/kg (\u00b1)\n                      <jats:italic>cis<\/jats:italic>\n                      -4,4\u2032-DMAR and 30\u2005mg\/kg (\u00b1)\n                      <jats:italic>trans<\/jats:italic>\n                      -4,4\u2032-DMAR.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>These treatments induced tachycardia and narrow-QRS arrhythmias, characterized by an increase in the corrected QT\/QT interval, tachypnea, and a decrease in relaxation time, with varying degrees of intensity, probably due to differences in metabolism. Moreover, immunohistochemical analysis of the heart specimens revealed significant alterations in inflammation\/oxidative stress markers in cardiomyocytes and blood vessel walls, accompanied by cytoarchitectural changes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings provide the first evidence of the severe toxicity of 4,4\u2032-DMAR to the cardiac and respiratory systems, highlighting the importance of dosage and stereoisomer coadministration. This serves as a warning of the complex nature and potential dangers of intoxication.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcvm.2026.1763456","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T04:27:45Z","timestamp":1781584065000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["4,4\u2032-DMAR in-vivo acute cardiotoxicity: differences between (\u00b1)cis-4,4\u2032-DMAR and its coadministration with the (\u00b1)trans-4,4\u2032-DMAR isomer"],"prefix":"10.3389","volume":"13","author":[{"given":"Giorgia","family":"Corli","sequence":"first","affiliation":[{"name":"Department of Translational Medicine, Section of Legal Medicine, LTTA Center and University Center of Gender Medicine, University of Ferrara","place":["Ferrara, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Roda","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical & Experimental Toxicology, Pavia Poison Centre, National Toxicology Information Centre, Toxicology Unit, Istituti Clinici Scientifici Maugeri IRCCS Pavia","place":["Pavia, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Marchetti","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, Section of Legal Medicine, LTTA Center and University Center of Gender Medicine, University of Ferrara","place":["Ferrara, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micaela","family":"Tirri","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, Section of Legal Medicine, LTTA Center and University Center of Gender Medicine, University of Ferrara","place":["Ferrara, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrine","family":"Bilel","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, Section of Legal Medicine, LTTA Center and University Center of Gender Medicine, University of Ferrara","place":["Ferrara, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Bassi","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, Section of Legal Medicine, LTTA Center and University Center of Gender Medicine, University of Ferrara","place":["Ferrara, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Benedetti","sequence":"additional","affiliation":[{"name":"Section of Legal Medicine, Department of Health Care Surveillance and Bioetics, Universit\u00e0 Cattolica del Sacro Cuore","place":["Rome, Italy"]},{"name":"Fondazione Policlinico Universitario A. 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