{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T07:50:14Z","timestamp":1791186614222,"version":"4.1.0"},"reference-count":21,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2012,12,14]],"date-time":"2012-12-14T00:00:00Z","timestamp":1355443200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2013,1]]},"abstract":"<jats:p><jats:bold>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT<\/jats:bold><\/jats:p><jats:p>\u2022\u2003A novel and highly selective sigma\u20101 receptor antagonist (S1RA) provides a new approach for pain management. S1RA has shown activity in animal models of neuropathic pain and potentiation of opioid analgesia.<\/jats:p><jats:p><jats:bold>WHAT THIS STUDY ADDS<\/jats:bold><\/jats:p><jats:p>\u2022\u2003Phase I studies of single and multiple oral dose administration show that S1RA is safe and well tolerated by healthy subjects. S1RA is rapidly absorbed and its rate and extent of exposure increases with dose.<\/jats:p><jats:p>\u2022\u2003The safety, tolerability, pharmacokinetic and pharmacodynamic profiles of S1RA support its further phase II development in different pain indications.<\/jats:p><jats:p><jats:bold>AIM<\/jats:bold>To assess the safety, tolerability, pharmacodynamics and pharmacokinetics in healthy subjects of a novel, highly selective, sigma\u20101 receptor antagonist (S1RA).<\/jats:p><jats:p><jats:bold>METHODS<\/jats:bold>Three randomized, double\u2010blind, placebo\u2010controlled trials evaluated single oral doses (5\u2013500\u2003mg, study 101; 500\u2013800\u2003mg, study 106) and multiple doses (50\u2013400\u2003mg once daily for 8\u2003days, study 102) of S1RA. Safety and tolerability were assessed by adverse event reporting, clinical laboratory, physical examinations, vital signs and electrocardiography, including Holter monitoring. Pharmacodynamic assessments included computerized cognitive testing. Plasma samples were analyzed using validated HPLC\u2010MS\/MS methods.<\/jats:p><jats:p><jats:bold>RESULTS<\/jats:bold>One hundred and seventy\u2010five subjects were enrolled. Single and multiple doses were safe and well tolerated, with no serious adverse events. The most common side effects were headache and dizziness. The highest single doses were associated with some mild to moderate transient CNS effects. The maximum tolerated dose was not reached. There were no clinically significant changes in the electrocardiogram (ECG), 24\u2003h Holter monitoring, or in vital signs and laboratory assessments. Subjective CNS pharmacodynamics evaluations showed no relevant differences<jats:italic>vs<\/jats:italic>. placebo. Cognitive testing showed no effects on visual memory, executive function, attention or somnolence, while revealing some transient slowing of response for simple reaction time and choice reaction time at 2\u2003h following the administration of higher doses. A fast absorption, rapid distribution and slow elimination were observed (<jats:italic>t<\/jats:italic><jats:sub>max<\/jats:sub>0.75\u20132.0\u2003h,<jats:italic>t<\/jats:italic><jats:sub>1\/2<\/jats:sub>compatible with once a day administration) and steady\u2010state was reached. No gender differences were observed.<\/jats:p><jats:p><jats:bold>CONCLUSIONS<\/jats:bold>S1RA exhibited an acceptable safety, tolerability, pharmacodynamic and pharmacokinetic profile in healthy subjects over the dose range studied.<\/jats:p>","DOI":"10.1111\/j.1365-2125.2012.04333.x","type":"journal-article","created":{"date-parts":[[2012,5,21]],"date-time":"2012-05-21T11:13:21Z","timestamp":1337598801000},"page":"103-117","source":"Crossref","is-referenced-by-count":66,"title":["Safety, tolerability and pharmacokinetics of single and multiple doses of a novel sigma\u20101 receptor antagonist in three randomized phase I studies"],"prefix":"10.1111","volume":"75","author":[{"given":"Montserrat","family":"Abadias","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisol","family":"Escriche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Vaqu\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariano","family":"Sust","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregorio","family":"Encina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,12,14]]},"reference":[{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2010.08.007"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.2174\/157015908787386113"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2009.07.001"},{"key":"e_1_2_7_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(93)90650-7"},{"key":"e_1_2_7_6_2","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1016\/S0022-3565(25)24045-9","article-title":"Selective antagonism of opioid analgesia by a sigma system","volume":"271","author":"Chien CC","year":"1994","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_7_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(95)11504-P"},{"key":"e_1_2_7_8_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.300.3.1070"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.109.057083"},{"key":"e_1_2_7_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2009.05.013"},{"key":"e_1_2_7_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2009.03.011"},{"key":"e_1_2_7_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-009-1513-8"},{"key":"e_1_2_7_13_2","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e3181895a83"},{"key":"e_1_2_7_14_2","first-page":"172","article-title":"Selective sigma\u20101 (sigma1) receptor antagonists: emerging target for the treatment of neuropathic pain. 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