{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T13:40:16Z","timestamp":1769434816818,"version":"3.49.0"},"reference-count":32,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2001,2]]},"abstract":"<jats:p><jats:italic>Background and Purpose<\/jats:italic>\u2014AR-R15896AR is a use-dependent, low-affinity blocker of the NMDA ion channel with neuroprotective effects in animal models of focal cerebral ischemia. This study aimed to establish the highest safe and tolerated loading and maintenance dosing regimen of AR-R15896AR in acute ischemic stroke patients and to determine the associated plasma concentrations of AR-R15896AR.<\/jats:p><jats:p><jats:italic>Methods<\/jats:italic>\u2014This was a 4-part, multicenter, randomized, double-blind, placebo-controlled study in 175 patients (mean age, 69 years) within 24 hours of acute stroke symptom recognition. Ascending 60-minute intravenous infusion loading doses of AR-R15896AR were initially examined (100, 150, 200, 250, or 300 mg or placebo in 3:1 randomization, n=36 treated); in part 2, 250, 275, or 300 mg was compared with placebo (n=33). In part 3, a 250-mg loading dose was followed by 9 maintenance doses of 60, 75, 90, 105, or 120 mg every 8 hours versus placebo in 3:1 randomization (n=59); subsequently, in part 4, maintenance doses of 90, 105, and 120 mg after the 250-mg loading dose were directly randomized against placebo (n=42). Safety, tolerability, and pharmacokinetics were the primary end points; NIHSS at 1 week and Barthel and modified Rankin scores at 1 month were also recorded, but the study was neither designed nor powered to assess efficacy.<\/jats:p><jats:p><jats:italic>Results<\/jats:italic>\u2014Rates for mortality and serious adverse events (SAE) were similar in active and placebo groups (9% mortality and 23% SAE for all active combined versus 11% mortality and 33% SAE for placebo). Adverse events associated with AR-R15896AR were dizziness, vomiting, nausea, stupor, and some agitation\/hallucination. Withdrawal from treatment occurred only in response to loading doses with AR-R15896AR: placebo, 3 of 46 (7%); 250 mg, 11 of 89 (12%); 275 mg, 1 of 8 (12.5%); and 300 mg, 3 of 15 (20%). No significant difference in outcome was observed between groups. Plasma concentrations of AR-R15896AR were 1524\u00b1536 ng\/mL at the end of the 250-mg loading infusion and were 1847\u00b1478 ng\/mL at steady state after the 9 maintenance doses of 120 mg.<\/jats:p><jats:p><jats:italic>Conclusions<\/jats:italic>\u2014The maximum tolerated loading infusion of AR-R15896AR in this study was 250 mg over a period of 1 hour. Subsequent maintenance infusions of 120 mg every 8 hours were well tolerated. With these doses, putative neuroprotective concentrations of 1240 ng\/mL are attained by the loading dose and are satisfactorily maintained thereafter. The loading dose may be improved further by adjustment on an individual patient basis, but tolerability issues remain.<\/jats:p>","DOI":"10.1161\/01.str.32.2.466","type":"journal-article","created":{"date-parts":[[2011,6,17]],"date-time":"2011-06-17T20:10:52Z","timestamp":1308341452000},"page":"466-472","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":27,"title":["Tolerability of the Low-Affinity, Use-Dependent NMDA Antagonist AR-R15896AR in Stroke Patients"],"prefix":"10.1161","volume":"32","author":[{"given":"Kennedy R.","family":"Lees","sequence":"first","affiliation":[{"name":"From the University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow, Scotland (K.R.L., A.G.D.); University Hospital, Aintree, Liverpool, England (A.S.); the Departments of Pharmacological Sciences and Medicine, University of Newcastle Upon Tyne (England) (G.A.F.); Leicester Royal Infirmary, Leicester, England (M.E.A.); and the Institute of Neurological Sciences, Southern General Hospital, Glasgow, Scotland (D.G.G.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander G.","family":"Dyker","sequence":"additional","affiliation":[{"name":"From the University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow, Scotland (K.R.L., A.G.D.); University Hospital, Aintree, Liverpool, England (A.S.); the Departments of Pharmacological Sciences and Medicine, University of Newcastle Upon Tyne (England) (G.A.F.); Leicester Royal Infirmary, Leicester, England (M.E.A.); and the Institute of Neurological Sciences, Southern General Hospital, Glasgow, Scotland (D.G.G.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anil","family":"Sharma","sequence":"additional","affiliation":[{"name":"From the University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow, Scotland (K.R.L., A.G.D.); University Hospital, Aintree, Liverpool, England (A.S.); the Departments of Pharmacological Sciences and Medicine, University of Newcastle Upon Tyne (England) (G.A.F.); Leicester Royal Infirmary, Leicester, England (M.E.A.); and the Institute of Neurological Sciences, Southern General Hospital, Glasgow, Scotland (D.G.G.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gary A.","family":"Ford","sequence":"additional","affiliation":[{"name":"From the University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow, Scotland (K.R.L., A.G.D.); University Hospital, Aintree, Liverpool, England (A.S.); the Departments of Pharmacological Sciences and Medicine, University of Newcastle Upon Tyne (England) (G.A.F.); Leicester Royal Infirmary, Leicester, England (M.E.A.); and the Institute of Neurological Sciences, Southern General Hospital, Glasgow, Scotland (D.G.G.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark E.","family":"Ardron","sequence":"additional","affiliation":[{"name":"From the University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow, Scotland (K.R.L., A.G.D.); University Hospital, Aintree, Liverpool, England (A.S.); the Departments of Pharmacological Sciences and Medicine, University of Newcastle Upon Tyne (England) (G.A.F.); Leicester Royal Infirmary, Leicester, England (M.E.A.); and the Institute of Neurological Sciences, Southern General Hospital, Glasgow, Scotland (D.G.G.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donald G.","family":"Grosset","sequence":"additional","affiliation":[{"name":"From the University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow, Scotland (K.R.L., A.G.D.); University Hospital, Aintree, Liverpool, England (A.S.); the Departments of Pharmacological Sciences and Medicine, University of Newcastle Upon Tyne (England) (G.A.F.); Leicester Royal Infirmary, Leicester, England (M.E.A.); and the Institute of Neurological Sciences, Southern General Hospital, Glasgow, Scotland (D.G.G.)."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.314.7088.1151"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(97)04010-5"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199512143332401"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)74846-7"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1992.tb04118.x"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)78865-6"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1159\/000015847"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/str.31.2.347"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(00)02326-6"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-2236(99)01463-0"},{"key":"e_1_3_2_11_2","unstructured":"Steinberg GK Perez-Pinzon MA Maier CM Sun GH Yoon E Kunis DM Bell TE Powell M Kotake A Giffard R. 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