{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T11:52:14Z","timestamp":1778673134860,"version":"3.51.4"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>AST-004 is a small-molecule adenosine A1\/A3 receptor agonist that has exhibited significant cerebroprotective efficacy in preclinical models of acute ischemic stroke and traumatic brain injury. The primary objectives of this clinical phase I first-in-human study were to evaluate the safety and tolerability profile of single ascending intravenous doses in healthy subjects. The secondary objectives were to characterize the single-dose pharmacokinetic profiles in plasma, cerebrospinal fluid (CSF), and urine.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>In part 1 of the study, AST-004 was administered in ascending dose cohorts of 5, 25, 50, 75, and 100 mg, with 6 subjects in each cohort receiving the study drug and 2 receiving placebo. In part 2, all 12 subjects received a 100 mg IV infusion of the study drug followed by a single CSF collection per subject via lumbar puncture at 20, 40, or 60 minutes after infusion.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>A total of 42 subjects received AST-004, with no severe or serious adverse events observed. Twelve of these subjects experienced a treatment-emergent adverse event, the most frequent across groups being headache. In part 2, pharmacokinetic analyses confirmed that AST-004 was distributed in the CSF, with the CSF-to-plasma ratio increasing over the 3 timepoints sampled. The mean half-life was 1.1 to 1.4 hours for doses of 25 to 100 mg, and the geometric mean maximum plasma concentration obtained in the highest dosing cohort (100 mg) was 2232\u00b1428 ng\/mL.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>AST-004 was safe and well-tolerated at plasma concentrations 3 to 8\u00d7 higher than those associated with significant efficacy in astrocyte\u2019s preclinical primate stroke efficacy studies, with CSF concentrations highest at the 60-minute collection timepoint, the last timepoint tested. This study supports additional clinical investigations, including evaluation of an extended infusion to support the phase 2 program in stroke and traumatic brain injury.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/strokeaha.124.047207","type":"journal-article","created":{"date-parts":[[2024,10,25]],"date-time":"2024-10-25T09:01:06Z","timestamp":1729846866000},"page":"2795-2803","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":8,"title":["First-in-Human Phase I Clinical Trial of the Adenosine A1R\/A3R Agonist AST-004 in Healthy Subjects"],"prefix":"10.1161","volume":"55","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-7075-2314","authenticated-orcid":true,"given":"Lisa M.","family":"Manna","sequence":"first","affiliation":[{"name":"Astrocyte Pharmaceuticals, Inc, Groton, CT (L.M.M., J.H., D.E.H., M.A.M., T.E.L., R.B.P., W.S.K., R.A.L.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7032-1491","authenticated-orcid":true,"given":"Juan","family":"Hernandez","sequence":"additional","affiliation":[{"name":"Astrocyte Pharmaceuticals, Inc, Groton, CT (L.M.M., J.H., D.E.H., M.A.M., T.E.L., R.B.P., W.S.K., R.A.L.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dawn E.","family":"Hunt","sequence":"additional","affiliation":[{"name":"Astrocyte Pharmaceuticals, Inc, Groton, CT (L.M.M., J.H., D.E.H., M.A.M., T.E.L., R.B.P., W.S.K., R.A.L.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G\u00e9za","family":"Lakner","sequence":"additional","affiliation":[{"name":"CRU Hungary, Kistarcsa (G.L.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4058-7211","authenticated-orcid":true,"given":"Mark A.","family":"Matson","sequence":"additional","affiliation":[{"name":"Astrocyte Pharmaceuticals, Inc, Groton, CT (L.M.M., J.H., D.E.H., M.A.M., T.E.L., R.B.P., W.S.K., R.A.L.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3614-0576","authenticated-orcid":true,"given":"Russell B.","family":"Poe","sequence":"additional","affiliation":[{"name":"Astrocyte Pharmaceuticals, Inc, Groton, CT (L.M.M., J.H., D.E.H., M.A.M., T.E.L., R.B.P., W.S.K., R.A.L.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6293-1623","authenticated-orcid":true,"given":"William S.","family":"Korinek","sequence":"additional","affiliation":[{"name":"Astrocyte Pharmaceuticals, Inc, Groton, CT (L.M.M., J.H., D.E.H., M.A.M., T.E.L., R.B.P., W.S.K., R.A.L.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3560-1447","authenticated-orcid":true,"given":"Robert A.","family":"Lancey","sequence":"additional","affiliation":[{"name":"Astrocyte Pharmaceuticals, Inc, Groton, CT (L.M.M., J.H., D.E.H., M.A.M., T.E.L., R.B.P., W.S.K., R.A.L.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0828-797X","authenticated-orcid":true,"given":"Theodore E.","family":"Liston","sequence":"additional","affiliation":[{"name":"Astrocyte Pharmaceuticals, Inc, Groton, CT (L.M.M., J.H., D.E.H., M.A.M., T.E.L., R.B.P., W.S.K., R.A.L.)."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1177\/17474930211065917"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/STR.0000000000000158"},{"key":"e_1_3_3_4_2","unstructured":"CDC. 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