{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T22:32:50Z","timestamp":1769207570335,"version":"3.49.0"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Heart Failure"],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>PDE1 (phosphodiesterase type 1) hydrolyzes cyclic adenosine and guanosine monophosphate. ITI-214 is a highly selective PDE1 inhibitor that induces arterial vasodilation and positive inotropy in larger mammals. Here, we assessed pharmacokinetics, hemodynamics, and tolerability of single-dose ITI-214 in humans with stable heart failure with reduced ejection fraction.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>Patients with heart failure with reduced ejection fraction were randomized 3:1 to 10, 30, or 90 mg ITI-214 single oral dose or placebo (n=9\/group). Vital signs and electrocardiography were monitored predose to 5 hours postdose and transthoracic echoDoppler cardiography predose and 2-hours postdose.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              Patient age averaged 54 years; 42% female, and 60% Black. Mean systolic blood pressure decreased 3 to 8 mm\u2009Hg (\n              <jats:italic>P<\/jats:italic>\n              &lt;0.001) and heart rate increased 5 to 9 bpm (\n              <jats:italic>P<\/jats:italic>\n              \u22640.001 for 10, 30 mg doses, RM-ANCOVA). After 4 hours, neither blood pressure or heart rate significantly differed among cohorts (supine or standing). ITI-214 increased mean left ventricular power index, a relatively load-insensitive inotropic index, by 0.143 Watts\/mL\n              <jats:sup>2<\/jats:sup>\n              \u00b710\n              <jats:sup>4<\/jats:sup>\n              (\n              <jats:italic>P<\/jats:italic>\n              =0.03, a +41% rise; 5\u201371 CI) and cardiac output by 0.83 L\/min (\n              <jats:italic>P<\/jats:italic>\n              =0.002, +31%, 13\u201349 CI) both at the 30 mg dose. Systemic vascular resistance declined with 30 mg (\u2013564 dynes\u00b7s\/cm\u2013\n              <jats:sup>5<\/jats:sup>\n              ,\n              <jats:italic>P<\/jats:italic>\n              &lt;0.001) and 90 mg (\u2013370,\n              <jats:italic>P<\/jats:italic>\n              =0.016). Diastolic changes were minimal, and no parameters were significantly altered with placebo. ITI-214 was well-tolerated. Five patients had mild-moderate hypotension or orthostatic hypotension recorded adverse events. There were no significant changes in arrhythmia outcome and no serious adverse events.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>Single-dose ITI-214 is well-tolerated and confers inodilator effects in humans with heart failure with reduced ejection fraction. Further investigations of its therapeutic utility are warranted.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Registration:<\/jats:title>\n            <jats:p>\n              URL:\n              <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrials.gov\">https:\/\/www.clinicaltrials.gov<\/jats:ext-link>\n              ; Unique identifier: NCT03387215.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circheartfailure.120.008236","type":"journal-article","created":{"date-parts":[[2021,8,31]],"date-time":"2021-08-31T09:01:34Z","timestamp":1630400494000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":23,"title":["Acute Hemodynamic Effects and Tolerability of Phosphodiesterase-1 Inhibition With ITI-214 in Human Systolic Heart Failure"],"prefix":"10.1161","volume":"14","clinical-trial-number":[{"clinical-trial-number":"nct03387215","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4511-8008","authenticated-orcid":true,"given":"Nisha A.","family":"Gilotra","sequence":"first","affiliation":[{"name":"Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (N.A.G., A.G.H., V.S.H., T.A.A., D.A.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam D.","family":"DeVore","sequence":"additional","affiliation":[{"name":"Duke University School of Medicine, Durham, NC (A.D.D.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0573-6565","authenticated-orcid":true,"given":"Thomas J.","family":"Povsic","sequence":"additional","affiliation":[{"name":"Duke Clinical Research Institute, Durham, NC (T.J.P., A.D.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2138-1589","authenticated-orcid":true,"given":"Allison G.","family":"Hays","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (N.A.G., A.G.H., V.S.H., T.A.A., D.A.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0578-2668","authenticated-orcid":true,"given":"Virginia S.","family":"Hahn","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (N.A.G., A.G.H., V.S.H., T.A.A., D.A.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tolu A.","family":"Agunbiade","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (N.A.G., A.G.H., V.S.H., T.A.A., D.A.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Allison","family":"DeLong","sequence":"additional","affiliation":[{"name":"Duke Clinical Research Institute, Durham, NC (T.J.P., A.D.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6523-3946","authenticated-orcid":true,"given":"Andrew","family":"Satlin","sequence":"additional","affiliation":[{"name":"Intra-Cellular Therapies, Inc, New York, NY (A.S., R.C., R.D.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard","family":"Chen","sequence":"additional","affiliation":[{"name":"Intra-Cellular Therapies, Inc, New York, NY (A.S., R.C., R.D.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1644-9553","authenticated-orcid":true,"given":"Robert","family":"Davis","sequence":"additional","affiliation":[{"name":"Intra-Cellular Therapies, Inc, New York, NY (A.S., R.C., 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