{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T13:11:28Z","timestamp":1787317888804,"version":"build-2736575974"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T00:00:00Z","timestamp":1770076800000},"content-version":"vor","delay-in-days":1070,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2023,2,25]],"date-time":"2023-02-25T00:00:00Z","timestamp":1677283200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Sirolimus, a mechanistic target of rapamycin inhibitor, suppresses insulin production in other species and has therapeutic potential for hyperinsulinemia in horses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Hypothesis\/Objective<\/jats:title>\n                    <jats:p>Determine the pharmacokinetics (PKs) of sirolimus and evaluate its effect on insulin dynamics in healthy and insulin dysregulation (ID) horses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Animals<\/jats:title>\n                    <jats:p>Eight Standardbred geldings.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A PK study was performed followed by a placebo-controlled, randomized, crossover study. Blood sirolimus concentrations were measured by liquid chromatography-mass-spectrometry. PK indices were estimated by fitting a 2-compartment model using nonlinear least squares regression. An oral glucose test (OGT) was conducted before and 4, 24, 72, and 144\u2009hours after administration of sirolimus or placebo. Effects of time, treatment and animal on blood glucose and insulin concentrations were analyzed using mixed-effects linear regression. Sirolimus was then administered to 4\u00a0horses with dexamethasone-induced ID and an OGT was performed at baseline, after ID induction and after 7\u2009days of treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Median (range) maximum sirolimus concentration was 277.0 (247.5-316.06) ng\/mL at 5 (5-10) min and half-life was 3552 (3248-4767) min. Mean (range) oral bioavailability was 9.5 (6.8-12.4)%. Sirolimus had a significant effect on insulin concentration 24\u2009hours after a single dose: median (interquartile range) insulin at 60\u2009min (5.0 [3.7-7.0] \u03bcIU\/mL) was 37 (\u22125 to 54)% less than placebo (8.7 [5.8-13.7] \u03bcIU\/mL, P\u00a0=\u00a0.03); and at 120\u2009min (10.2 [8.4-12.2] \u03bcIU\/mL) was 28 (\u221215 to 53)% less than placebo (14.9 [8.4-24.8] \u03bcIU\/mL, P\u00a0=\u00a0.02). There was minimal effect on glucose concentration. Insulin responses decreased toward baseline in ID horses after 7\u2009days of treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Clinical Importance<\/jats:title>\n                    <jats:p>Sirolimus decreased the insulinemic response to glucose and warrants further investigation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/jvim.16650","type":"journal-article","created":{"date-parts":[[2023,2,25]],"date-time":"2023-02-25T03:08:32Z","timestamp":1677294512000},"page":"703-712","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Effect of sirolimus on insulin dynamics in horses"],"prefix":"10.1093","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7104-7920","authenticated-orcid":false,"given":"Demia J.","family":"de Tonnerre","sequence":"first","affiliation":[{"name":"School of Veterinary Science, The 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Pennsylvania,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate L.","family":"Kemp","sequence":"additional","affiliation":[{"name":"School of Veterinary Science, The University of Queensland , Gatton, Queensland,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2820-8431","authenticated-orcid":false,"given":"Fran\u00e7ois-Ren\u00e9","family":"Bertin","sequence":"additional","affiliation":[{"name":"School of Veterinary Science, The University of Queensland , Gatton, Queensland,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6108-2503","authenticated-orcid":false,"given":"Andrew W.","family":"van Eps","sequence":"additional","affiliation":[{"name":"University of Pennsylvania Department of Clinical Studies \u2013 New Bolton Center, , Kennett Square, 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