{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T19:30:23Z","timestamp":1778787023486,"version":"3.51.4"},"reference-count":27,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T00:00:00Z","timestamp":1668384000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100007343","name":"Universit\u00e0 degli Studi di Brescia","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007343","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2023,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Nirmatrelvir, in combination with ritonavir, is one of the first orally available antiviral treatment for coronavirus disease 2019 (COVID\u201019). Symptomatic pregnant women are at increased risk for severe illness and complications that can affect the developing baby. No malformations or lower embryo\u2010fetal survival have been observed when nirmatrelvir were administered to pregnant rats and rabbits. Safety evaluation of drugs used for treating COVID\u201019 also in pregnancy is urgent for public health, then in this study we further investigated nirmatrelvir developmental toxicity using zebrafish as in vivo model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Material and Methods<\/jats:title><jats:p>Using the standardized Fish Embryo Toxicity (FET) test, we first determined the lethal concentration 50 (LC50), exposing embryos from gastrula stage up to 120\u2009hr post fertilization (hpf) and daily recording lethality. Then, we exposed embryos to five doses comprising the human therapeutic one and up to the LC50 (25\u2009\u03bcM). Morphology was evaluated at 72 and 120 hpf.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Nirmatrelvir did not affect survival rate and did not induce morphological defects up to the human therapeutic dose. Exposure at higher doses (2.4\u00d7 and 3\u00d7 the human <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>) however resulted in decreased hatching rate, reduced growth, slower heartbeat with pericardial edema, reduction of eye dimension, absence of the swim bladder and disruption of the anterior\u2013posterior axis, with lack of tail detachment, spinal curvature and straight and smaller head.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings in zebrafish embryos add further information about developmental nirmatrelvir safety. Further studies are needed for pharmacological safety assessment of nirmatrelvir exposure during pregnancy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bdr2.2128","type":"journal-article","created":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T12:37:07Z","timestamp":1668429427000},"page":"430-440","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Developmental safety of nirmatrelvir in zebrafish (<i>Danio rerio<\/i>) embryos"],"prefix":"10.1002","volume":"115","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0451-8029","authenticated-orcid":false,"given":"Daniela","family":"Zizioli","sequence":"first","affiliation":[{"name":"Department of Molecular and Translational Medicine University of Brescia  Brescia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Ferretti","sequence":"additional","affiliation":[{"name":"Division of Infectious and Tropical Diseases ASST Spedali Civili di Brescia  Brescia Italy"},{"name":"Department of Clinical and Experimental Sciences University of Brescia  Brescia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luca","family":"Mignani","sequence":"additional","affiliation":[{"name":"Department of Molecular and Translational Medicine University of Brescia  Brescia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9161-7804","authenticated-orcid":false,"given":"Francesco","family":"Castelli","sequence":"additional","affiliation":[{"name":"Division of Infectious and Tropical Diseases ASST Spedali Civili di Brescia  Brescia Italy"},{"name":"Department of Clinical and Experimental Sciences University of Brescia  Brescia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giorgio","family":"Tiecco","sequence":"additional","affiliation":[{"name":"Division of Infectious and Tropical Diseases ASST Spedali Civili di Brescia  Brescia 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