{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:39:44Z","timestamp":1760060384221,"version":"build-2065373602"},"reference-count":42,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T00:00:00Z","timestamp":1756252800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"State Key Laboratory of Drug Regulatory Science","award":["2025SKLDRS0322"],"award-info":[{"award-number":["2025SKLDRS0322"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Intrathecal drug delivery is essential for treating CNS disorders, but the safety of commonly used excipients such as citric acid\/sodium citrate (SC) remains unclear. This study aims to systematically evaluate the potential neuropharmacological effects of repeated intrathecal SC administration. Methods: Multimodal approaches were applied across murine and lagomorph models. Doses ranged from 1.833\u201314.664 \u03bcg\/g in mice and 0.104\u20133.290 mg\/rabbit. Behavioral, neurophysiological, and fiber photometry analyses were conducted to assess sensorimotor function, cortical activity, and calcium dynamics. Results: SC induced dose-dependent sensorimotor deficits, including hypolocomotion (45.7% reduced distance, p &lt; 0.001) and impaired coordination (latency reduction 48.3\u201364.1%, p &lt; 0.001). Mortality increased with dosage and repeated exposure. Neurophysiological data revealed biphasic cortical modulation: acute c-Fos suppression followed by delayed hyperactivity. Fiber photometry confirmed calcium chelation-mediated attenuation and subsequent potentiation of Ca2+ signals. Rabbits exhibited similar neurological symptoms, correlating with transient CSF calcium\/magnesium depletion, though no structural neural damage was observed. Conclusions: These results provide the first comprehensive evidence that SC buffers can significantly disrupt neuronal calcium homeostasis and induce functional impairments upon intrathecal delivery. The findings emphasize the need for reassessing excipient safety in CNS-targeted formulations.<\/jats:p>","DOI":"10.3390\/pharmaceutics17091112","type":"journal-article","created":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T08:19:32Z","timestamp":1756282772000},"page":"1112","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Neurotoxicological Evaluation of Intrathecal Citrate Excipients: Calcium Homeostasis Disruption and Safety Implications in CNS Drug Delivery"],"prefix":"10.3390","volume":"17","author":[{"given":"Jue","family":"Wang","sequence":"first","affiliation":[{"name":"Center for Research Development and Evaluation of Pharmaceutical Excipients and Generic Drugs, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China"},{"name":"National Institutes for Food and Drug Control, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"National Institutes for Food and Drug Control, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing","family":"He","sequence":"additional","affiliation":[{"name":"National Institutes for Food and Drug Control, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Du","sequence":"additional","affiliation":[{"name":"National Institutes for Food and Drug Control, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xia","family":"Zhang","sequence":"additional","affiliation":[{"name":"National Institutes for Food and Drug Control, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinru","family":"Tan","sequence":"additional","affiliation":[{"name":"Center for Research Development and Evaluation of Pharmaceutical Excipients and Generic Drugs, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinting","family":"Zhou","sequence":"additional","affiliation":[{"name":"Center for Research Development and Evaluation of Pharmaceutical Excipients and Generic Drugs, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susu","family":"Tang","sequence":"additional","affiliation":[{"name":"Center for Research Development and Evaluation of Pharmaceutical Excipients and Generic Drugs, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7495-9095","authenticated-orcid":false,"given":"Baoming","family":"Ning","sequence":"additional","affiliation":[{"name":"National Institutes for Food and Drug Control, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3046-5688","authenticated-orcid":false,"given":"Rui","family":"Yang","sequence":"additional","affiliation":[{"name":"National Institutes for Food and Drug Control, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xia","family":"Zhao","sequence":"additional","affiliation":[{"name":"National Institutes for Food and Drug Control, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dejiang","family":"Tan","sequence":"additional","affiliation":[{"name":"National Institutes for Food and Drug Control, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0966-5001","authenticated-orcid":false,"given":"Huimin","family":"Sun","sequence":"additional","affiliation":[{"name":"National Institutes for Food and Drug Control, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiasheng","family":"Tu","sequence":"additional","affiliation":[{"name":"Center for Research Development and Evaluation of Pharmaceutical Excipients and Generic Drugs, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1472945","DOI":"10.3389\/fphar.2025.1472945","article-title":"A review on intrathecal administration of medications for leptomeningeal metastases in solid tumors","volume":"16","author":"Wang","year":"2025","journal-title":"Front. 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