Minimum effective dose of clemastine in a mouse model of preterm white matter injury.
| Autor: | Odell EP; Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA., Jabassini N; Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA., Schniedewind B; iC42 Clinical Research and Development, Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Pease-Raissi SE; Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA., Frymoyer A; Department of Pediatrics, Stanford University, Palo Alto, CA, USA., Christians U; iC42 Clinical Research and Development, Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Green AJ; Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.; Department of Ophthalmology, University of California, San Francisco, San Francisco, CA, USA., Chan JR; Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA., Ostrem BEL; Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA. bridget.ostrem@ucsf.edu. |
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| Jazyk: | angličtina |
| Zdroj: | Pediatric research [Pediatr Res] 2024 Sep; Vol. 96 (4), pp. 933-941. Date of Electronic Publication: 2024 Jun 28. |
| DOI: | 10.1038/s41390-024-03326-w |
| Abstrakt: | Background: Preterm white matter injury (PWMI) is the most common cause of brain injury in premature neonates. PWMI involves a differentiation arrest of oligodendrocytes, the myelinating cells of the central nervous system. Clemastine was previously shown to induce oligodendrocyte differentiation and myelination in mouse models of PWMI at a dose of 10 mg/kg/day. The minimum effective dose (MED) of clemastine is unknown. Identification of the MED is essential for maximizing safety and efficacy in neonatal clinical trials. We hypothesized that the MED in neonatal mice is lower than 10 mg/kg/day. Methods: Mouse pups were exposed to normoxia or hypoxia (10% FiO2) from postnatal day 3 (P3) through P10. Vehicle or clemastine at one of four doses (0.5, 2, 7.5 or 10 mg/kg/day) was given to hypoxia-exposed pups. Myelination was assessed at age P14 and 10 weeks to determine the MED. Clemastine pharmacokinetics were evaluated at steady-state on day 8 of treatment. Results: Clemastine rescued hypoxia-induced hypomyelination with a MED of 7.5 mg/kg/day. Pharmacokinetic analysis of the MED revealed C Conclusions: Based on these results, myelination-promoting exposures should be achievable with oral doses of clemastine in neonates with PWMI. Impact: Preterm white matter injury (PWMI) is the most common cause of brain injury and cerebral palsy in premature neonates. Clemastine, an FDA-approved antihistamine, was recently identified to strongly promote myelination in a mouse model of PWMI and is a possible treatment. The minimum effective dose in neonatal rodents is unknown and is critical for guiding dose selection and balancing efficacy with toxicity in future clinical trials. We identified the minimum effective dose of clemastine and the associated pharmacokinetics in a murine chronic hypoxia model of PWMI, paving the way for a future clinical trial in human neonates. (© 2024. The Author(s).) |
| Databáze: | MEDLINE |
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