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Published on: May 18, 2010
Minimum effective dose of clemastine in a mouse model of preterm white matter injury
Elizabeth P Odell1, Nora Jabassini1, Björn Schniedewind2
1Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
Insights
The minimum effective dose of clemastine for treating preterm white matter injury (PWMI) in neonatal mice was found to be 7.5 mg/kg/day. This finding is crucial for developing safe and effective clemastine treatments for neonates with PWMI.
Area of Science:
- Neuroscience
- Pharmacology
- Neonatology
Background:
- Preterm white matter injury (PWMI) is a leading cause of brain damage in premature infants.
- PWMI is characterized by impaired oligodendrocyte differentiation, affecting myelination.
- Clemastine has shown potential in promoting myelination in PWMI mouse models.
Purpose of the Study:
- To determine the minimum effective dose (MED) of clemastine in neonatal mice with PWMI.
- To establish pharmacokinetic parameters for clemastine at its MED.
- To guide safe and effective dosing for future human clinical trials.
Main Methods:
- Neonatal mice were exposed to hypoxia to model PWMI.
- Clemastine was administered at various doses (0.5, 2, 7.5, 10 mg/kg/day) or vehicle.
- Myelination was assessed at P14 and 10 weeks; pharmacokinetics were evaluated at steady-state.
Main Results:
- The MED of clemastine for rescuing hypoxia-induced hypomyelination was 7.5 mg/kg/day.
- Pharmacokinetics at the MED included Cmax 44.0 ng/mL, t1/2 4.6 h, and AUC24 280.1 ng*hr/mL.
- These results suggest therapeutic clemastine exposures are achievable in neonates.
Conclusions:
- A clemastine dose of 7.5 mg/kg/day effectively promotes myelination in a murine model of PWMI.
- The identified MED and pharmacokinetic data are essential for designing neonatal clinical trials.
- Clemastine holds promise as a myelination-promoting therapy for preterm infants with brain injury.
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 Cmax 44.0 ng/mL, t1/2 4.6 h, and AUC24 280.1 ng*hr/mL.
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.
