New study on Meclozine for achondroplasia

The research team from Nagoya University

Japan, formed by Masaki Matsushita, Ryusaku Esaki, Kenichi Mishima, Naoki Ishiguro, Kinji Ohno & Hiroshi Kitoh that has been studying meclozine as a potential treatment for achondroplasia presented recently new data in the article "Clinical dosage of meclozine promotes longitudinal bone growth, bone volume, and trabecular bone quality in transgenic mice with achondroplasia"1

The team identified that meclozine, an anti-histamine drug that has been used as an anti-motion-sickness for more than 50 years, inhibited FGFR3 signaling in various chondrocytic cell lines.

In the current study, the researchers executed specific pharmacokinetic and pharmacological studies of meclozine and determined the optimal effective dose of the drug on promoting longitudinal bone growth using the ACH mouse model. Researchers further demonstrated additional FGFR3 inhibitory effects of meclozine on bone volume and bone quality. The animal model that was used in this study was a Fgfr3ach mouse, which growth was compared with regular mice from the same species. The Fgfr3 ACH mice were genetically modified to be born with achondroplasia.

Pharmacokinetics studies how an organism affects a drug, where pharmacodynamics is the study of how the drug affects the organism. Both together influence dosing, benefit, and adverse effects.2

 

The highlights of this study reveal the following:

1. The administration of 2 mg/kg of meclozine to mice is clinically relevant;

2. Short stature Fgfr3ach was rescued by twice-daily administration of 1 and 2 mg/kg/day of meclozine for 10 days. 

3. 1 and 2 mg/kg/day of meclozine enhanced the bone growth of Fgfr3ach mice (meaning that the bone volume and mass was improved)

4. The administration of 1 mg/kg/day of meclozine treatment revealed that the area of foramen magnum was increased.

6. Treatment of 1 or 2 mg/kg/day of meclozine significantly increased cranium bone volume without affecting cranium length and width.

 

Figure 1. Twice-daily oral administration of 1 and 2 mg/kg/day of meclozine reverses the dwarfed phenotype in Fgfr3ach mice. Credits: Matsushita M et al., 2017

 

The foramen magnum stenosis can produce a cervical medullary compression and tends to occur very early in the life of infants.3 For this reason, if a treatment can be effective in preventing this compression to happen, it should be administered the sooner in life as possible. Curiously, only the 1mg/kg/day produced an increase in the foramen magnum area but not the 2 mg/kg/day.

Beyond all these positive results, further studies are needed to evaluate toxicity and adverse events associated with long-term administration of meclozine for a future clinical application in children with achondroplasia.1

 

 

Bibliography: 

1. Matsushita M, Esaki R, Mishima K, Ishiguro N, Ohno K, Kitoh H. Clinical dosage of meclozine promotes longitudinal bone growth, bone volume, and trabecular bone quality in transgenic mice with achondroplasia. Sci Rep. 2017 Aug 7;7(1):7371

2. https://en.wikipedia.org/wiki/Pharmacokinetics

3. Shimony N, Ben-Sira L, Sivan Y, Constantini S, Roth J. Surgical treatment for cervicomedullary compression among infants with achondroplasia. Childs Nerv Syst. 2015 May;31 (5):743-50. 

 

Published 14 August 2017