Kugako Sugimoto, NOST Tokyo
Origineel gepubliceerd op de site van Agentschap NL.
Een onderzoekgroep van de Nagoya University heeft ontdekt dat een geneesmiddel tegen wagenziekte waarschijnlijk tegen dwerggroei (achondroplasie) gebruikt kan worden. Dit geneesmiddel, meclozine, is een H1 blocker tegen wagenziekte en kan zonder recept verkregen worden bij de apotheek. Meclozine als meest belovende kandidaatgeneesmiddel naar voren gekomen na het testen van 1186 bestaande en reeds door de FDA goedgekeurde geneesmiddelen.
Meclozine, an anti-histamine drug for motion sickness, as a potential therapeutic agent for growing taller
Summary
A research group of Nagoya University found that meclozine, an over-the counter H1 blocker for motion sickness, facilitated proliferation and differentiation of chondrocytes in Achondroplasia (ACH) caused by gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Currently, there are no effective treatments for FGFR-3 related skeletal dysplasias. The team tested 1,186 FDA-approved compounds in rat chondrosarcoma (RCS) cells induced to have a similar condition of ACH for a drug repositioning strategy to identify new indications for the existing drugs. Meclozine looks a potential therapeutic agent for growing taller. Since the optimal doses and adverse effects of the approved drugs are already established, application to clinical practice seems smoother than inventing a new drug.
Details
Achondroplasia[i] (ACH) is a skeletal dysplasias[ii] with the clinical features of short stature. ACH is caused by gain-of-function mutations in the fibroblast[iii] growth factor receptor 3 (FGFR3) gene. Recent findings show that FGFR3 signals regulate the endochondral bone growth. There are no effective treatments for FGFR3-related skeletal dysplasias. Recently, antagonists of the FGFR3 signals such as c-type natriuretic peptides[iv] (CNP) were developed as a treatment chemical. However, the toxicity of this antagonist chemical compound is not yet fully understood.
A research team of Nagoya University conducted screening of 1,186 FDA-approved compounds to find out their efficacy on ACH. Since the compounds are well understood including the adverse effects, findings on the screening test would be an attractive therapeutic agent to treat ACH.
For screening, rat chondrosarcoma[v] (RCS) cells induced to have a similar condition of ACH were cultured. 10 micromolar of 1,186 FDA-approved chemical compounds and 5 ng/ml of FGF2vi were added to RCS cells. Cell proliferation and cell numbers were monitored.
The research team observed that meclozine, an over-the counter H1 blockervii for motion sickness, induced 1.4-fold or more increases of viability of RCS cells (RCS proliferation) through observation of the MTS assayviii. Dose dependency also was observed up to 20 micromolar of meclozine. In addition, the increased number of RCS cells, cell division, were observed at the concentration of 10 and 20 micromolar of meclozine addition.
The restoration signs of FGF2-treated RCS cells by addition of meclozine were observed through the production of cartilage-like sulfated proteoglycans by the RCS cells. The cells also showed round chondrocyte-like cell shapes. The team concluded that application of meclozine partly restored the production of cartilage-like sulfated proteoglycans.
The team also investigated the effect of meclozine on cartilage development in a bone organ culture by employing limb rudiments isolated from murine embryonic tibia. Combinations of 100 ng/ml FGF2, 0.2 micromolar CNP, and 20 miclromolar meclozine were added to the culture medium. The length of treated tibiae with that of contralateral control tibia from the same individual were compared. CNP and meclozine significantly attenuated the growth inhibition caused by FGF2. Meclozine also increased the length of tibia without FGF2 treatment (same condition of no ACH symptoms), though it is not statistically insignificant.
Other drugs with anti-histamine, anti-muscarinic, and anti-OXPHOS did not show inhibitory effect on the FGFR3 signaling.
Associate Professor Hiroshi Kitoh of Department of Orthopaedic Surgery of Nagoya University Graduate School of Medicine is planning to feed meclozine to mice and expects an early clinical study.
Source
2. Asahi Shimbun Digital (Dec. 5, 2013) (in Japanese)
3. Nihon Keizai Shimbun (Dec. 5, 2013) (in Japanese)
