Clinical dosage of meclozine promotes longitudinal bone growth, bone volume, and trabecular bone quality in transgenic mice with achondroplasia

Matsushita, Masaki; Esaki, Ryusaku; Mishima, Kenichi; Ishiguro, Naoki; Ohno, Kinji; Kitoh, Hiroshi

doi:10.1038/s41598-017-07044-8

Cited by 16 publications

(13 citation statements)

References 24 publications

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“…Recent studies raise questions about the mechanism whereby statins might have consequence on achondroplastic bone [369]. Meclizine (an over the counter medication for motion sickness) improves long bone growth in a mouse model of achondroplasia, apparently through inhibition of activity of downstream effectors of FGFR3 [370–372]. Apparently a phase I clinical trial of meclizine will commence shortly (http://www.growingstronger.org/).…”

Section: Natural History and Managementmentioning

confidence: 99%

Achondroplasia: a comprehensive clinical review

Pauli¹

2019

Orphanet J Rare Dis

300

342

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Achondroplasia is the most common of the skeletal dysplasias that result in marked short stature (dwarfism). Although its clinical and radiologic phenotype has been described for more than 50 years, there is still a great deal to be learned about the medical issues that arise secondary to this diagnosis, the manner in which these are best diagnosed and addressed, and whether preventive strategies can ameliorate the problems that can compromise the health and well being of affected individuals. This review provides both an updated discussion of the care needs of those with achondroplasia and an exploration of the limits of evidence that is available regarding care recommendations, controversies that are currently present, and the many areas of ignorance that remain.

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Section: Natural History and Managementmentioning

confidence: 99%

Achondroplasia: a comprehensive clinical review

Pauli¹

2019

Orphanet J Rare Dis

300

342

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“…By comprehensive drug screening, we identified that meclizine hydrochloride (meclizine), an over-the-counter (OTC) histamine H1 receptor inhibitor used to treat motion sickness, inhibited FGFR3 signaling in various chondrocytic cells [12]. We also confirmed that oral administration of clinically feasible dose of meclizine for the indication of "motion sickness" promoted longitudinal bone growth in mouse model of ACH [13,14]. Meclizine is a prescription medicine approved in 1957 in the United States, and has been used as both prescription medicine and various OTC medicines in the world.…”

Section: Introductionmentioning

confidence: 69%

“…Each subject was hospitalized in Nagoya University Hospital on Day -1, discharged on Day 2, and then visited the study site on Day 8. We determined two different doses of meclizine for the PK analysis according to our previous preclinical experiments using mouse model of ACH [14]. Since this was an exploratory study, it was not subject to a formal sample size calculation.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics and safety after once and twice a day doses of meclizine hydrochloride administered to children with achondroplasia

et al. 2020

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Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by activating mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. We identified that meclizine hydrochloride inhibited FGFR3 signaling in various chondrocytic cells and promoted longitudinal bone growth in mouse model of ACH. Meclizine has safely been used for more than 50 years, but it lacks the safety data for repeated administration and pharmacokinetics (PK) when administered to children. We performed a phase Ia study to evaluate the PK and safety of meclizine administered orally to ACH children. Twelve ACH children aged from 5 to younger than 11 years were recruited, and the first 6 subjects received once a day of meclizine in the fasted condition, subsequent 6 subjects received twice a day of meclizine in the fed condition. Meclizine was well tolerated in ACH children with no serious adverse events. The mean C max , T max , AUC 0-24h , t1/2 during 24 hours in the fasted condition were 130 ng/mL, 1.7 hours, 761 ng�h/mL, and 8.5 hours respectively. The simulation of repeated administration of meclizine for 14 days demonstrated that plasma concentration apparently reached steady state around 10 days after the first dose both at once a day and twice a day administration. The AUC 0-10h of the fasting and fed condition were 504 ng�h/mL and 813 ng�h/mL, respectively, indicating exposure of meclizine increased with the diet. Although higher drug exposure was confirmed in ACH children compared to adults, a single administration of meclizine seemed to be well tolerated.

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“…Surprisingly, these effects were also observed in mice without the ACH mutation. Additionally, it strengthened the trabecular bone by increasing its thickness [ 76 , 77 ].…”

Section: Methods Of Treatmentmentioning

confidence: 99%

Advantages and Disadvantages of Different Treatment Methods in Achondroplasia: A Review

Wrobel

Pach

Beń‐Skowronek

2021

IJMS

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Achondroplasia (ACH) is a disease caused by a missense mutation in the FGFR3 (fibroblast growth factor receptor 3) gene, which is the most common cause of short stature in humans. The treatment of ACH is necessary and urgent because untreated achondroplasia has many complications, both orthopedic and neurological, which ultimately lead to disability. This review presents the current and potential pharmacological treatments for achondroplasia, highlighting the advantages and disadvantages of all the drugs that have been demonstrated in human and animal studies in different stages of clinical trials. The article includes the potential impacts of drugs on achondroplasia symptoms other than short stature, including their effects on spinal canal stenosis, the narrowing of the foramen magnum and the proportionality of body structure. Addressing these effects could significantly improve the quality of life of patients, possibly reducing the frequency and necessity of hospitalization and painful surgical procedures, which are currently the only therapeutic options used. The criteria for a good drug for achondroplasia are best met by recombinant human growth hormone at present and will potentially be met by vosoritide in the future, while the rest of the drugs are in the early stages of clinical trials.

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Clinical dosage of meclozine promotes longitudinal bone growth, bone volume, and trabecular bone quality in transgenic mice with achondroplasia

Cited by 16 publications

References 24 publications

Achondroplasia: a comprehensive clinical review

Achondroplasia: a comprehensive clinical review

Pharmacokinetics and safety after once and twice a day doses of meclizine hydrochloride administered to children with achondroplasia

Advantages and Disadvantages of Different Treatment Methods in Achondroplasia: A Review

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